16 February 2005

1
FDA Advisory Committee Meeting
16 February 2005
Cardiovascular Safety of Celecoxib
Risk-Benefit Assessment
2
Delegation

• Dr Jeffrey Borer Cardiology
• Dr Andrew Dannenberg Gastroenterology
• Dr Gerry Faich Epidemiology/Drug Safety
• Dr Norman Gitlin Gastroenterology
• Dr Gary Koch Statistician
• Dr Bernard Levin Oncology
• Dr Scott Lippman Oncology
• Dr Nancy Nussmeier Anesthesiology
• Dr Lee Simon Rheumatology
• Dr Vibeke Strand Rheumatology
• Dr Andrew Whelton Nephrology
• Dr William White Hypertension

3
Overall Conclusions

• There are few therapeutic alternatives for
  patients with chronic arthritis-related pain
• Patients who discontinue celecoxib will likely
  turn to NSAIDs
• Celecoxib provides improved GI safety compared to
  NSAIDs
• All lines of evidence show the CV safety of
  celecoxib is similar to NSAIDs for up to 1 yr
• beyond 1 yr little is known for any of these
  agents
• evidence for COXIB vs NSAID class effect on CV
  safety is not established
• rofecoxib is distinct from celecoxib and NSAIDs
• Only further study of NSAIDs/COXIBs will define
  the longer-term CV risks against the known risks
  of GI ulcer complications

4
Arthritis is a Leading Cause of Disability
Arthritis
17.5
16.5
Back or Spine
7.8
Heart Trouble, Hardening of the Arteries
4.7
Lung or Respiratory
4.4
Deafness or Hearing
Limb/Extremity Stiffness
4.2
3.7
Mental or Emotional
3.4
Diabetes
About 39 million physician visits/ yr1More than
500,000 hospitalizations/ yr1
3.3
Blindness or Vision
2.8
Stroke
0
2
4
6
8
10
12
14
16
18
All Disabilities
Census data for 1999.CDC. MMWR Morb Mortal Wkly
Rep. 200150120-125.
1 CDC, Arthritis Foundation. National Arthritis
Action Plan A Public Health Strategy. 1999.
5
Efficacy in OA
NSAIDs are an important treatment option
50
Acetaminophen 1000 mg qid Diclofenac 75
mg/misoprostol 200 mg bid N227
J
45
acetaminophen
J
J
40
J
J
diclofenac misoprostol
WOMAC Target Joint Score (mm)
J
35
acetaminophen
J
30
Greater improvement
J
diclofenac misoprostol

25

washout crossover
washout
0
0
6
0
6
Weeks
plt0.05 vs acetaminophen
Pincus et al. Arthritis Rheum 2001441587-1598
6
Incidence of Hospitalization for GI Bleeding or
Perforations
Saskatchewan, Canada
25
Non-users Men
Non-users Women
20
Current users Men
Current users Women
15
Per 1000 Pt-yrs
10
5
0
Age Group (yrs)
Perez-Gutthann et al. Epidemiology 1997818-24
7
COX-2 Inhibitor Hypothesis 1992
Arachidonic Acid
COX-2 (Inducible)
COX-1 (Constitutive)
COX-2 inhibitor
x
NSAIDs
Stomach Intestine Kidney Platelet

• Disease Targets
• Arthritis, Pain

8
Clinical Effects of Celecoxib in RA
Efficacy
Upper GI Safety

Placebo
N 1149
25
50
Celecoxib

Naproxen


20
40

15
30
Patients with Ulcer ()
ACR 20 Responders ()
10
20
5
10
0
0
Placebo
200
400
500
100
100
200
400
500
Placebo
Celecoxib (mg bid)
Naproxen (mg bid)
Celecoxib (mg bid)
Naproxen (mg bid)
p lt0.001 vs other treatments
p lt0.001 vs placebo
Simon et al. JAMA 282 201921-1928, 1999
9
GI Safety Profile of Celecoxib
Meta Analysis of Arthritis RCTs
39,605 OA/RA patients mean exposure 7 mo
Relative Risk (95CI)
Symptomatic ulcers/GI bleeding
0.35 (0.22, 0.56)
Celecoxib (200/400 mg) vs NSAIDs
Celecoxib (any dose) vs NSAIDs
0.61 (0.46, 0.81)
Reductions in Hgb gt 2g/dL
Celecoxib (200/400 mg) vs NSAIDs
0.71 (0.55, 0.91)
0.72 (0.56, 0.92)
Celecoxib (any dose) vs NSAIDs
Withdrawal due to GI intolerance
0.70 (0.60, 0.80)
Celecoxib (200/400 mg) vs NSAIDs
0.75 (0.70, 0.80)
Celecoxib (any dose) vs NSAIDs
0.50
0.25
1.0
0.75
1.25
0.0
Favors NSAIDs
Favors celecoxib
Moore et al. Arthritis Research Therapy 2005
(Feb)
10
Risk of Hospitalization for Upper GI Bleeding
with COXIBs

• gt55 womenMean age gt75 yrs
• gt1 with Hx of GI bleed gt16 Use of
  gastroprotective agent
• gt12 Use of aspirin

7
6
5
4.0
4
Adjusted Rate Ratio
3.0
3
1.9
2
1.0
1.0
1
0
Non-use
celecoxib
rofecoxib
diclomiso
NSAIDs
100,000 (2.2)
18,908 (3.6)
14,583 (7.3)
5,087 (9.6)
5,391 (12.6)
n (no. upper GI bleeds per 1000 person-yrs)
Mamdani et al. BMJ 2002325(7365)624-7
11
Risk of Hospitalization of Upper GI Bleeding in
High Risk Patients
Patients with prior gastrointestinal diseases

• 46 female Mean age gt68 yrs
• gt22 with Hx of non-bleeding GI ulcer gt70 Use
  of gastroprotective agent
• gt21 Use of aspirin

5
4
3.3
3
Adjusted Odds Ratio
2.1
2
1.3
1.0
1
0
Non-use
celecoxib
rofecoxib
NSAIDs
Nøgård et al. Aliment Pharmacol Ther
200419817-25
12
GI Safety Benefit - Conclusions

• Medical need for improved GI safety is fulfilled
  with celecoxib
• Randomized Controlled Trials
• Celecoxib has a favorable GI safety profile vs
  NSAIDs
• Epidemiology Studies
• Celecoxib is associated with a lower risk of
  hospitalization due to GI bleeding than NSAIDs

13
Thromboembolic CV Adverse EventsVIGOR and CLASS
Studies
VIGOR
CLASS
R
J
Rofecoxib 50 mg qd (n4047)
Celecoxib 400 mg bid (n3987)
P
Q
NSAIDs (n3981)
Naproxen 500 mg bid (n4029)
R
2.5
2.5
R
R
2.0
2.0
R
J
P
J
R
P
J
R
P
R
J
R
P
J
R
P
J
J
P
R
P
1.5
1.5
J
P
R
J
R
of Patients
J
of Patients
R
P
R
J
P
R
J
R
P
R
J
R
P
R
J
P
J
P
R
J
R
R
P
J
P
J
R
1.0
P
R
R
1.0
P
R
J
P
J
R
P
J
P
P
P
R
J
P
R
J
P
P
R
J
P
P
p 0.973
J
R
R
P
R
J
p lt 0.05
R
P
P
J
P
R
P
R
R
P
J
P
R
P
J
0.5
J
P
0.5
P
R
J
J
P
P
P
R
J
P
R
P
P
P
R
J
P
J
P
R
R
J
P
P
R
J
R
J
P
P
P
J
R
P
J
P
J
P
R
P
J
P
P
P
R
R
P
P
P
P
J
P
J
0
R
0
P
J
P
0
40
80
120
160
200
240
280
320
360
0
40
80
120
160
200
240
280
320
360
Days
Days
White et al. Am J Cardiol200289425-430
www.fda.gov/ohrms/dockets/ac/01/briefing/3677b2_6_
cardio.doc
14
Overview

• Celecoxib - CV safety vs placebo
• Longer-term studies
• Celecoxib CV safety vs NSAIDs
• Meta analysis of RCTs
• Risk factors
• Epidemiology studies
• Considerations of mechanism
• Conclusions Risk-benefit

15
Overview

• Celecoxib - CV safety vs placebo
• Longer-term studies
• Celecoxib CV safety vs NSAIDs
• Meta analysis of RCTs
• Risk factors
• Epidemiology studies
• Considerations of mechanism
• Conclusions Risk-benefit

16
CV Event Definitions

• APTC composite endpoint
• non-fatal myocardial infarctions,
• non-fatal strokes, or
• vascular deaths (all deaths attributed to
  cardiac, cerebral, hemorrhagic, embolic, other
  vascular, or unknown causes)
• Meta-analysis similar construct to APTC based
  upon investigator reports of serious adverse
  events
• Epidemiologic studies - hospitalization for acute
  MI alone or plus coronary death (1 study with
  APTC endpoint)

Antiplatelet Trialists Collaboration. BMJ.
199430881-106
17
Sporadic Adenoma Prevention Trials (SAP)

• Colorectal adenomas precursors of colon cancer
• Over-expression of COX-2 (pre-cancer, cancer,
  metastatic disease)
• Two celecoxib SAP trials (still ongoing)
• APC (005) PreSAP (018)
• 3 year placebo controlled RCTs
• Hypothesis celecoxib will reduce polyp
  recurrence by gt35 in a high risk cohort (prior
  adenoma).

Setting allowed for first longer-term placebo
comparison Celecoxib - agent of choice based on
GI safety
18
Sources Available to Evaluate CV Safety of
Celecoxib
Patient Population
19
Alzheimers Disease Anti-Inflammatory Prevention
Trial (ADAPT)

• RCT evaluating celecoxib 200 mg bid or naproxen
  220 mg bid vs placebo
• Elderly population (gt70 yrs) at risk for AD
  (first degree relative with the disease)
• Except for uncontrolled hypertension, no other
  restrictions for CV disease
• Hypothesis celecoxib will reduce the incidence
  of AD by gt30 in a high risk cohort.

First longer-term placebo-controlled trial with
an NSAID
20
Sources Available to Evaluate CV Safety of
Celecoxib
Patient Population
21
CV Safety of Chronic Celecoxib vs Placebo
Conclusions Longer-term Studies

• Three longer-term placebo-controlled trials with
  celecoxib
• APC - showed a CV risk with celecoxib vs placebo
  after 1 yr of continuous treatment
• Pre-SAP - no differences observed with
  continuous treatment of celecoxib up to 3 yrs
• ADAPT - Naproxen showed a CV risk (over 1.5 yrs)
  vs placebo, in contrast to celecoxib
• Celecoxib requires further study to estimate
  longer-term CV risks an NSAID comparator in such
  a trial is critical

22
Overview

• Celecoxib - CV safety vs placebo
• Longer-term studies
• Celecoxib CV safety vs NSAIDs
• Meta analysis of RCTs
• Risk factors
• Epidemiology studies
• Considerations of mechanism
• Conclusions Risk-benefit

23
Cardiovascular Safety of Celecoxib
Meta-analysis of RCTs

• 41 completed randomized controlled trials and a
  total of 44,307 treated patients (gt91 OA/RA)
• 24,932 celecoxib-treated patients
• 4,057 placebo-treated patients
• 15,318 patients treated with active comparators
• Celecoxib doses 50 800 mg daily
• Primary NSAIDs naproxen, ibuprofen, diclofenac
• Study duration 2 wks to 1 yr

Celecoxib exposure gt 3 months 11206 (55) of
patients gt 9 months 2472 (12) of patients gt 1
yr 803 (4) of patients
24
Meta-analysis CV Endpoints

• Composite endpoint of any CV death, non-fatal MI
  or non-fatal stroke
• Any CV death
• Non-fatal MI
• Non-fatal stroke

25
Sources Available to Evaluate CV Safety of
Celecoxib
Patient Population
26
CV Death, MI and StrokeCelecoxib vs. NSAIDs
n (events per 100 patient-years)
27
CV Death, MI and StrokeCelecoxib vs. NSAIDs
Relative Risk (95CI)
0.86 (0.59, 1.26)
CV death, MI, or stroke
0.72 (0.37, 1.39)
CV death
1.49 (0.82, 2.70)
MI
0.33 (0.14, 0.78)
Stroke
Favors celecoxib
Favors NSAIDs
Celecoxib daily dose gt 200 mg
28
CV Death, MI and StrokeCelecoxib vs. Pbo,
NSAIDs Combined Individually
Relative Risk (95CI)
1.26 (0.57, 2.80)
vs. Placebo
0.86 (0.59, 1.26)
vs. NSAID
1.11 (0.41, 3.01)
vs. Naproxen
0.81 (0.49, 1.35)
vs. Diclofenac
0.88 (0.43, 1.82)
vs. Ibuprofen
0.3
3.0
10.0
0.1
1.0
Favors comparator
Favors celecoxib
Celecoxib daily dose gt 200 mg
29
CV Death, MI and StrokeCelecoxib vs. NSAIDs By
Dose
Relative Risk (95CI)
0.86 (0.59, 1.26)
? 200 mg
0.93 (0.52, 1.68)
200 mg
0.75 (0.34, 1.67)
400 mg
0.91 (0.53, 1.58)
800 mg
Favors celecoxib
Favors NSAIDs
30
CV Death, MI and StrokeCLASS and CAESAR Studies
3.0
Celecoxib 200 800 mg daily, n4445 NSAIDs
(diclofenac, ibuprofen), n4439
J
P
p 0.601, by log rank test
2.0
P
of Patients
P
J
P
P
P
J
P
J
1.0
P
J
P
J
P
J
J
P
P
J
P
J
P
P
J
P
J
P
P
J
J
P
J
P
J
P
J
J
P
J
J
P
J
P
J
P
J
P
J
P
P
J
P
J
J
P
J
P
P
J
0
J
P
J
P
J
P
0
30
60
90
120
150
180
210
240
270
300
330
360
390
Days
31
CV Safety in RCTs - Conclusions

• No association for increased CV risk detected
  with use of celecoxib up to 1 yr compared to
• NSAIDs combined
• naproxen, diclofenac or ibuprofen individually
• A dose-related increase in CV risk with celecoxib
  is not observed

32
Overview

• Celecoxib - CV safety vs placebo
• Longer-term studies
• Celecoxib CV safety vs NSAIDs
• Meta analysis of RCTs
• Risk factors
• Epidemiology studies
• Considerations of mechanism
• Conclusions Risk-benefit

33
CV Death, MI and StrokeCelecoxib vs. NSAIDs
By CV Risk Factors
1 Risk Factor (n 6,710)
? 2 Risk Factors (n 5,079)
No Risk Factors (n 21,974)
Celecoxib ? 200 mg
NSAIDs
3.0
3.0
2.0
2.0
Events per 100 pt yrs
1.0
1.0
0.0
0.0
MI
MI
Stroke
Stroke
CV death
CV death
CV death, MI, stroke
CV death, MI, stroke
Hypertension, diabetes, hyperlipidemia, CHD
34
CV Death, MI and StrokeCelecoxib vs. NSAIDs
By CV Risk Factors
Hypertension, diabetes, hyperlipidemia, CHD
Celecoxib daily dose gt 200 mg
35
CV Death, MI and StrokeCelecoxib vs. NSAIDs
By Aspirin Use
Celecoxib daily dose gt 200 mg
36
CV Death, MI and StrokeCLASS Study
No Aspirin
Aspirin
4.0
Celecoxib 400 mg BID (n3105)
4.0
Celecoxib 400 mg BID (n882)
J
J
NSAIDs (n3124)
NSAIDs (n857)
P
P
J
P
p 0.333Log-rank test
p 0.666Log-rank test
3.0
3.0
P
J
J
J
P
J
2.0
2.0
of Patients
J
P
J
J
P
J
P
1.0
1.0
J
P
P
J
P0
P
J
P
J
P
J
P
P
P
J
P
J
P
P
J
P
J
J
P
J
P
J
J
P
P
J
P
J
J
P
P
P
J
J
60
90
120
150
270
300
330
30
0
180
210
240
360
390
60
90
120
150
180
210
240
270
300
330
360
390
30
0
Days
37
Risk Factors - Conclusion

• The CV safety profile of celecoxib remains
  comparable to NSAIDs regardless of CV risk
  factors
• as determined by medical history or use of low
  dose aspirin

38
Overview

• Celecoxib - CV safety vs placebo
• Longer-term studies
• Celecoxib CV safety vs NSAIDs
• Meta analysis of RCTs
• Risk factors
• Epidemiology studies
• Considerations of mechanism
• Conclusions Risk-benefit

39
Risk of MI with COXIBs

• Ray WA et al. Lancet 2002
• Mamdani M et al. Arch Intern Med 2003
• Solomon DH et al. Circulation 2004
• Kimmel SE et al. Ann Intern Med 2005
• Graham DJ et al. Lancet 2005
• Lévesque LE et al. Ann Intern Med 2005
• Shaya FT et al. Arch Intern Med 2005

40
Risk of MI and Use of COXIBs
Ray WA and Graham DJ include MI and CHD death.
Kimmel SE non-fatal MI only Person-time of
exposure to celecoxib not provided in studies of
Graham DJ, Shaya FT, and Lévesque LE. Number of
cases exposed to celecoxib not provided in Shaya
FT.
41
Relative Risk of MI/Coronary Death Use of
COXIBs or NSAIDs vs. Non-use
mean age gt60 yrs 66 women37 with Hx of major
CV disease
3
Celecoxib 22,337 users 3 months mean
exposure
2
1.70
Adjusted Rate Ratio
1.03
1
1
0.93
0.96
0.94
0.91
0
Non-use
naproxen
celecoxib
rofecoxib
ibuprofen
celecoxib
rofecoxib
gt300mg
gt25mg
lt300mg
lt25mg
Ray et al. Lancet 2002 3601071-73
42
Relative Risk of MI Use of COXIBs or NSAIDs vs.
Non-use
mean age gt75 yrs gt56 womengt5 with Hx of MI,
gt9 with Hx of CHD
Celecoxib 15,271 users 5.5 months mean
follow-up
3
2
Adjusted Rate Ratio
1.20
1.00
1.00
1
1
0.90
0
Non-use
celecoxib
rofecoxib
naproxen
other
NSAIDs
Mamdani et al. Arch Intern Med 2003163481-86
43
Relative Risk of MI Use of COXIBs vs. Non-use

• mean age gt80 yrs
• 77 women
• 57 with Hx of Htn
• 14 with Hx of angina
• 9 with Hx of MI

Adjusted Odds Ratio
Non-use
celecoxib
celecoxib
celecoxib
rofecoxib
rofecoxib
rofecoxib
lt 200 mg
gt 200 mg
lt 25 mg
gt 25 mg
Solomon et al. Circulation 20041092068-73
Arthritis Rheum 200348 (Suppl 9) S697
(Presentation ACR Oct 2003)
44
Relative Risk of MI Use of COXIBs or NSAIDs vs.
Non-use

• mean age gt52 yrs
• 59 women31 with Hx of Htn
• 4 with Hx of angina/CHD

Adjusted Odds Ratio
Kimmel et al. Ann Intern Med 2005 142157-164
45
Relative Risk of MI/Coronary Death Use of
COXIBs or NSAIDs vs. Remote-use

• mean age gt66 yrs
• 38 women1 with Hx of MI/ revascularization

4
3
3.00
Adjusted Odds Ratio
2
1.60
1.30
1.14
1.06
1.23
1
1
0.84
0
celecoxib
ibuprofen
naproxen
diclofenac
Remote use
indomethacin
rofecoxib gt25 mg
rofecoxib lt 25 mg
Graham et al. Lancet 2005365475-481
46
Relative Risk of CV Death, MI or StrokeUse of
COXIBs vs. Non-naproxen NSAIDs

• 11 gt60 yrs
• 70 women43 with Hx of Htn
• 12 with Hx of CV event

3
2
Adjusted Odds Ratio
1.19
1.09
1
1
0.99
0
Non-naproxen
COXIBs
celecoxib
rofecoxib
NSAIDs
Shaya et al. Arch Intern Med 2005165181-6
47
Relative Risk of MI Use of COXIBs or NSAIDs vs.
Non-use

• mean age gt78 yrs
• 67 women50 with Hx of Htn
• 17 with Hx of CHD

3
2
1.73
Adjusted Rate Ratio
1.17
1.21
1.06
1
1.00
1.00
1
0.98
0
Non-use
naproxen
meloxicam
other NSAIDs
rofecoxib lt 25 mg
rofecoxib gt 25 mg
celecoxib lt 200 mg
celecoxib gt 200 mg
Lévesque et al. Ann Intern Med 2005142(7),
www.annals.org
48
Risk of MI by ASA Use Relative Risk of COXIBs
vs. Non-use
No ASA use
ASA use
4
3
2.36
2
Adjusted Rate Ratio
1.38
1.16
1.23
1
1.04
1.00
1
1
0.91
0.80
0
Non-use
Non-use
Rofecoxib gt 25 mg
Rofecoxib gt 25 mg
Rofecoxib lt 25 mg
Rofecoxib lt 25 mg
Celecoxib gt 200 mg
Celecoxib gt 200 mg
Celecoxib lt 200 mg
Celecoxib lt 200 mg
Lévesque et al. Ann Intern Med 2005142(7),
www.annals.org
49
Summary of MI Risk by DoseRelative Risk vs.
Non-use/Remote Use
Low dose
High dose
4
celecoxib
rofecoxib
rofecoxib
celecoxib
3
3.00
2
Relative Risk
1.73
1.70
1.58
1.23
1.21
1.11
1.03
1.00
1
1
0.94
0.94
0.92
0.96
0.98
0
Non-use
Ray WA
Ray WA
Ray WA
Ray WA
Graham DJ
Graham DJ
Solomon DH
Solomon DH
Solomon DH
Solomon DH
Lévesque LE
Lévesque LE
Lévesque LE
Lévesque LE
High-dose rofecoxib gt25 mgr/day celecoxib
gt200 mg/day in Solomon DH and Lévesque LE
celecoxib gt 300 mg/day in Ray WA
50
CV Epidemiology Studies - Conclusions

• The risk of MI with celecoxib as used in the real
  world population (dose duration)
• is consistently similar to nonselective NSAIDs,
  and non- or remote use of NSAIDs
• These findings are in contrast to increased risk
  with rofecoxib
• The available data suggest that the risk of MI is
  similar for low and high celecoxib doses

51
Overview

• Celecoxib - CV safety vs placebo
• Longer-term studies
• Celecoxib CV safety vs NSAIDs
• Meta analysis of RCTs
• Risk Factors
• Epidemiology Studies
• Considerations of Mechanism
• Conclusions Risk-benefit

52
Potential Mechanism(s) of CV Risk

• Hypothesis that attributes CV risk to COXIBs
  only
• Could explain
• VIGOR, APPROVe and APC results
• Could not explain consistent comparability
  between celecoxib and NSAIDs
• meta-analysis
• vs non-use in epidemiology studies
• Could not explain Pre-SAP and ADAPT results

53
Potential Mechanisms
Can PGI2/TxA2 imbalance lead to prothrombotic
potential?

• NSAIDs may not provide effective blockade of
  platelets even though TxA2 production is
  reduced
• Does not account for other PGs produced from
  COX-2 (e.g. PGE2, TxA2)

54
Pharmacologic Responses to Celecoxib and
Ibuprofen
H
Celecoxib 400 mg (n9)
B
Placebo (n7)
F
Celecoxib 800 mg (n7)
J
Celecoxib 100 mg (n7)
P
Ibuprofen 800 mg (n7)
Platelet Aggregation
Urinary PGI-M
20
200
H
J
J
F
B
B
J
H
P
B
J
P
175
B
H
0
F
H
F
F
150
-20
pg/ mg creatinine
125
P
-40
(Mean Change SE)
100


75
-60
P


50



-80
25
NR
NR
-100
0
Pre-Dose
2
4
6
0
24
8
4-6 hrs
6-12 hrs
Hours
Significant difference from baseline plt0.05
Significantly different from placebo plt0.05
McAdam et al. PNAS 199996272-277
NR not reported
55
COX-2 Prostaglandins Linked to CV Disease
? COX-2 expression
? PGI2
? TxA2
? PGE2

• Endothelial function
• ? Platelet aggregation

• Endothelial function
• ? Platelet aggregation

? MMPs
? Plaque stability
56
Putative Novel Rofecoxib Pathways Leading to
Increased HTN and CV Risk
Rofecoxib and/or Reactive Metabolites
?F2-Isoprostanes
?Ox-LDL
?Nitric Oxide Bioavailability
?Blood Pressure /?Atherothrombosis
Walter M et al. Atherosclerosis 177 (2004)
235-243 Chikani G et al. Am J Physiol Endocrinol
Metab 287 (2004) E386-E389
57
24-Hour Mean SBP Change at 6 12 Wks in OA
Hypertensive Patients
SBP from ABPM data
6

5

4
3
2
Mean SBP Change (mm Hg)
1
0
-1
-2
6 Wks
12 Wks
6 Wks
12 Wks
6 Wks
12 Wks
-3
Celecoxib 200 mg qd n136
Rofecoxib 25 mg qd n138
Naproxen 500 mg bid n130
Sowers et al. Arch Int Med 2005165161-168
p lt 0.05 vs other treatments
58
Mechanism Summary

• It is not established that PGI2/TxA2 imbalance
  contributes to effects observed for COXIBs or
  NSAIDs
• Furthermore, the underlying pharmacology is more
  complex involving other PGs and pathways and
  raises the potential for benefit with a COX-2
  blockade
• Evidence for molecule-specific mechanisms is
  emerging

59
Overview

• Celecoxib - CV safety vs placebo
• Longer-term studies
• Celecoxib CV safety vs NSAIDs
• Meta analysis of RCTs
• Risk Factors
• Epidemiology Studies
• Considerations of Mechanism
• Conclusions Risk-benefit

60
Summary of GI and CV Safety

• Celecoxib vs NSAIDs
• GI safety
• RCTs lower incidence of clinically significant
  GI outcomes
• Epidemiology studies similar risk of
  hospitalization for GI bleeding vs non-users
• CV safety
• RCTs comparable CV safety profile
• Epidemiology studies similar CV risk vs
  non-users

61
Risk-Benefit of Celecoxib in Arthritis -
Conclusions

• In the currently approved arthritis indications,
  the risk-benefit of celecoxib remains positive
  relative to NSAIDs
• Comparable efficacy
• GI safety benefit
• Comparable CV risk
• Shared uncertainty of the CV safety beyond 1
  year of continuous treatment

Further studies are planned to evaluate the
longer-term GI and CV safety of celecoxib vs
NSAIDs in arthritis patients