PPT

1

16 February 200516 February 2005

FDA Advisory Committee MeetingFDA Advisory Committee Meeting

Cardiovascular Safety of CelecoxibCardiovascular Safety of Celecoxib

& &

Risk-Benefit Assessment Risk-Benefit Assessment

A2

DelegationDelegation

Dr Jeffrey BorerDr Jeffrey Borer CardiologyCardiologyDr Andrew Dannenberg Dr Andrew Dannenberg GastroenterologyGastroenterologyDr Gerry FaichDr Gerry Faich Epidemiology/Drug SafetyEpidemiology/Drug SafetyDr Norman GitlinDr Norman Gitlin GastroenterologyGastroenterologyDr Gary Koch Dr Gary Koch StatisticianStatisticianDr Bernard LevinDr Bernard Levin OncologyOncologyDr Scott LippmanDr Scott Lippman Oncology Oncology Dr Nancy NussmeierDr Nancy Nussmeier AnesthesiologyAnesthesiologyDr Lee SimonDr Lee Simon RheumatologyRheumatologyDr Vibeke Strand Dr Vibeke Strand RheumatologyRheumatologyDr Andrew WheltonDr Andrew Whelton NephrologyNephrology Dr William WhiteDr William White HypertensionHypertension

A3

Overall ConclusionsOverall Conclusions

There are few therapeutic alternatives for patients with There are few therapeutic alternatives for patients with chronic arthritis-related painchronic arthritis-related pain

– Patients who discontinue celecoxib will likely turn to Patients who discontinue celecoxib will likely turn to NSAIDsNSAIDs

Celecoxib provides improved GI safety compared to NSAIDsCelecoxib provides improved GI safety compared to NSAIDs All lines of evidence show the CV safety of celecoxib is All lines of evidence show the CV safety of celecoxib is

similar to NSAIDs for up to 1 yr; similar to NSAIDs for up to 1 yr;

– beyond 1 yr little is known for any of these agentsbeyond 1 yr little is known for any of these agents

– evidence for COXIB vs NSAID class effect on CV safety evidence for COXIB vs NSAID class effect on CV safety is not establishedis not established

– rofecoxib is distinct from celecoxib and NSAIDs rofecoxib is distinct from celecoxib and NSAIDs Only further study of NSAIDs/COXIBs will define the longer-Only further study of NSAIDs/COXIBs will define the longer-

term CV risks against the known risks of GI ulcer term CV risks against the known risks of GI ulcer complicationscomplications

A4

Census data for 1999.CDC. MMWR Morb Mortal Wkly Rep. 2001;50:120-125.

% All Disabilities

Stroke

Blindness or Vision

Diabetes

Mental or Emotional

Limb/Extremity Stiffness

Deafness or Hearing

Lung or Respiratory

Heart Trouble, Hardening of the Arteries

Back or Spine

Arthritis

0 2 4 6 8 10 12 14 16 18

2.8%

3.3%

3.4%

3.7%

4.2%

4.4%

4.7%

7.8%

16.5%

17.5%

Arthritis is a Leading Cause of Disability

About 39 million physician visits/ yr1

More than 500,000 hospitalizations/ yr1

1 CDC, Arthritis Foundation. National Arthritis Action Plan: A Public Health Strategy. 1999.

A5

Efficacy in OA Efficacy in OA

NSAIDs are an important treatment optionNSAIDs are an important treatment option

Pincus et al. Arthritis Rheum 2001;44:1587-1598Pincus et al. Arthritis Rheum 2001;44:1587-1598* p<0.05 vs acetaminophen * p<0.05 vs acetaminophen

00

2525

3030

3535

4040

4545

5050

JJ

JJ

JJJJ

JJ

JJ

JJJJ

acetaminophenacetaminophen

diclofenac + diclofenac + misoprostolmisoprostol acetaminophenacetaminophen

diclofenac + diclofenac + misoprostolmisoprostol

WO

MA

C T

arg

et J

oin

t S

core

(m

m)

WO

MA

C T

arg

et J

oin

t S

core

(m

m)

00 66 00 66

washout washout &&

crossovercrossover

washout washout

Acetaminophen 1000 mg qidAcetaminophen 1000 mg qidDiclofenac 75 mg/misoprostol 200 Diclofenac 75 mg/misoprostol 200 g bid g bid N=227N=227

**

**

GreaterGreaterimprovementimprovement

WeeksWeeks

A6

Age Group (yrs)Age Group (yrs)

00

55

1010

1515

2020

2525

15-1

915

-19

20-2

420

-24

25-2

925

-29

30-3

430

-34

35-3

935

-39

40-4

440

-44

45-4

945

-49

50-5

450

-54

55-5

955

-59

60-6

460

-64

65-6

965

-69

70-7

470

-74

75-7

975

-79

80-8

480

-84

85+

85+

Non-users MenNon-users Men

Non-users WomenNon-users Women

Current users Men Current users Men

Current users WomenCurrent users Women

Saskatchewan, Canada Saskatchewan, Canada

Per

100

0 P

t-yr

sP

er 1

000

Pt-

yrs

Perez-GutthaPerez-Gutthannn et al. Epidemiology 1997;8:18-24n et al. Epidemiology 1997;8:18-24

Incidence of Hospitalization for GI Bleeding or Incidence of Hospitalization for GI Bleeding or PerforationsPerforations

A7

Arachidonic AcidArachidonic Acid

COX-1COX-1(Constitutive)(Constitutive)

COX-2COX-2(Inducible)(Inducible)

StomachStomachIntestineIntestineKidneyKidneyPlateletPlatelet

Disease Targets:Disease Targets:• Arthritis, PainArthritis, Pain

xx

COX-2 Inhibitor Hypothesis: COX-2 Inhibitor Hypothesis: 19921992

NSAIDsNSAIDs

COX-2 inhibitorCOX-2 inhibitor

A8

Clinical Effects of Celecoxib in RAClinical Effects of Celecoxib in RA

**p**p <0.001 vs other treatments <0.001 vs other treatments

****

Pat

ien

ts w

ith

Ulc

er (

%)

Pat

ien

ts w

ith

Ulc

er (

%)

Celecoxib Celecoxib (mg bid)(mg bid)

Naproxen Naproxen (mg bid)(mg bid)

2525

00

55

1010

1515

2020

PlaceboPlacebo 200200 400400 500500 100100

AC

R 2

0 R

esp

on

der

s A

CR

20

Res

po

nd

ers

(%)

(%)

00

1010

2020

3030

4040

5050

100100 200200 400400 500500

CelecoxibCelecoxib(mg bid)(mg bid)

NaproxenNaproxen(mg bid)(mg bid)

****

****

PlaceboPlacebo

Simon et al. JAMA 282 20:1921-1928, 1999Simon et al. JAMA 282 20:1921-1928, 1999 *p*p <0.001 vs placebo <0.001 vs placebo

CelecoxibCelecoxibNaproxen Naproxen

Placebo Placebo N =1149N =1149

EfficacyEfficacy Upper GI SafetyUpper GI Safety

A9

Relative Risk (95%CI)Relative Risk (95%CI)

GI Safety Profile of Celecoxib GI Safety Profile of Celecoxib Meta Analysis of Arthritis RCTsMeta Analysis of Arthritis RCTs

0.35 (0.22, 0.56)0.35 (0.22, 0.56)

Reductions in Hgb > 2g/dL Reductions in Hgb > 2g/dL

Symptomatic ulcers/GI bleeding Symptomatic ulcers/GI bleeding

Withdrawal due to GI intolerance Withdrawal due to GI intolerance

Celecoxib (200/400 mg) vs NSAIDs Celecoxib (200/400 mg) vs NSAIDs

Celecoxib (any dose) vs NSAIDs Celecoxib (any dose) vs NSAIDs





0.61 (0.46, 0.81)0.61 (0.46, 0.81)

0.71 (0.55, 0.91)0.71 (0.55, 0.91)

0.72 (0.56, 0.92)0.72 (0.56, 0.92)

0.70 (0.60, 0.80)0.70 (0.60, 0.80)

0.75 (0.70, 0.80)0.75 (0.70, 0.80)

Favors NSAIDsFavors NSAIDs

0.500.500.250.25 1.01.00.750.75 1.251.25

Favors celecoxibFavors celecoxib

0.00.0

Moore et al. Arthritis Research & Therapy 2005: (Feb) Moore et al. Arthritis Research & Therapy 2005: (Feb)

39,605 OA/RA patients; mean exposure ~7 mo39,605 OA/RA patients; mean exposure ~7 mo

A10

3.03.0

4.04.0

1.91.9

11

22

33

44

55

66

77

Ad

just

ed

Ra

te R

ati

oA

dju

ste

d R

ate

Ra

tio

00Non-useNon-use celecoxibcelecoxib rofecoxibrofecoxib diclo+misodiclo+miso NSAIDsNSAIDs

Mamdani et al. BMJ 2002;325(7365):624-7Mamdani et al. BMJ 2002;325(7365):624-7

1.01.01.01.0

Risk of Hospitalization for Upper GI Risk of Hospitalization for Upper GI Bleeding with COXIBsBleeding with COXIBs

>55% women>55% womenMean age >75 yrsMean age >75 yrs>1% with Hx of GI bleed >1% with Hx of GI bleed >16% Use of gastroprotective agent>16% Use of gastroprotective agent>12% Use of aspirin>12% Use of aspirin

100,000 (2.2)*100,000 (2.2)* 18,908 (3.6)*18,908 (3.6)* 14,583 (7.3)*14,583 (7.3)* 5,087 (9.6)*5,087 (9.6)* 5,391 (12.6)*5,391 (12.6)*

*n (no. upper GI bleeds per 1000 person-yrs)*n (no. upper GI bleeds per 1000 person-yrs)

A11

3.33.3

1.31.3

2.12.1

1.01.0

00

11

22

33

44

55

Non-useNon-use celecoxibcelecoxib rofecoxibrofecoxib NSAIDsNSAIDs

Ad

just

ed

Od

ds

Ra

tio

Ad

just

ed

Od

ds

Ra

tio

Risk of Hospitalization of Upper GI Risk of Hospitalization of Upper GI Bleeding in High Risk PatientsBleeding in High Risk Patients

NNøøggåård et al. Aliment Pharmacol Ther 2004;19:817-25rd et al. Aliment Pharmacol Ther 2004;19:817-25

Patients with prior gastrointestinal diseasesPatients with prior gastrointestinal diseases

46% female 46% female Mean age >68 yrsMean age >68 yrs>22% with Hx of non-bleeding GI ulcer >22% with Hx of non-bleeding GI ulcer >70% Use of gastroprotective agent>70% Use of gastroprotective agent>21% Use of aspirin>21% Use of aspirin

A12

GI Safety Benefit - ConclusionsGI Safety Benefit - Conclusions

Medical need for improved GI safety is fulfilled Medical need for improved GI safety is fulfilled with celecoxib with celecoxib – Randomized Controlled TrialsRandomized Controlled Trials

Celecoxib has a favorable GI safety profile Celecoxib has a favorable GI safety profile vs NSAIDsvs NSAIDs

– Epidemiology StudiesEpidemiology Studies Celecoxib is associated with a lower risk Celecoxib is associated with a lower risk

of hospitalization due to GI bleeding than of hospitalization due to GI bleeding than NSAIDsNSAIDs

A13

Thromboembolic CV Adverse Events:Thromboembolic CV Adverse Events:VIGOR and CLASS StudiesVIGOR and CLASS Studies

DaysDays00 4040 8080 120120 160160 200200 240240 280280 320320 360360

VIGORVIGOR

PPPPPPPPPPPPPPPPPP

PPPPPPPPPPPPPPPPPPPPPPPPPPPPPP

RR

RRRR

RRRRRRRRRRRRRR

RRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRR

RRRRRRRRRRRRRRRRRRRRRRRRRR00

0.50.5

1.01.0

1.51.5

2.02.0

2.52.5

RR Rofecoxib 50 mg qd (n=4047)Rofecoxib 50 mg qd (n=4047)

Naproxen 500 mg bid (n=4029)Naproxen 500 mg bid (n=4029)QQ

p < 0.05p < 0.05

White et al. Am J Cardiol;2002:89:425-430White et al. Am J Cardiol;2002:89:425-430 www.fda.gov/ohrms/dockets/ac/01/briefing/3677b2_6_cardio.docwww.fda.gov/ohrms/dockets/ac/01/briefing/3677b2_6_cardio.doc

% o

f P

atie

nts

% o

f P

atie

nts

JJ Celecoxib 400 mg bid (n=3987)Celecoxib 400 mg bid (n=3987)

PP NSAIDs (n=3981)NSAIDs (n=3981)

CLASSCLASS

JJJJJJJJJJJJJJ

JJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJ

PPPPPPPPPPPPPPPP

PPPPPPPPPPPPPPPPPPPPPPPPPPPPPPPPPPPPPP

PPPPPPPPPPPPPPPPPPPPPPPPPP00

0.50.5

1.01.0

1.51.5

2.02.0

2.52.5

pp = 0.973= 0.973

DaysDays00 4040 8080 120120 160160 200200 240240 280280 320320 360360

PPPP

% o

f P

atie

nts

% o

f P

atie

nts

A14

Overview Overview

Celecoxib - CV safety vs placebo Celecoxib - CV safety vs placebo

– Longer-term studiesLonger-term studies

Celecoxib – CV safety vs NSAIDsCelecoxib – CV safety vs NSAIDs

– Meta analysis of RCTs Meta analysis of RCTs

– Risk factorsRisk factors

– Epidemiology studiesEpidemiology studies

– Considerations of mechanism Considerations of mechanism

Conclusions: Risk-benefitConclusions: Risk-benefit

A15

Overview Overview









A16

CV Event DefinitionsCV Event Definitions APTC* composite endpoint APTC* composite endpoint

– non-fatal myocardial infarctions, non-fatal myocardial infarctions, – non-fatal strokes,non-fatal strokes, or or – vascular deathsvascular deaths ( (all deaths attributed to cardiac, all deaths attributed to cardiac,

cerebral, hemorrhagic,cerebral, hemorrhagic, embolic, other vascular, embolic, other vascular, or unknown causes)or unknown causes)

Meta-analysis – similar construct to APTC; based Meta-analysis – similar construct to APTC; based upon investigator reports of serious adverse eventsupon investigator reports of serious adverse events

Epidemiologic studies - hospitalization for acute MI alone Epidemiologic studies - hospitalization for acute MI alone or plus coronary death (1 study with APTC endpoint)or plus coronary death (1 study with APTC endpoint)

*Antiplatelet Trialists Collaboration. *Antiplatelet Trialists Collaboration. BMJBMJ. 1994;308:81-106. 1994;308:81-106

A17

Sporadic Adenoma Prevention Trials (SAP)Sporadic Adenoma Prevention Trials (SAP)

Colorectal adenomas: precursors of colon cancerColorectal adenomas: precursors of colon cancer Over-expression of COX-2 (pre-cancer, cancer, Over-expression of COX-2 (pre-cancer, cancer,

metastatic disease)metastatic disease) Two celecoxib SAP trials (still ongoing)Two celecoxib SAP trials (still ongoing)

– APC (005) & PreSAP (018)APC (005) & PreSAP (018)– 3 year placebo controlled RCTs3 year placebo controlled RCTs– Hypothesis: celecoxib will reduce polyp Hypothesis: celecoxib will reduce polyp

recurrence by >35% in a high risk cohort recurrence by >35% in a high risk cohort (prior adenoma).(prior adenoma).

Setting allowed for first longer-term placebo comparison; Setting allowed for first longer-term placebo comparison; Celecoxib - agent of choice based on GI safety Celecoxib - agent of choice based on GI safety

A18

APCAPC Pre-SAP Pre-SAP

Study DescriptionStudy Description

Number of patientsNumber of patients 20352035 15611561

Pt-yearsPt-years 47784778 39393939

Mean exposure (yrs)Mean exposure (yrs) 2.32.3 2.52.5

Number of CV eventsNumber of CV events 4141 3131

Mean age (yrs)Mean age (yrs) 6060 6161

Hx of hypertensionHx of hypertension 41%41% 35%35%

Hx of CHDHx of CHD 39%39% 48%48%

Concomitant aspirinConcomitant aspirin 30%30% 16%16%

Sources Available to Evaluate CV Safety Sources Available to Evaluate CV Safety of Celecoxibof Celecoxib

Patient PopulationPatient Population

A19

Alzheimer’s Disease Anti-Inflammatory Alzheimer’s Disease Anti-Inflammatory Prevention Trial (ADAPT)Prevention Trial (ADAPT)

RCT evaluating celecoxib 200 mg bid or RCT evaluating celecoxib 200 mg bid or naproxen 220 mg bid vs placebo naproxen 220 mg bid vs placebo – Elderly population (>70 yrs) at risk for AD Elderly population (>70 yrs) at risk for AD

(first degree relative with the disease)(first degree relative with the disease)– Except for uncontrolled hypertension, no other Except for uncontrolled hypertension, no other

restrictions for CV diseaserestrictions for CV disease– Hypothesis: celecoxib will reduce the incidence Hypothesis: celecoxib will reduce the incidence

of AD by >30% in a high risk cohort.of AD by >30% in a high risk cohort.

First longer-term placebo-controlled trial with an NSAIDFirst longer-term placebo-controlled trial with an NSAID

A20

APCAPC Pre-SAP Pre-SAP ADAPTADAPT


Number of patientsNumber of patients 20352035 15611561 24632463

Pt-yearsPt-years 47784778 39393939 38883888

Mean exposure (yrs)Mean exposure (yrs) 2.32.3 2.52.5 1.61.6

Number of CV eventsNumber of CV events 4141 3131 ~70~70

Mean age (yrs)Mean age (yrs) 6060 6161 >70>70

Hx of hypertensionHx of hypertension 41%41% 35%35% n/an/a

Hx of CHDHx of CHD 39%39% 48%48% n/an/a

Concomitant aspirinConcomitant aspirin 30%30% 16%16% n/an/a



A21

CV Safety of Chronic Celecoxib vs Placebo – CV Safety of Chronic Celecoxib vs Placebo – Conclusions: Longer-term StudiesConclusions: Longer-term Studies

Three longer-term placebo-controlled trials with Three longer-term placebo-controlled trials with celecoxibcelecoxib

– APC - showed a CV risk with celecoxib vs APC - showed a CV risk with celecoxib vs placebo after ~1 yr of continuous treatmentplacebo after ~1 yr of continuous treatment

– Pre-SAP - no differences observed with Pre-SAP - no differences observed with continuous treatment of celecoxib up to 3 yrs continuous treatment of celecoxib up to 3 yrs

– ADAPT - Naproxen showed a CV risk (over 1.5 yrs) ADAPT - Naproxen showed a CV risk (over 1.5 yrs) vs placebo, in contrast to celecoxibvs placebo, in contrast to celecoxib

Celecoxib requires further study to estimate longer-term Celecoxib requires further study to estimate longer-term CV risks; an NSAID comparator in such a trial is critical CV risks; an NSAID comparator in such a trial is critical

A22

Overview Overview









A23

Cardiovascular Safety of Celecoxib: Meta-analysis of RCTs

41 completed randomized controlled trials and a total of 44,307 treated patients (>91% 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 exposureCelecoxib exposure >> 3 months – 11206 (55%) of patients 3 months – 11206 (55%) of patients>> 9 months – 2472 (12%) of patients 9 months – 2472 (12%) of patients>> 1 yr – 803 (4%) of patients 1 yr – 803 (4%) of patients

A24

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

A25

APCAPC Pre-SAP Pre-SAP ADAPTADAPT Meta-analysis of RCTsMeta-analysis of RCTs

2 wks – 1 yr2 wks – 1 yr


vs. vs. PlaceboPlacebo

vs. vs.

NSAIDs NSAIDs

Number of patientsNumber of patients 20352035 15611561 24632463 1151911519 3376333763

Pt-yearsPt-years 47784778 39393939 38883888 18531853 1003710037

Mean exposure (yrs)Mean exposure (yrs) 2.32.3 2.52.5 1.61.6 0.160.16 0.300.30

Number of CV eventsNumber of CV events 4141 3131 ~70~70 3131 111111

Mean age (yrs)Mean age (yrs) 6060 6161 >70>70 5959 6060

Hx of hypertensionHx of hypertension 41%41% 35%35% n/an/a 45%45% 25%25%

Hx of CHDHx of CHD 39%39% 48%48% n/an/a 22%22% 10%10%

Concomitant aspirinConcomitant aspirin 30%30% 16%16% n/an/a 13%13% 11%11%



A26

CV Death, MI and Stroke:CV Death, MI and Stroke:Celecoxib vs. NSAIDs Celecoxib vs. NSAIDs

CelecoxibCelecoxib 200 mg 200 mgN=19773N=19773

NSAIDsNSAIDs

N=13990N=13990

Patient-yearsPatient-years 56515651 43864386

Mean exposure/patient (mos.)Mean exposure/patient (mos.) 3.43.4 3.83.8

CV death, MI, strokeCV death, MI, stroke 57 (1.0)57 (1.0) 54 (1.2)54 (1.2)

CV deathCV death 15 (0.3)15 (0.3) 19 (0.4)19 (0.4)

MIMI 35 (0.6)35 (0.6) 19 (0.4)19 (0.4)

StrokeStroke 7 (0.1)7 (0.1) 16 (0.4)16 (0.4)

n (events per 100 patient-years)n (events per 100 patient-years)

A27

0.86 (0.59, 1.26)0.86 (0.59, 1.26)

0.72 (0.37, 1.39)0.72 (0.37, 1.39)

1.49 (0.82, 2.70)1.49 (0.82, 2.70)

Celecoxib daily dose Celecoxib daily dose >> 200 mg 200 mg

0.33 (0.14, 0.78)0.33 (0.14, 0.78)

CV death, MI, or strokeCV death, MI, or stroke

CV deathCV death

MIMI

StrokeStroke

Favors celecoxibFavors celecoxib Favors NSAIDsFavors NSAIDs

0.1 1.0 10.00.30.3 3.03.0


CV Death, MI and Stroke:CV Death, MI and Stroke:Celecoxib vs. NSAIDs Celecoxib vs. NSAIDs

A28

1.26 (0.57, 2.80)

0.86 (0.59, 1.26)

0.81 (0.49, 1.35)

0.88 (0.43, 1.82)

Celecoxib daily dose > 200 mg

1.11 (0.41, 3.01)

vs. Placebo

vs. NSAID

vs. Naproxen

vs. Diclofenac

vs. Ibuprofen

0.1 1.0 10.0

Favors celecoxib Favors comparator

0.3 3.0


CV Death, MI and Stroke:Celecoxib vs. Pbo, NSAIDs Combined & Individually

A29

0.86 (0.59, 1.26)0.86 (0.59, 1.26)

0.93 (0.52, 1.68)0.93 (0.52, 1.68)

0.75 (0.34, 1.67)0.75 (0.34, 1.67)

0.91 (0.53, 1.58)0.91 (0.53, 1.58)

200 mg200 mg

200 mg200 mg

400 mg400 mg

800 mg800 mg


0.10.1 1.01.0 10.010.00.30.3 3.03.0

CV Death, MI and Stroke:CV Death, MI and Stroke:Celecoxib vs. NSAIDs: By Dose Celecoxib vs. NSAIDs: By Dose


A30

CV Death, MI and Stroke:CV Death, MI and Stroke:CLASS and CAESAR StudiesCLASS and CAESAR Studies

PPPP PP

PP JJ

PP PP

PPPP PP

PP PPPPPP

PPPPPP PPPP PP PP PPPP

PP PP PPPPPPPP

PP PPPP

PP

PPPP

JJJJ JJ

JJ

JJ

JJ

JJ

JJJJ

JJ

JJ

JJJJ

JJJJ JJ

JJ JJJJ

JJ

JJ JJ

JJJJJJ JJJJ

JJ

3.03.0

2.02.0

1.01.0

00 3030 6060 9090 120120 150150 180180 210210 240240 270270 300300 330330 360360 390390

Celecoxib 200 – 800 mg daily, n=4445Celecoxib 200 – 800 mg daily, n=4445

NSAIDs (diclofenac, ibuprofen), n=4439NSAIDs (diclofenac, ibuprofen), n=4439

% o

f P

atie

nts

% o

f P

atie

nts

DaysDays

PP

JJ

p = 0.601, by log rank testp = 0.601, by log rank test

JJ

00

JJ

A31

CV Safety in RCTs - ConclusionsCV Safety in RCTs - Conclusions

No association for increased CV risk No association for increased CV risk detected with use of celecoxib up to 1 yr detected with use of celecoxib up to 1 yr compared to: compared to: – NSAIDs combined NSAIDs combined – naproxen, diclofenac or ibuprofen individuallynaproxen, diclofenac or ibuprofen individually

A dose-related increase in CV risk with A dose-related increase in CV risk with celecoxib is not observedcelecoxib is not observed

A32

Overview Overview









A33

0.00.0

1.01.0

2.02.0

3.03.0

CV dea

th, M

I, st

roke

CV dea

th, M

I, st

roke

CV dea

th

CV dea

th MIMI

Stroke

Stroke

Eve

nts

per

100

pt

yrs

Eve

nts

per

100

pt

yrs

0.00.0

1.01.0

2.02.0

3.03.0

CV dea

th, M

I, st

roke

CV dea

th, M

I, st

roke

CV dea

th

CV dea

th MIMI

Stroke

Stroke

No Risk Factors (n = 21,974)No Risk Factors (n = 21,974)

Celecoxib Celecoxib 200 mg 200 mg NSAIDsNSAIDs

CV Death, MI and Stroke:CV Death, MI and Stroke:Celecoxib vs. NSAIDs – By CV Risk Factors*Celecoxib vs. NSAIDs – By CV Risk Factors*

*Hypertension, diabetes, hyperlipidemia, CHD *Hypertension, diabetes, hyperlipidemia, CHD

1 Risk Factor (n = 6,710)1 Risk Factor (n = 6,710) 2 Risk Factors (n = 5,079)2 Risk Factors (n = 5,079)

A34 Celecoxib daily dose Celecoxib daily dose >> 200 mg 200 mg

CV Death, MI and Stroke:CV Death, MI and Stroke:Celecoxib vs. NSAIDs – By CV Risk Factors*Celecoxib vs. NSAIDs – By CV Risk Factors*

*Hypertension, diabetes, hyperlipidemia, CHD *Hypertension, diabetes, hyperlipidemia, CHD

No CV Risk FactorsNo CV Risk Factors 1 CV Risk Factor1 CV Risk Factor 2 CV Risk Factors2 CV Risk Factors

0.10.1 1.01.0 10.010.0Favors celecoxibFavors celecoxib Favors NSAIDsFavors NSAIDs


CV deathCV death

MIMI

StrokeStroke

0.10.1 1.01.0 10.010.0 0.10.1 1.01.0 10.010.0Favors celecoxibFavors celecoxib Favors NSAIDsFavors NSAIDs Favors celecoxibFavors celecoxib Favors NSAIDsFavors NSAIDs

Relative Risk (95%CI)Relative Risk (95%CI) Relative Risk (95%CI)Relative Risk (95%CI) Relative Risk (95%CI)Relative Risk (95%CI)

0.30.3 3.03.0 0.30.3 3.03.0 0.30.3 3.03.0

Cohort size = 21,974Cohort size = 21,974 Cohort size = 6,710Cohort size = 6,710 Cohort size = 5,079Cohort size = 5,079

A35

CV Death, MI and Stroke:CV Death, MI and Stroke:Celecoxib vs. NSAIDs – By Aspirin UseCelecoxib vs. NSAIDs – By Aspirin Use

Celecoxib daily dose Celecoxib daily dose >> 200 mg 200 mg

AspirinAspirinNo AspirinNo Aspirin

0.10.1 1.01.0 10.010.0


0.30.3 3.03.0 0.10.1 1.01.0 10.010.00.30.3 3.03.0

0.67 (0.40, 1.13)0.67 (0.40, 1.13)

0.60 (0.29, 1.24)0.60 (0.29, 1.24)

1.17 (0.44, 3.09)1.17 (0.44, 3.09)

0.41 (0.13, 1.25)0.41 (0.13, 1.25)


CV deathCV death

MIMI

StrokeStroke

1.17 (0.65, 2.12)1.17 (0.65, 2.12)

1.73 (0.31, 9.79)1.73 (0.31, 9.79)

1.74 (0.81, 3.73)1.74 (0.81, 3.73)

0.25 (0.06, 0.95)0.25 (0.06, 0.95)


Relative Risk (95%CI)Relative Risk (95%CI) Relative Risk (95%CI)Relative Risk (95%CI)

Cohort size = 29,954Cohort size = 29,954 Cohort size = 3,809Cohort size = 3,809

A36

PPPP

CV Death, MI and Stroke:CV Death, MI and Stroke:CLASS StudyCLASS Study

PPPP

P0P0 PP

PPPPPPPPPPPPPP

JJ

JJJJJJJJ

JJPPJJJJJJ

6060 9090 120120 150150 180180 210210 240240 270270 300300 330330 360360 390390303000

1.01.0

2.02.0

3.03.0

PP

JJ

No AspirinNo Aspirin

4.04.0

p p = 0.333= 0.333Log-rank testLog-rank test

% o

f P

atie

nts

% o

f P

atie

nts

Celecoxib 400 mg BID (n=3105)Celecoxib 400 mg BID (n=3105)NSAIDs (n=3124)NSAIDs (n=3124)

JJ

PP

6060 9090 120120 150150 180180 210210 240240 270270 300300 330330 360360 390390303000

1.01.0

2.02.0

3.03.0

AspirinAspirin

PP

JJ

PP

JJ

PP

JJ

PPJJ

JJ

JJ

JJ

JJ

JJJJ

JJJJJJ

JJ

JJJJ

PPPPPP

PP

PP

PP

PP

JJ

4.04.0

p p = 0.666= 0.666Log-rank testLog-rank test

Celecoxib 400 mg BID (n=882)Celecoxib 400 mg BID (n=882)NSAIDs (n=857)NSAIDs (n=857)

JJ

PP PP

DaysDays

A37

Risk Factors - ConclusionRisk Factors - Conclusion

The CV safety profile of celecoxib remains The CV safety profile of celecoxib remains comparable to NSAIDs regardless of CV risk comparable to NSAIDs regardless of CV risk factors factors

– as determined by medical history or use as determined by medical history or use of low dose aspirinof low dose aspirin

A38

Overview Overview









A39

Risk of Risk of MI with COXIBsMI with COXIBs

Ray WA et al. Ray WA et al. Lancet 2002Lancet 2002

Mamdani M et al. Mamdani M et al. Arch Intern Med 2003Arch Intern Med 2003

Solomon DH et al. Solomon DH et al. Circulation 2004Circulation 2004

Kimmel SE Kimmel SE et al. et al. Ann Intern Med 2005Ann Intern Med 2005

Graham DJ et al. Graham DJ et al. Lancet 2005Lancet 2005

Lévesque LE et al.Lévesque LE et al. Ann Intern Med 2005Ann Intern Med 2005

Shaya FT et al.Shaya FT et al. Arch Intern Med 2005Arch Intern Med 2005

A40

Risk of MI and UseRisk of MI and Use of COXIBs of COXIBs

Epidemiological StudiesEpidemiological Studies

Number of events*Number of events*

TotalTotal 30,36730,367

CelecoxibCelecoxib 1,0051,005

Number of patientsNumber of patients CohortCohort Case-controlCase-control

TotalTotal 2,135,8672,135,867 12,613 / 50,38012,613 / 50,380

CelecoxibCelecoxib 94,16994,169 443 / 1,802443 / 1,802

Person-yearsPerson-years

TotalTotal 2,795,4522,795,452 NANA

CelecoxibCelecoxib 12,64712,647††

Source dataSource data Cohort/nested - Mamdani M, Ray WA, Graham DJ, Shaya FT, Cohort/nested - Mamdani M, Ray WA, Graham DJ, Shaya FT, Lévesque LELévesque LECase-control - Solomon DH, Kimmel SECase-control - Solomon DH, Kimmel SE

* Ray WA and Graham DJ include MI and CHD death. Kimmel SE non-fatal MI only* 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.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.Number of cases exposed to celecoxib not provided in Shaya FT.

A41

1.701.70

11

0.930.930.910.91

1.031.03

0.960.96 0.940.94

00

11

22

33

Non-useNon-use naproxennaproxen celecoxibcelecoxib

>>300mg300mgrofecoxibrofecoxib

>25mg>25mg

Ad

just

ed

Ra

te R

ati

oA

dju

ste

d R

ate

Ra

tio

Ray et al. Lancet 2002; 360:1071-73Ray et al. Lancet 2002; 360:1071-73

ibuprofenibuprofen celecoxibcelecoxib

<300mg<300mgrofecoxibrofecoxib

<<25mg25mg

Relative Risk of Relative Risk of MI/Coronary DeathMI/Coronary Death: : Use of COXIBs or NSAIDs vs. Non-useUse of COXIBs or NSAIDs vs. Non-use

mean age >60 yrsmean age >60 yrs66% women66% women37% with Hx of major CV disease 37% with Hx of major CV disease

Celecoxib Celecoxib 22,337 users22,337 users 3 months mean exposure3 months mean exposure

A42 Mamdani et al. Arch Intern Med 2003;163:481-86Mamdani et al. Arch Intern Med 2003;163:481-86

Relative Risk of Relative Risk of MIMI: : Use of COXIBs or NSAIDs vs. Non-useUse of COXIBs or NSAIDs vs. Non-use

mean age >75 yrsmean age >75 yrs>56% women>56% women>5% with Hx of MI, >5% with Hx of MI, >9% with Hx of CHD>9% with Hx of CHD

Celecoxib Celecoxib 15,271 users15,271 users 5.5 months mean follow-up5.5 months mean follow-up

1.201.201.001.00

0.900.90

1.001.0011

00

11

22

33

Non-useNon-use celecoxibcelecoxib rofecoxibrofecoxib naproxennaproxen otherotherNSAIDsNSAIDs

Ad

just

ed

Ra

te R

ati

oA

dju

ste

d R

ate

Ra

tio

A43

Non-use Non-use celecoxibcelecoxib celecoxibcelecoxib<< 200 mg 200 mg

celecoxibcelecoxib> 200 mg> 200 mg

rofecoxibrofecoxib rofecoxibrofecoxib<< 25 mg 25 mg

rofecoxibrofecoxib> 25 mg> 25 mg

Solomon et al. Circulation 2004;109:2068-73 &Solomon et al. Circulation 2004;109:2068-73 &Arthritis Rheum 2003;48 (Suppl 9) S697 (Presentation Arthritis Rheum 2003;48 (Suppl 9) S697 (Presentation ACR Oct 2003)ACR Oct 2003)

Relative Risk of Relative Risk of MIMI: : Use of COXIBs vs. Non-useUse of COXIBs vs. Non-use

1.581.58

1.141.140.940.94

1.111.11

0.930.93 0.920.9211

00

11

22

33

Ad

just

ed

Od

ds

Ra

tio

Ad

just

ed

Od

ds

Ra

tio

mean age >80 yrsmean age >80 yrs77% women77% women57% with Hx of Htn57% with Hx of Htn14% with Hx of 14% with Hx of anginaangina9% with Hx of MI 9% with Hx of MI

A44 Kimmel et al. Ann Intern Med 2005; 142:157-164Kimmel et al. Ann Intern Med 2005; 142:157-164

Relative Risk of Relative Risk of MIMI: : Use of COXIBs or NSAIDs vs. Non-useUse of COXIBs or NSAIDs vs. Non-use

Ad

just

ed

Od

ds

Ra

tio

Ad

just

ed

Od

ds

Ra

tio

0.610.610.430.43

1.161.1611

00

11

22

33

Non-useNon-use celecoxibcelecoxib rofecoxibrofecoxib NSAIDsNSAIDs

mean age >52 yrsmean age >52 yrs59% women59% women31% with Hx of Htn31% with Hx of Htn4% with Hx of angina/CHD 4% with Hx of angina/CHD

A45

1.301.301.601.60

11 1.231.23

0.840.84

1.141.14

3.003.00

1.061.06

00

11

22

33

44

Remote

use

Remote

use

celecoxib

celecoxib

rofe

coxib

rofe

coxib << 25 m

g

25 mg

rofe

coxib >

25 mg

rofe

coxib >

25 mg

ibupro

fen

ibupro

fen

naproxen

naproxen

indom

ethacin

indom

ethacin

diclofe

nac

diclofe

nac

Ad

just

ed

Od

ds

Ra

tio

Ad

just

ed

Od

ds

Ra

tio

Relative Risk of Relative Risk of MI/Coronary DeathMI/Coronary Death: : Use of COXIBs or NSAIDs vs. Remote-useUse of COXIBs or NSAIDs vs. Remote-use

Graham et al. Lancet 2005;365:475-481Graham et al. Lancet 2005;365:475-481

mean age >66 yrsmean age >66 yrs38% women38% women1% with Hx of MI/ 1% with Hx of MI/ revascularizationrevascularization

A46

0.990.991.091.09 1.191.1911

00

11

22

33

Non-naproxenNon-naproxenNSAIDsNSAIDs

COXIBsCOXIBs celecoxibcelecoxib rofecoxibrofecoxib

Ad

just

ed O

dd

s R

atio

Ad

just

ed O

dd

s R

atio

Relative Risk of CV Death, MI or StrokeRelative Risk of CV Death, MI or StrokeUse of COXIBs vs. Non-Use of COXIBs vs. Non-naproxennaproxen NSAIDs NSAIDs

Shaya et al. Arch Intern Med 2005;165:181-6Shaya et al. Arch Intern Med 2005;165:181-6

11% >60 yrs11% >60 yrs70% women70% women43% with Hx of Htn43% with Hx of Htn12% with Hx of CV event 12% with Hx of CV event

A47

1.061.06 1.001.0011 1.001.000.980.98

1.171.171.211.21

1.731.73

00

11

22

33

Non-use

Non-use

celecoxib

celecoxib << 200 m

g

200 mg

celecoxib >

200 mg

celecoxib >

200 mg

rofe

coxib

rofe

coxib << 25 m

g

25 mg

rofe

coxib >

25 mg

rofe

coxib >

25 mg

naproxen

naproxen

melo

xicam

melo

xicam

other N

SAIDs

other N

SAIDs

Relative Risk of Relative Risk of MIMI::Use of COXIBs or NSAIDs vs. Use of COXIBs or NSAIDs vs. NonNon-use-use

Ad

just

ed

Ra

te R

ati

oA

dju

ste

d R

ate

Ra

tio

LévesqueLévesque et al. Ann Intern Med 2005;142(7), www.annals.org et al. Ann Intern Med 2005;142(7), www.annals.org

mean age >78 yrsmean age >78 yrs67% women67% women50% with Hx of Htn50% with Hx of Htn17% with Hx of CHD 17% with Hx of CHD

A48

Non-use

Non-use

Celec

oxib

Celec

oxib <<

200

mg

200

mg

Celec

oxib >

200

mg

Celec

oxib >

200

mg

Rofeco

xib

Rofeco

xib <<

25

mg

25

mg

Rofeco

xib >

25

mg

Rofeco

xib >

25

mg

Non-use

Non-use

Celec

oxib

Celec

oxib <<

200

mg

200

mg

Celec

oxib >

200

mg

Celec

oxib >

200

mg

Rofeco

xib

Rofeco

xib <<

25

mg

25

mg

Rofeco

xib >

25

mg

Rofeco

xib >

25

mg

1.041.04 1.161.161.381.38

1.231.23 1.001.00

0.910.91 0.800.80

2.362.36

11 11

00

11

22

33

44No ASA useNo ASA use ASA useASA use

Risk of MI by Risk of MI by ASA UseASA Use Relative Risk of COXIBs vs. Non-use Relative Risk of COXIBs vs. Non-use

Ad

just

ed

Ra

te R

ati

oA

dju

ste

d R

ate

Ra

tio

LévesqueLévesque et al. Ann Intern Med 2005;142(7), www.annals.org et al. Ann Intern Med 2005;142(7), www.annals.org

A49

1.231.23

3.003.00

0.940.94

11

0.920.920.960.96

1.031.03

0.980.98

1.111.11 1.211.21

0.940.94

1.001.00

1.701.70

1.581.58

1.731.73

00

11

22

33

44

Non-use

Non-use

Ray W

A

Ray W

A

Solom

on DH

Solom

on DH

Léves

que LE

Léves

que LE

Ray W

A

Ray W

A

Solom

on DH

Solom

on DH

Léves

que LE

Léves

que LE

Graham

DJ

Graham

DJ

Ray W

A

Ray W

A

Solom

on DH

Solom

on DH

Léves

que LE

Léves

que LE

Ray W

A

Ray W

A

Solom

on DH

Solom

on DH

Léves

que LE

Léves

que LE

Graham

DJ

Graham

DJ

Low doseLow dose High doseHigh dose**

celecoxibcelecoxib rofecoxibrofecoxib celecoxibcelecoxib rofecoxibrofecoxib

Summary of MI Risk by Dose:Summary of MI Risk by Dose:Relative Risk vs. Non-use/Remote UseRelative Risk vs. Non-use/Remote Use

*High-dose: *High-dose: rofecoxib >25 mgr/day rofecoxib >25 mgr/day celecoxib >200 mg/day in Solomon DH and Lévesque LE celecoxib >200 mg/day in Solomon DH and Lévesque LE celecoxib celecoxib >> 300 mg/day in Ray WA 300 mg/day in Ray WA

Re

lati

ve

Ris

kR

ela

tiv

e R

isk

A50

CV Epidemiology Studies - ConclusionsCV Epidemiology Studies - Conclusions

The risk of MI with celecoxib as used in the The risk of MI with celecoxib as used in the real world population (dose & duration) real world population (dose & duration)

– is consistently similar to nonselective is consistently similar to nonselective NSAIDs, and non- or remote use of NSAIDs, and non- or remote use of NSAIDsNSAIDs

– These findings are in contrast to These findings are in contrast to increased risk with rofecoxibincreased risk with rofecoxib

The available data suggest that the risk of The available data suggest that the risk of MI is similar for low and high celecoxib MI is similar for low and high celecoxib dosesdoses

A51

Overview Overview





– Risk FactorsRisk Factors

– Epidemiology StudiesEpidemiology Studies

– Considerations of MechanismConsiderations of Mechanism


A52

Potential Mechanism(s) of CV Risk Potential Mechanism(s) of CV Risk

Hypothesis that attributes CV risk to COXIBs only;Hypothesis that attributes CV risk to COXIBs only;

Could explainCould explain– VIGOR, APPROVe and APC results VIGOR, APPROVe and APC results

Could not explain consistent comparability Could not explain consistent comparability between celecoxib and NSAIDsbetween celecoxib and NSAIDs– meta-analysismeta-analysis– vs non-use in epidemiology studiesvs non-use in epidemiology studies

Could not explain Pre-SAP and ADAPT results Could not explain Pre-SAP and ADAPT results

A53

Potential MechanismsPotential Mechanisms

NSAIDs may not provide ‘effective’ blockade NSAIDs may not provide ‘effective’ blockade of platelets – even though TxAof platelets – even though TxA2 2 production production

is reducedis reduced Does not account for other PGs produced Does not account for other PGs produced

from COX-2 (e.g. PGEfrom COX-2 (e.g. PGE22, TxA, TxA22))

Can PGICan PGI22/TxA/TxA22 imbalance lead to imbalance lead to

prothrombotic potential?prothrombotic potential?

A54

PP

*Significant difference from baseline; p<0.05 *Significant difference from baseline; p<0.05

HH Celecoxib 400 mg (n=9)Celecoxib 400 mg (n=9)BB Placebo (n=7)Placebo (n=7)

JJ Celecoxib 100 mg (n=7)Celecoxib 100 mg (n=7) FF Celecoxib 800 mg (n=7)Celecoxib 800 mg (n=7)

Ibuprofen 800 mg (n=7)Ibuprofen 800 mg (n=7)

HoursHours

**

BB BBHHFF FF FF

PP

PP

-100-100

-80-80

-60-60

-40-40

-20-20

00

2020

Pre-Pre-DoseDose

22 44 6600 242488

% (

Mea

n C

han

ge

% (

Mea

n C

han

ge

S

E)

SE

)

BB JJ

Platelet AggregationPlatelet Aggregation

Pharmacologic Responses to Celecoxib Pharmacologic Responses to Celecoxib and Ibuprofen and Ibuprofen

JJHHFFPP JJ HHJJ BBPPHH

McAdam et al. PNAS 1999;96:272-277McAdam et al. PNAS 1999;96:272-277**Significantly different from placebo; p<0.05

00

2525

5050

7575

100100

125125

150150

175175

200200

4-6 hrs 6-12 hrs

Urinary PGI-M

pg

/ mg

cre

atin

ine

NRNR NRNR

******** **** **** ****

****

NR = not reported

A55

PGIPGI22 TxATxA22 PGEPGE22

MMPsMMPs

Plaque stabilityPlaque stability

Endothelial Endothelial functionfunction

Platelet Platelet aggregationaggregation

Endothelial Endothelial functionfunction

Platelet Platelet aggregationaggregation

COX-2 Prostaglandins Linked to CV DiseaseCOX-2 Prostaglandins Linked to CV Disease

COX-2 expressionCOX-2 expression

A56 Walter M et al. Atherosclerosis 177 (2004) 235-243Chikani G et al. Am J Physiol Endocrinol Metab 287 (2004): E386-E389

Rofecoxib and/or Reactive Metabolites

↑Ox-LDL↑F2-Isoprostanes

↑Blood Pressure /↑Atherothrombosis

↓Nitric Oxide Bioavailability

Putative Novel Rofecoxib Pathways Leading to Increased HTN and CV Risk

A57

24-Hour Mean SBP Change at 6 &12 Wks 24-Hour Mean SBP Change at 6 &12 Wks in OA Hypertensive Patientsin OA Hypertensive Patients

Sowers et al. Arch Int Med; 2005;165:161-168Sowers et al. Arch Int Med; 2005;165:161-168

-3-3

-2-2

-1-1

00

11

22

33

44

55

66

CelecoxibCelecoxib200 mg qd200 mg qd

n=136n=136

RofecoxibRofecoxib25 mg qd25 mg qd

n=138n=138

NaproxenNaproxen500 mg bid500 mg bid

n=130n=130

Mea

n S

BP

Ch

ang

e (m

m H

g)

Mea

n S

BP

Ch

ang

e (m

m H

g)

6 Wks6 Wks 12 Wks12 Wks 6 Wks6 Wks 12 Wks12 Wks 6 Wks6 Wks 12 Wks12 Wks

****

* p < 0.05 vs other treatments* p < 0.05 vs other treatments

SBP from ABPM dataSBP from ABPM data

A58

Mechanism SummaryMechanism Summary

It is not established that PGIIt is not established that PGI22/TxA/TxA22 imbalance imbalance

contributes to effects observed for COXIBs or contributes to effects observed for COXIBs or NSAIDsNSAIDs

Furthermore, the underlying pharmacology is Furthermore, the underlying pharmacology is more complex involving other PGs and more complex involving other PGs and pathways and raises the potential for benefit pathways and raises the potential for benefit with a COX-2 blockadewith a COX-2 blockade

Evidence for molecule-specific mechanisms is Evidence for molecule-specific mechanisms is emerging emerging

A59

Overview Overview





– Risk FactorsRisk Factors

– Epidemiology StudiesEpidemiology Studies

– Considerations of Mechanism Considerations of Mechanism


A60

Summary of GI and CV Safety Summary of GI and CV Safety

Celecoxib vs NSAIDsCelecoxib vs NSAIDs– GI safetyGI safety

RCTs: lower incidence of clinically significant GI RCTs: lower incidence of clinically significant GI outcomesoutcomes

Epidemiology studies: similar risk of Epidemiology studies: similar risk of hospitalization for GI bleeding vs non-users hospitalization for GI bleeding vs non-users

– CV safetyCV safety RCTs: comparable CV safety profileRCTs: comparable CV safety profile Epidemiology studies: similar CV risk Epidemiology studies: similar CV risk

vs non-usersvs non-users

A61

Risk-Benefit of Celecoxib in Arthritis - Risk-Benefit of Celecoxib in Arthritis - ConclusionsConclusions

In the currently approved arthritis indications, In the currently approved arthritis indications, the risk-benefit of celecoxib remains positive the risk-benefit of celecoxib remains positive relative to NSAIDsrelative to NSAIDs– Comparable efficacy Comparable efficacy – GI safety benefit GI safety benefit – Comparable CV riskComparable CV risk

Shared uncertainty of the CV safety beyond Shared uncertainty of the CV safety beyond 1 year of continuous treatment 1 year of continuous treatment

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

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