a risk-benefit analysis of the use of nsaids in the management of arthritis anne-barbara mongey, md,...

A Risk-Benefit Analysis of the A Risk-Benefit Analysis of the use of NSAIDs in the use of NSAIDs in the

Management of ArthritisManagement of Arthritis

A Risk-Benefit Analysis of the A Risk-Benefit Analysis of the use of NSAIDs in the use of NSAIDs in the

Management of ArthritisManagement of Arthritis

Anne-Barbara Mongey, MD, DCH, MRCPIAnne-Barbara Mongey, MD, DCH, MRCPI

Associate Professor of Internal MedicineAssociate Professor of Internal Medicine

University of CincinnatiUniversity of Cincinnati

Risk of GI Complications and Death Risk of GI Complications and Death With Nonspecific NSAIDs With Nonspecific NSAIDs

Risk of GI Complications and Death Risk of GI Complications and Death With Nonspecific NSAIDs With Nonspecific NSAIDs

GI Ulcers/Bleeding/Perforation (FDA Data) :

1% patients ≥ 6 months of NSAID use

2-4% patients ≥ I year of NSAID use

103,000 hospitalizations and 16,500 103,000 hospitalizations and 16,500 deaths annually related to nonspecific deaths annually related to nonspecific NSAID use NSAID use (Wolfe et al. N Engl J Med 1999)(Wolfe et al. N Engl J Med 1999)

GI Risks of NS-NSAIDsGI Risks of NS-NSAIDsGI Risks of NS-NSAIDsGI Risks of NS-NSAIDs

With at least 2 months of NSAID or ASA treatment :-With at least 2 months of NSAID or ASA treatment :-

1 in 5 patients will have an ulcer verified by EGD 1 in 5 patients will have an ulcer verified by EGD 1 in 70 patients will have a symptomatic ulcer1 in 70 patients will have a symptomatic ulcer 1 in 150 patients will have a bleeding ulcer1 in 150 patients will have a bleeding ulcer 1 in 1200 patients will die of a bleeding ulcer1 in 1200 patients will die of a bleeding ulcer

Tramer et al. Pain. 2000;85:169-182.

Odds Ratio (OR) of Subjects Taking Analgesics Odds Ratio (OR) of Subjects Taking Analgesics Developing UGI Bleeding*Developing UGI Bleeding*

Odds Ratio (OR) of Subjects Taking Analgesics Odds Ratio (OR) of Subjects Taking Analgesics Developing UGI Bleeding*Developing UGI Bleeding*

CI=confidence interval.*Analysis involved subjects with upper and lower GI bleeding.Blot et al. J Epidemiol Biostat. 2000;5:137-142.

Analgesic Analgesic (Prescription and OTC)(Prescription and OTC)

% % Cases Cases (n=627)(n=627)

% % Controls Controls (n=590)(n=590) OROR 95% CI 95% CI

Over-the-counter (OTC) Over-the-counter (OTC)

ASAASA 2727 1212 2.72.7 1.9-3.8 1.9-3.8

IbuprofenIbuprofen 10.110.1 5.85.8 2.42.4 1.5-3.9 1.5-3.9

AcetaminophenAcetaminophen 4.54.5 6.36.3 0.90.9 0.5-1.6 0.5-1.6

Total OTC NSAIDsTotal OTC NSAIDs 36.236.2 17.517.5 33 2.2-4.1 2.2-4.1

Rx NS-NSAIDsRx NS-NSAIDs 9.39.3 5.95.9 2.12.1 1.2-3.4 1.2-3.4

Total NSAIDsTotal NSAIDs 42.942.9 2222 3.13.1 2.3-4.1 2.3-4.1

Without symptoms With symptoms

58%

42%

81%19%

Majority of Nonselective NSAID-Related Majority of Nonselective NSAID-Related GI Complications Are AsymptomaticGI Complications Are Asymptomatic

Majority of Nonselective NSAID-Related Majority of Nonselective NSAID-Related GI Complications Are AsymptomaticGI Complications Are Asymptomatic

Armstrong CP, Blower AL. Gut. 1987;28:527-532. Singh G et al. Arch Intern Med. 1996;156:1530-1536

Introduction of COX-2–Specific Introduction of COX-2–Specific InhibitorsInhibitors

Introduction of COX-2–Specific Introduction of COX-2–Specific InhibitorsInhibitors

CH3

F3C

N N

SO

O NH2

S

CH3

O

O

O

O

CelecoxibCelecoxib RofecoxibRofecoxib ValdecoxibValdecoxib

NO

CH3

Sulfone-basedSulfonamide-based Sulfonamide-based

SO

O NH2

Study Design: Study Design: CLASS Trial vs VIGOR TrialCLASS Trial vs VIGOR TrialStudy Design: Study Design: CLASS Trial vs VIGOR TrialCLASS Trial vs VIGOR Trial

CLASS TrialCLASS Trial

OA and RA patientsOA and RA patients

Allowed aspirin useAllowed aspirin use

Minimum duration: Minimum duration: 6 months6 months

Celecoxib 400mgs BIDCelecoxib 400mgs BID

Comparators:Comparators: Ibuprofen 800 mg TIDIbuprofen 800 mg TID Diclofenac 75 mg BIDDiclofenac 75 mg BID

VIGOR TrialVIGOR Trial

RA patientsRA patients

No aspirin allowedNo aspirin allowed

Minimum duration: Minimum duration: 6 months6 months

Rofecoxib 50mgs qd Rofecoxib 50mgs qd

Comparator:Comparator:

Naproxen 500 mg BIDNaproxen 500 mg BID

Silverstein FE et al. JAMA. 2000;284:1247-1255.

An

nu

aliz

ed in

cid

ence

(%

)(p

er N

o. o

f p

atie

nt-

year

s)

0

1

2

3

4

Upper GI ulcercomplications

Complications andsymptomatic ulcers

P=.09

P=.02

0.76%

1.45%

2.08%

3.54%

CLASS: UGI Ulcer Complications and Symptomatic Ulcers at 6 Months—All Patients

CLASS: UGI Ulcer Complications and Symptomatic Ulcers at 6 Months—All Patients

Nonspecific NSAIDs* (n=3981)

Celecoxib 400 mg BID(n=3987)

0

1

2

3

4

P=.04

P=.02

0.44%

1.27%1.40%

2.91%

CLASS: Ulcer Complications and Symptomatic CLASS: Ulcer Complications and Symptomatic Ulcers at 6 MonthsUlcers at 6 Months——Nonusers of ASANonusers of ASA

CLASS: Ulcer Complications and Symptomatic CLASS: Ulcer Complications and Symptomatic Ulcers at 6 MonthsUlcers at 6 Months——Nonusers of ASANonusers of ASA

Nonspecific NSAIDs (n=3981)

Celecoxib 400 mg BID(n=3987)

Upper GI ulcercomplications

Complications andsymptomatic ulcers

An

nu

aliz

ed in

cid

ence

(%

)(p

er N

o. o

f p

atie

nt-

year

s)

Silverstein FE et al. JAMA. 2000;284:1247-1255.

SUCCESS=Successive Celecoxib Efficacy and Safety Study in OA.*Celecoxib 200 mg/day or 400 mg/day; †Diclofenac 50 mg BID or naproxen 500 mg BID.Singh G et al. Presented at: EULAR; June 13-16, 2001; Prague, Czech Republic.

SUCCESS-1: UGI Ulcer Complications SUCCESS-1: UGI Ulcer Complications and Symptomatic Ulcersand Symptomatic Ulcers

SUCCESS-1: UGI Ulcer Complications SUCCESS-1: UGI Ulcer Complications and Symptomatic Ulcersand Symptomatic Ulcers

0.1

0.8 1.0

2.1

0

1

2

3

4

Ulcer complications Complications andsymptomatic ulcers

RRR=87.5%P<.05

RRR=51.5%P<.05

An

nu

aliz

ed r

ate

(eve

nts

per

100

pat

ien

t-ye

ars)

Nonspecific NSAIDs† (n=4394)

Celecoxib*(n=8800)

GI Healthcare Resource UtilizationGI Healthcare Resource UtilizationSUCCESS-1SUCCESS-1

GI Healthcare Resource UtilizationGI Healthcare Resource UtilizationSUCCESS-1SUCCESS-1

–100

–80

–60

–40

–20

0

Physicianvisits

Specialistvisits

GIhospitalizations

ICUhospitalizations

Blood transfusions

*Celecoxib 200 mg/day or 400 mg/day; †Diclofenac 50 mg BID or naproxen 500 mg BID.Goldstein JL et al. Arthritis Rheum. 2001;44:S136. Abstract 503.

75%

52%

86%

34%45%

Few

er e

ven

ts

CelecoxibCelecoxib** vs Pooled Comparator NSAIDs vs Pooled Comparator NSAIDs††

Visits for upper GI

complications

%

Upper GI Safety of COX-2Upper GI Safety of COX-2 s specific pecific Inhibitor & Nonspecific NSAIDsInhibitor & Nonspecific NSAIDs

Upper GI Safety of COX-2Upper GI Safety of COX-2 s specific pecific Inhibitor & Nonspecific NSAIDsInhibitor & Nonspecific NSAIDs

An Ontario, Canada, population-based, retrospective An Ontario, Canada, population-based, retrospective cohort study:cohort study:

- Celecoxib (n=18,908)- Celecoxib (n=18,908)- Rofecoxib (n=14,583)- Rofecoxib (n=14,583)- Nonspecific NSAIDs (n=5391)- Nonspecific NSAIDs (n=5391)- Diclofenac + misoprostol (n=5087)- Diclofenac + misoprostol (n=5087)- Control (NSAID-naïve; n=100,000)- Control (NSAID-naïve; n=100,000)

Patients Patients 66 years of age 66 years of age

Main outcome measure:Main outcome measure:

Rate of hospitalization for upper GI hemorrhageRate of hospitalization for upper GI hemorrhage

Mamdani M et al. BMJ. 2002;325:624-627.

Adjusted Hazard Estimates for Hospitalization for UGI Adjusted Hazard Estimates for Hospitalization for UGI Hemorrhage Among Elderly Patients Using Prescribed Hemorrhage Among Elderly Patients Using Prescribed

NSAIDs NSAIDs

Adjusted Hazard Estimates for Hospitalization for UGI Adjusted Hazard Estimates for Hospitalization for UGI Hemorrhage Among Elderly Patients Using Prescribed Hemorrhage Among Elderly Patients Using Prescribed

NSAIDs NSAIDs P

atie

nts

Ho

spit

aliz

ed (

%)

Pat

ien

ts H

osp

ital

ized

(%

) 0.350.35

0.300.30

0.250.25

0.200.20

0.150.15

0.100.10

0.050.05

0.000.0000 6060 120120 180180 240240 295295

Time From index Date (days)Time From index Date (days)

Nonselective NSAIDsNonselective NSAIDs 4.0 (2.3 to 6.9)4.0 (2.3 to 6.9)Diclofenac + misoprostolDiclofenac + misoprostol 3.0 (1.7 to 5.6)3.0 (1.7 to 5.6)RofecoxibRofecoxib 1.9 (1.3 to 2.8)1.9 (1.3 to 2.8)CelecoxibCelecoxib 1.0 (0.7 to 1.6)1.0 (0.7 to 1.6)ControlsControls 1.01.0

Rate ratio (95% CI)Rate ratio (95% CI)

Mamdani et al. BMJ. 2002;325:624-627.

Celecoxib vs Diclofenac + Omeprazole Celecoxib vs Diclofenac + Omeprazole in Reducing the Risk of Recurrent in Reducing the Risk of Recurrent

Bleeding Ulcer in Patients with ArthritisBleeding Ulcer in Patients with Arthritis

Celecoxib vs Diclofenac + Omeprazole Celecoxib vs Diclofenac + Omeprazole in Reducing the Risk of Recurrent in Reducing the Risk of Recurrent

Bleeding Ulcer in Patients with ArthritisBleeding Ulcer in Patients with ArthritisDesignDesign

Prospective, double-blind randomized control trial Prospective, double-blind randomized control trial comparing celecoxib 200mgs BID with diclofenac comparing celecoxib 200mgs BID with diclofenac 75mgs BID plus omeprazole 20mgs qd75mgs BID plus omeprazole 20mgs qd

Patient PopulationPatient Population::

Patients with arthritis who presented with ulcer Patients with arthritis who presented with ulcer bleeding confirmed by EGDbleeding confirmed by EGD

OutcomeOutcome:: Recurrence of a bleeding ulcerRecurrence of a bleeding ulcer

Chan et al. N Engl J Med. 2002;347:2104-2110.

Chan et al. N Engl J Med. 2002;347:2104-2110.

Probability of Recurrent Bleeding Probability of Recurrent Bleeding Ulcer in 6 Months Ulcer in 6 Months

Probability of Recurrent Bleeding Probability of Recurrent Bleeding Ulcer in 6 Months Ulcer in 6 Months

CelecoxibCelecoxib 4.9% 4.9% ( (3.1-6.73.1-6.7) )

Omeprazole + Diclofenac Omeprazole + Diclofenac 6.4%6.4% ( (4.3-8.44.3-8.4) )

CelecoxibCelecoxib 4.5% 4.5% ((2.7-6.32.7-6.3) )

Omeprazole + Diclofenac Omeprazole + Diclofenac 5.6% 5.6% ((3.6-7.73.6-7.7) )

Without Without concomitant concomitant

ASAASA

All All patientspatients

Percent (95% CI)Percent (95% CI)00 22 44 66 88 1010

Therapeutic Arthritis Research and Therapeutic Arthritis Research and Gastrointestinal Event Trial (TARGET)Gastrointestinal Event Trial (TARGET)


RandomizationRandomization

ScreeningScreening


BaselineBaseline Week 52Week 52 Week 56Week 56

FinalFinalvisitvisit

Follow-upFollow-up

Ibuprofen 800 mg tidIbuprofen 800 mg tid

n=4415n=4415

n=4399n=4399

LumiracoxibLumiracoxib 400 mg qd400 mg qd

Naproxen 500 mg bidNaproxen 500 mg bid

n=4754n=4754

n=4757n=4757

Lumiracoxib 400 mg qdLumiracoxib 400 mg qd



52 week study of 18,325 Patients, aged ≥ 50 years, randomized for low-dose ASA use and age:

9,156 Lumiracoxib 400 mgs qd4,754 Naproxen 500 mgs BID4,415 Ibuprofen 800 mgs TID

Primary end point: difference in time-to-event distribution of upper GI ulcer complications

Incidence of ulcer complications among non ASA users:

NSAIDS: 1.09% (64 events)Lumiracoxib: 0.25% (14 events) * p<0.0001

Risk Factors for NSAID Risk Factors for NSAID Induced GI Adverse EventsInduced GI Adverse Events

The The National Institute for Clinical ExcellenceNational Institute for Clinical Excellence

Risk Factors for NSAID Risk Factors for NSAID Induced GI Adverse EventsInduced GI Adverse Events

The The National Institute for Clinical ExcellenceNational Institute for Clinical Excellence

• Age > 65 years• History of Peptic Ulcer Disease• History of GI Bleed• Concomitant Anticoagulant Usage• Concomitant Steroid Usage• High Dose NSAID Usage• Comorbid Medical Conditions

Available at: http://www.nice.org.uk//. Accessed September 22, 2005.Available at: http://www.nice.org.uk//. Accessed September 22, 2005.

Utilization of Gastroprotective Strategies by Utilization of Gastroprotective Strategies by Presence of GI Risk Factors Among New NSAID UsersPresence of GI Risk Factors Among New NSAID Users

Utilization of Gastroprotective Strategies by Utilization of Gastroprotective Strategies by Presence of GI Risk Factors Among New NSAID UsersPresence of GI Risk Factors Among New NSAID Users

Sturkenboom et al. Rheumatology. 2003;42(suppl 3):iii23-iii31.

≥≥22 Risk Factors Risk Factors1 Risk Factor1 Risk Factor

86.6% 81.2%

0.1%0.1% 2.5%2.5% 10.8%10.8% 0.2%0.2% 4.0%4.0% 14.7%14.7%

Coxib aloneCoxib alone NSAID+GPANSAID+GPA Coxib+GPACoxib+GPA No gastroprotectionNo gastroprotection

Cardiovascular Cardiovascular Thromboembolic Data:Thromboembolic Data:

Coronary Artery Disease Coronary Artery Disease

Cardiovascular Cardiovascular Thromboembolic Data:Thromboembolic Data:

Coronary Artery Disease Coronary Artery Disease

Serious Thromboembolic CV Adverse Serious Thromboembolic CV Adverse Events in ASA NonusersEvents in ASA Nonusers

Serious Thromboembolic CV Adverse Serious Thromboembolic CV Adverse Events in ASA NonusersEvents in ASA Nonusers

DaysDays00 4040 8080 120120 160160 200200 240240 280280 320320 360360

0.00.0

0.50.5

1.01.0

1.51.5

2.02.0

2.52.5

PP <.05 <.05

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

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

RR=2.38RR=2.38

Inci

den

ce o

f In

cid

ence

of

Th

rom

bo

emb

oli

c S

AE

s (%

) T

hro

mb

oem

bo

lic

SA

Es

(%)

Mukherjee et al. JAMA. 2001;286:954-959.

VIGORVIGOR

CLASS: Thromboembolic CV AEsCLASS: Thromboembolic CV AEsCLASS: Thromboembolic CV AEsCLASS: Thromboembolic CV AEsASA NonusersASA NonusersASA Users*ASA Users*

PP=.899=.899PP=.947=.947

00

0.50.5

1.01.0

1.51.5

2.02.0

2.52.5

3.03.0

3.53.5

4.54.5

5.05.0

4.04.0

00 4040 8080 120120 160160 200200 240240 280280 320320 360360

DaysDays

Celecoxib 400 mg bid (n=3105)Celecoxib 400 mg bid (n=3105)

NS-NSAIDs (n=3124)NS-NSAIDs (n=3124)

Celecoxib 400 mg bid (n=882)Celecoxib 400 mg bid (n=882)

NS-NSAIDs (n=857)NS-NSAIDs (n=857)

Pat

ien

ts (

%)

Pat

ien

ts (

%)

00 4040 8080 120120 160160 200200 240240 280280 320320 360360

DaysDays

00

0.50.5

1.01.0

1.51.5

2.02.0

2.52.5

3.03.0

3.53.5

4.54.5

5.05.0

4.04.0

White et al. White et al. Am J CardiolAm J Cardiol. 2002;89:425-430. Data on file. Pfizer Inc., New York, NY; FDA Advisory Committee Briefing Document. . 2002;89:425-430. Data on file. Pfizer Inc., New York, NY; FDA Advisory Committee Briefing Document. Available at: http://www.fda.gov/ohrms/dockets/ac/05/briefing/2005-4090B1_03_Pfizer-Celebrex-Bextra.pdf. Accessed January 12, Available at: http://www.fda.gov/ohrms/dockets/ac/05/briefing/2005-4090B1_03_Pfizer-Celebrex-Bextra.pdf. Accessed January 12, 2005. 2005.

COX-2COX-2––Specific Inhibitors, Nonselective Specific Inhibitors, Nonselective NSAIDs, and Risk of Serious CHDNSAIDs, and Risk of Serious CHD

COX-2COX-2––Specific Inhibitors, Nonselective Specific Inhibitors, Nonselective NSAIDs, and Risk of Serious CHDNSAIDs, and Risk of Serious CHD

DesignDesign

Retrospective observational study of Tennessee Medicaid dataRetrospective observational study of Tennessee Medicaid data

Matched for age, sex, and date NSAID use beganMatched for age, sex, and date NSAID use began

Patient PopulationPatient Population

202,916 nonusers (patients who had not used an NSAID within 202,916 nonusers (patients who had not used an NSAID within 365 days of enrollment) and 251,046 NSAID current users365 days of enrollment) and 251,046 NSAID current users

Patients aged 50-84 years without noncardiovascular life-threatening Patients aged 50-84 years without noncardiovascular life-threatening illnessesillnesses

OutcomeOutcome

Serious CHD, defined as hospital admission for AMI or death from CHD, in Serious CHD, defined as hospital admission for AMI or death from CHD, in patients taking rofecoxib, celecoxib, ibuprofen, and naproxenpatients taking rofecoxib, celecoxib, ibuprofen, and naproxen

Ray WA et al. Lancet. 2002;360:1071-1073.

COX-2–Specific Inhibitors, COX-2–Specific Inhibitors, NS-NSAIDs, and Risk of Serious CHDNS-NSAIDs, and Risk of Serious CHD

COX-2–Specific Inhibitors, COX-2–Specific Inhibitors, NS-NSAIDs, and Risk of Serious CHDNS-NSAIDs, and Risk of Serious CHD

† P = 0.024 vs reference; Ray WA et al. Lancet. 2002;360:1071-1073.

101Better than nonuser Worse than nonuser

0.1

Reference: Nonusers IRR = 1.0

Celecoxib (n = 4509)0.88 (0.67-1.16)

Rofecoxib >25 mg/day (n = 500)1.93 (1.09-3.43)†

Naproxen (n = 6489)0.92 (0.73-1.16)

Ibuprofen (n = 4319)1.01 (0.77-1.33)

Rofecoxib 25 mg/day (n = 3430)1.02 (0.76-1.37)

Risk of CV Events for Rofecoxib, Risk of CV Events for Rofecoxib, Celecoxib relative to Placebo & NSAIDsCelecoxib relative to Placebo & NSAIDs

Risk of CV Events for Rofecoxib, Risk of CV Events for Rofecoxib, Celecoxib relative to Placebo & NSAIDsCelecoxib relative to Placebo & NSAIDsDesignDesign

Population-based, retrospective cohort analysis of health Population-based, retrospective cohort analysis of health records in Ontario, Canadarecords in Ontario, Canada

Patient PopulationPatient Population::

Patients aged Patients aged ≥66 years with a prescription for celecoxib, ≥66 years with a prescription for celecoxib, rofecoxib, naproxen or non-naproxen NSAIDs rofecoxib, naproxen or non-naproxen NSAIDs

Control group was NSAID-naïve Control group was NSAID-naïve

OutcomeOutcome:: Hospitalization for acute myocardial infarction (AMI)Hospitalization for acute myocardial infarction (AMI)

Mamdani et al. Arch Interrn Med 2003; 163: 481-486

Decreased Incidence Increased Incidence

Risk of AMI with COX-2–Specific Inhibitors Risk of AMI with COX-2–Specific Inhibitors and NS-NSAIDs Compared With Nonusersand NS-NSAIDs Compared With Nonusers

Risk of AMI with COX-2–Specific Inhibitors Risk of AMI with COX-2–Specific Inhibitors and NS-NSAIDs Compared With Nonusersand NS-NSAIDs Compared With Nonusers

0.9

1.0

1.0

1.2

1.0

Mamdani et al. Arch Intern Med 2003; 163: 481-486

Celecoxib (n = 15,271)

Rofecoxib (n = 12,156)

Naproxen (n = 5669)

Non-naproxen NSAIDs(n = 33,868)

Nonusers (n = 100,000)

0.5 1.0 1.5 2.0

Risk for Myocardial Infarction in Risk for Myocardial Infarction in NSAID and Coxib Users NSAID and Coxib Users ≥ 65 Years≥ 65 Years

Risk for Myocardial Infarction in Risk for Myocardial Infarction in NSAID and Coxib Users NSAID and Coxib Users ≥ 65 Years≥ 65 Years

Observational, matched case-control, Observational, matched case-control, population-based study:population-based study:- 54,475 patients - 54,475 patients 65 years of age 65 years of age - received their medications through 2 state-received their medications through 2 state-

sponsored pharmaceutical benefits programsponsored pharmaceutical benefits program- matched for age, gender, and month of index date matched for age, gender, and month of index date

Main outcome measure:Main outcome measure:Relative risk of acute myocardial infarction Relative risk of acute myocardial infarction

Solomon et al. Circulation. 2004;109:2068-2073

Relative risk of AMI With Relative risk of AMI With COX-2COX-2––Specific InhibitorsSpecific InhibitorsRelative risk of AMI With Relative risk of AMI With COX-2COX-2––Specific InhibitorsSpecific Inhibitors

†p<0.05. Solomon et al. Circulation. 2004;109:2068-2073

Decreased Incidence

Rofecoxib all doses (vs no NSAID users)

Increased Incidence

Celecoxib all doses (vs no NSAID users)

Current Users

Rofecoxib >25mg (vs no NSAID users)

Rofecoxib <25mg (vs no NSAID users)

Rofecoxib all doses (vs celecoxib all doses )

Rofecoxib >25 mg (vs celecoxib >200 mg)

Rofecoxib <25 mg (vs celecoxib <200 mg)

0.5 1 1.5 2 2.5

0.93

1.14

1.58†

1.11

1.24†

1.70†

1.21†

Risk of Acute Cardiac Events among Patients Risk of Acute Cardiac Events among Patients treated with Coxibs & non-selective NSAIDstreated with Coxibs & non-selective NSAIDs

Risk of Acute Cardiac Events among Patients Risk of Acute Cardiac Events among Patients treated with Coxibs & non-selective NSAIDstreated with Coxibs & non-selective NSAIDs

All patients, aged 18-84 years, who received at least one NSAID prescription between 1/99 - 12/01:

Celecoxib (n= 40,405); Rofecoxib (n= 27,248) Ibuprofen (n= 991,261); Naproxen (n= 435,492)

Nested Case Control study Matched with living controls for index date,age,gender,region Conditional logistic regression analysis

Mean Age: 66.8 years; 61.8% were males

No. of Acute Cardiac Events: 8,143 (6635 AMI; 1508 SCD)

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

Risk of AMI and SCD With Current Use of Risk of AMI and SCD With Current Use of COX-2 Selective and NS-NSAIDsCOX-2 Selective and NS-NSAIDs

Risk of AMI and SCD With Current Use of Risk of AMI and SCD With Current Use of COX-2 Selective and NS-NSAIDsCOX-2 Selective and NS-NSAIDs

0.00.0

0.50.5

1.01.0

1.51.5

2.02.0

2.52.5

3.03.0

3.53.5

Control Control (remote use)(remote use)

CelecoxibCelecoxib IbuprofenIbuprofen NaproxenNaproxen RofecoxibRofecoxib>25 mg>25 mg

Other Other NSAIDsNSAIDs

IndomethacinIndomethacin DiclofenacDiclofenac

Adj

uste

dA

djus

ted†† O

dds

Rat

io (9

5% C

I) O

dds

Rat

io (9

5% C

I)

1.001.00(reference)(reference)

0.86 0.86 (0.69-1.07)(0.69-1.07)

1.09 1.09 (0.99-1.21)(0.99-1.21)

1.18 1.18 (1.04-1.35)(1.04-1.35)

3.15 3.15 (1.14-8.75)(1.14-8.75)

1.16 1.16 (1.04-1.30)(1.04-1.30)

1.33 1.33 (1.09-1.63)(1.09-1.63)

1.69 1.69 (0.97-2.93)(0.97-2.93)

PP=.01=.01 PP<.01<.01 PP=.005=.005

RofecoxibRofecoxib25 mg25 mg

1.291.29(0.93-1.79)(0.93-1.79)

PP<.01<.01

PP=.06=.06

Adjusted for age, sex, health plan region, medical history, smoking, and medication use.Adjusted for age, sex, health plan region, medical history, smoking, and medication use.Adapted from Graham et al. Adapted from Graham et al. LancetLancet. 2005;365:475-481.. 2005;365:475-481.

0.0

0.5

1.0

1.5

2.0

2.5

3.0

3.5

Ad

jus

ted*

Od

ds

Rat

io

Control (no use)

1.00(reference)

Naproxen

1.27

P =.04

Other ns-NSAIDs

1.21

P =.03

Other SelectiveNSAIDS

1.27

P =.046

Diclofenac

1.55

P <.001

Data for drugs prescribed within 3 months of the index date.*Adjusted for smoking, comorbidity, socioeconomic deprivation, ASA use, & comcomitant medication.Hippisley-Cox et al. BMJ. 2005.

Observational Case-control StudyObservational Case-control Study

Risk of MI among Patients receiving Risk of MI among Patients receiving COX-2 Selective Inhibitors & ns-NSAIDsCOX-2 Selective Inhibitors & ns-NSAIDs

Celecoxib

1.21

P =.11

Rofecoxib

1.32

P =.005

Ibuprofen

1.24

P <.001

p value of .01 was prespecified as significant

Cox-2 inhibitors & non-selective NSAIDs Cox-2 inhibitors & non-selective NSAIDs increase the risk of AMI in patients with increase the risk of AMI in patients with Arthritis: Selectivity is with the patients, Arthritis: Selectivity is with the patients,

not with the drug classnot with the drug class

Cox-2 inhibitors & non-selective NSAIDs Cox-2 inhibitors & non-selective NSAIDs increase the risk of AMI in patients with increase the risk of AMI in patients with Arthritis: Selectivity is with the patients, Arthritis: Selectivity is with the patients,

not with the drug classnot with the drug class

PPatients > 18 years with physician-diagnosed arthritis atients > 18 years with physician-diagnosed arthritis treated with a NSAID between 1/1/99 - 6/30/04treated with a NSAID between 1/1/99 - 6/30/04

Nested case control study Nested case control study

Cases of acute myocardial infarction were risk-set matched Cases of acute myocardial infarction were risk-set matched with 4 controls with 4 controls forfor age, gender and index date age, gender and index date

Analyses were adjusted for 38 confounding risk factors as Analyses were adjusted for 38 confounding risk factors as well as concomitant aspirin treatment.well as concomitant aspirin treatment.

Singh G et al. Abstract - EULAR 2005

Medi-Cal: NSAIDs and Risk for AMIMedi-Cal: NSAIDs and Risk for AMIMedi-Cal: NSAIDs and Risk for AMIMedi-Cal: NSAIDs and Risk for AMI

0 0.2 0.4 0.6 0.8 1 1.2 1.4 1.6 1.8

2,356,885 person-years of follow-up; 15,343 cases of AMI2,356,885 person-years of follow-up; 15,343 cases of AMI

OR for AMI (95% CI)OR for AMI (95% CI)

Singh et al. EULAR. 2005. Singh et al. EULAR. 2005.

0.83 (0.60-1.14); 0.83 (0.60-1.14); PP=.26=.26

0.99 (0.72-1.37); 0.99 (0.72-1.37); PP=.97=.97

1.08 (0.95-1.22); 1.08 (0.95-1.22); PP=.22=.22

1.09 (1.02-1.15); 1.09 (1.02-1.15); PP<.008<.008

1.11 (1.01-1.22); 1.11 (1.01-1.22); PP<.02<.02

1.32 (1.22-1.42); 1.32 (1.22-1.42); PP<.0001<.0001

1.37 (1.05-1.78); 1.37 (1.05-1.78); PP<.02<.02

1.41 (1.01-1.96); 1.41 (1.01-1.96); PP<.04<.04

1.71 (1.35-2.17); 1.71 (1.35-2.17); PP<.0001<.0001

1.00 (reference)1.00 (reference)

NabumetoneNabumetone

ValdecoxibValdecoxib

NaproxenNaproxen

CelecoxibCelecoxib

IbuprofenIbuprofen

RofecoxibRofecoxib

MeloxicamMeloxicam

SulindacSulindac

IndomethacinIndomethacin

Remote useRemote use

APPROVe StudyAPPROVe StudyAPPROVe StudyAPPROVe Study

Multicenter, randomized, placebo-controlled, double-blinded 3 year study of Rofecoxib 25 mgs qd. (2/2000-11/2001)

Primary End point: Recurrence of colorectal adenomas of the large bowel in patients with a history of colorectal adenomas

Inclusion criteria: ≥ 1 adenomas; ≥ 40 years;

Exclusion criteria: angina; CHF; uncontrolled HTN; MI, PTCA

or CABG within 1 yr or CVA/TIA within 2 yrs of study entry

Low dose ASA allowed in up to 20% Bresalier et al. Bresalier et al. N Engl J MedN Engl J Med. 2005;352. 2005;352

APPROVe Study APPROVe Study APPROVe Study APPROVe Study

2586 Patients: 62% male; mean age = 59 years;

72 confirmed thrombotic events: Rofecoxib (n=46) : 1.5 events/100 patient yearsPlacebo (n=26) : 0.78 events/100 patient years

Relative risk: 1.92 (95% CI 1.19, 3.11; p=0.008)

52 events by APTC criteria:

Relative risk: 2.06 (95% CI 1.16, 3.64; p=0.008)

Increased relative risk occurred after 18 months of therapy

No difference in overall Mortality

APPROVe: Cumulative Incidence of APPROVe: Cumulative Incidence of Confirmed Serious Thrombotic CV Events*Confirmed Serious Thrombotic CV Events*

APPROVe: Cumulative Incidence of APPROVe: Cumulative Incidence of Confirmed Serious Thrombotic CV Events*Confirmed Serious Thrombotic CV Events*

Bresalier et al. N Engl J Med. 2005;352:1092-1102.

00 66 1212 1818 2424 3030 3636

PP=.008=.008

Cum

ulat

ive

Inci

denc

e of

Con

firm

ed

Cum

ulat

ive

Inci

denc

e of

Con

firm

ed

Thro

mbo

tic E

vent

s (%

)Th

rom

botic

Eve

nts

(%)

00

11

22

33

44

55

66

MonthMonth

RofecoxibRofecoxibPlaceboPlacebo 12991299 11951195 11561156 10791079 10421042 10011001 835835

12871287 11291129 10571057 989989 938938 896896 727727No. at RiskNo. at Risk

Rofecoxib 25 mg qd Rofecoxib 25 mg qd 1.92 (1.19-3.11) 1.92 (1.19-3.11)

PlaceboPlacebo

* Fatal and nonfatal MI, unstable angina, sudden death due to cardiac causes, fatal and nonfatal ischemic stroke, * Fatal and nonfatal MI, unstable angina, sudden death due to cardiac causes, fatal and nonfatal ischemic stroke, transient ischemic attack, peripheral arterial thrombosis, peripheral venous thrombosis, and pulmonary embolismtransient ischemic attack, peripheral arterial thrombosis, peripheral venous thrombosis, and pulmonary embolism

Bars represent 95% CI.

Adenoma Prevention with Adenoma Prevention with Celecoxib (APC) TrialCelecoxib (APC) Trial


Prospective, randomized, placebo-controlled, double-blinded multicenter trial comparing the efficacy and safety of celecoxib

Primary End point: Recurrence of adenomatous polyps of the large bowel in patients who had undergone polypectomy

Participants: 2035 patients, aged 32-88 years

Follow-up: 2.8-3.1 years

Solomon et al. N Engl J Med. 2005;352-362.



Solomon et al. N Engl J Med. 2005;352-362.

AgentAgent n/Nn/N % of % of patientspatients

Relative risk Relative risk compared with compared with

placeboplacebo

95% 95% confidence confidence

intervalsintervals

PlaceboPlacebo 6/6796/679 0.9%0.9% ------ ------

Celecoxib Celecoxib 200 mgs bid200 mgs bid

15/68515/685 2.2%2.2% 2.3*2.3* 0.9-5.50.9-5.5

Celecoxib Celecoxib 400 mgs bid400 mgs bid

20/67120/671 3.0%3.0% 3.4*3.4* 1.4-7.81.4-7.8

Average duration of treatment = 33 monthsAverage duration of treatment = 33 months

* Statistically significant* Statistically significant

Fatal and nonfatal cardiovascular eventsFatal and nonfatal cardiovascular events

Celecoxib Colon Polyp Prevention Trials: Composite End Celecoxib Colon Polyp Prevention Trials: Composite End Point (Death From CV Causes, MI, Stroke, or Heart Failure)Point (Death From CV Causes, MI, Stroke, or Heart Failure)Celecoxib Colon Polyp Prevention Trials: Composite End Celecoxib Colon Polyp Prevention Trials: Composite End

Point (Death From CV Causes, MI, Stroke, or Heart Failure)Point (Death From CV Causes, MI, Stroke, or Heart Failure)

00 66 1212 1818 2424 3030 36360.0000.000

0.0100.010

0.0200.020

0.0300.030

0.0400.040

0.0500.050

Estim

ated

Pro

babi

lity

of C

umul

ativ

e Es

timat

ed P

roba

bilit

y of

Cum

ulat

ive

Com

posi

te E

nd P

oint

Com

posi

te E

nd P

oint PP=.01=.01

Solomon et al. Solomon et al. N Engl J MedN Engl J Med. 2005;352:1071-1080; Levin. February 17, 2005. Gaithersburg, Md.. 2005;352:1071-1080; Levin. February 17, 2005. Gaithersburg, Md.

Adenoma Prevention with Celecoxib trialAdenoma Prevention with Celecoxib trial

Months After First DoseMonths After First Dose

Celecoxib Celecoxib 400 mg bid400 mg bidCelecoxib Celecoxib 200 mg bid200 mg bid

PlaceboPlacebo 679679 677677 675675 672672 668668 667667 585585

685685 681681 676676 675675 673673 670670 595595

671671 669669 665665 655655 651651 648648 576576

No. at RiskNo. at Risk

Celecoxib 400 mg bid 3.4 (1-4-7.8)Celecoxib 400 mg bid 3.4 (1-4-7.8)

PlaceboPlacebo

Celecoxib 200 mg bid 2.3 (0.9-5.5) Celecoxib 200 mg bid 2.3 (0.9-5.5)

0.9%0.9%

2.2%2.2%

3.0%3.0%

Prevention of Spontaneous Prevention of Spontaneous Adenomatous Polyposis (PreSAP) Adenomatous Polyposis (PreSAP)

TrialTrial

Prevention of Spontaneous Prevention of Spontaneous Adenomatous Polyposis (PreSAP) Adenomatous Polyposis (PreSAP)

TrialTrial

AgentAgent n/Nn/N % of % of patientspatients

Relative risk Relative risk compared with compared with

placeboplacebo

95% 95% confidence confidence

intervalinterval

PlaceboPlacebo 12/62812/628 1.9%1.9% ------ ------

Celecoxib Celecoxib 400 mg qd400 mg qd

20/93320/933 2.1%2.1% 1.11.1 0.6-2.30.6-2.3

Fatal and nonfatal cardiovascular eventsFatal and nonfatal cardiovascular events

Average duration of treatment = 33 monthsAverage duration of treatment = 33 months

Celecoxib Colon Polyp Prevention Trials: Composite End Celecoxib Colon Polyp Prevention Trials: Composite End Point (Death From CV Causes, MI, Stroke, or Heart Failure)Point (Death From CV Causes, MI, Stroke, or Heart Failure)Celecoxib Colon Polyp Prevention Trials: Composite End Celecoxib Colon Polyp Prevention Trials: Composite End

Point (Death From CV Causes, MI, Stroke, or Heart Failure)Point (Death From CV Causes, MI, Stroke, or Heart Failure)

00 66 1212 1818 2424 3030 36360.0000.000

0.0100.010

0.0200.020

0.0300.030

0.0400.040

0.0500.050

Estim

ated

Pro

babi

lity

of C

umul

ativ

e Es

timat

ed P

roba

bilit

y of

Cum

ulat

ive

Com

posi

te E

nd P

oint

Com

posi

te E

nd P

oint

PP=.10=.10

Solomon et al. Solomon et al. N Engl J MedN Engl J Med. 2005;352:1071-1080; Levin. February 17, 2005. Gaithersburg, Md.. 2005;352:1071-1080; Levin. February 17, 2005. Gaithersburg, Md.

Prevention of Spontaneous Adenomatous Prevention of Spontaneous Adenomatous Polyps trialPolyps trial

Months After First DoseMonths After First Dose

Celecoxib Celecoxib 400 mg qd400 mg qd

PlaceboPlacebo 828828 823823 620620 618618 618618 453453

929929 925925 923923 917917 914914 688688

No. at RiskNo. at Risk

Celecoxib 400 mg qd 1.1 (0.6-2.3)Celecoxib 400 mg qd 1.1 (0.6-2.3)

PlaceboPlacebo2.1%2.1%

1.9%1.9%

TARGET—Study DesignTARGET—Study DesignTARGET—Study DesignTARGET—Study Design


ScreeningScreening


BaselineBaseline Week 52Week 52 Week 56Week 56

FinalFinalvisitvisit

Follow-upFollow-up

Ibuprofen 800 mg tidIbuprofen 800 mg tid

n=4415n=4415

n=4399n=4399

LumiracoxibLumiracoxib 400 mg qd400 mg qd

Naproxen 500 mg bidNaproxen 500 mg bid

n=4754n=4754

n=4757n=4757

Lumiracoxib 400 mg qdLumiracoxib 400 mg qd

TARGET=the Therapeutic Arthritis Research and Gastrointestinal Event Trial.



Primary end point: APTC endpoint (MI, CVA, CV death)

NSAIDS: 0.55% (50 events) Lumiracoxib: 0.65% (59 events) (p=0.5074)

Myocardial Infarction:

Lumiracoxib: 0.38% (18) vs Naproxen: 0.21% (10)

Lumiracoxib: 0.11% (5) vs Ibuprofen: 0.16% (7)

Lumiracoxib: APTC End Point in the Lumiracoxib: APTC End Point in the Overall PopulationOverall Population

Lumiracoxib: APTC End Point in the Lumiracoxib: APTC End Point in the Overall PopulationOverall Population

*Log-rank test for treatment group comparison based on a stratified test with the strata sub-study and low-dose ASA use. APTC=Antiplatelet Trialists’ Collaboration.Farkouh et al. Lancet. 2004;364:675-684.

00

1.01.0

6060

Cu

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ate

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)C

um

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Inc

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Ra

te (

%)

00 120120 180180 240240 360360

Study DayStudy Day

LumiracoxibLumiracoxib

0.60.6

300300 420420

0.80.8

0.40.4

NSAIDsNSAIDs

0.20.2

Kaplan-Meier EstimatesKaplan-Meier Estimates

Does the use of

NSAIDs affect the

cardioprotective

effect of Aspirin?

Effect of NSAIDs on the Anti-Platelet Effect of NSAIDs on the Anti-Platelet Effects of AspirinEffects of Aspirin

Effect of NSAIDs on the Anti-Platelet Effect of NSAIDs on the Anti-Platelet Effects of AspirinEffects of Aspirin

0102030405060708090

100

% inhibition

ofplatelet

aggregation

2 hrs 6 hrs 12 hrs 24 hrs

IbuprofenDiclofenac

Catella-Lawson et al. N Engl J Med 2001; 345:1809-1817

Pharmacodynamic Interaction of Pharmacodynamic Interaction of Naproxen with Low-Dose ASANaproxen with Low-Dose ASA

Pharmacodynamic Interaction of Pharmacodynamic Interaction of Naproxen with Low-Dose ASANaproxen with Low-Dose ASA

• Naproxen reversibly and competitively inhibited COX-1• This inhibition could be overcome by increasing concentrations of arachidonic acid• Pretreatment of platelets with naproxen prevented inhibition of COX-1 by ASA

Concurrent administration of a single dose of Naproxenwith ASA prevented inhibition of platelet aggregration

Chronic administration of Naproxen and ASAresulted in similar inhibition of TXB2 production and platelet aggregation

Capone et al. J Am Coll Cardiol. 2005;45:1295-1301.

Effect of Nonselective NSAID Use Effect of Nonselective NSAID Use on Aspirin Cardioprotectionon Aspirin Cardioprotection

Effect of Nonselective NSAID Use Effect of Nonselective NSAID Use on Aspirin Cardioprotectionon Aspirin Cardioprotection

Subgroup analysis from the 5-year prospective Subgroup analysis from the 5-year prospective Physician’s Health Study comparing ASA 325 mgs to Physician’s Health Study comparing ASA 325 mgs to placeboplacebo

22,071 male physicians, aged 40-84 years22,071 male physicians, aged 40-84 years

378 MIs: 139 ASA group; 239 Placebo378 MIs: 139 ASA group; 239 Placebo

Kurth et al. Kurth et al. CirculationCirculation 2003; 108: 1191-95. 2003; 108: 1191-95.

Relative Risk (RR) of MI according to Relative Risk (RR) of MI according to ASA use and time-varying NSAID use ASA use and time-varying NSAID use Relative Risk (RR) of MI according to Relative Risk (RR) of MI according to ASA use and time-varying NSAID use ASA use and time-varying NSAID use

Medication MI (n) Age-adjusted RR (95% CI)

Aspirin 107 1.0+ 1-59 days/yr NSAIDs 26 1.21 (0.76-1.87)+ ≥ 60 days/yr NSAIDs 6 2.86 (1.25-6.56)*

Placebo 193 1.00+ 1-59 days/yr NSAIDs 44 1.14 (0.81-1.60)≥ 60 days/yr NSAIDs 6 0.21 (0.03-1.48)

* Positive association

Kurth et al. Kurth et al. CirculationCirculation 2003; 108: 1191-95 2003; 108: 1191-95

Relative Risk of MI in Men Taking ASA Relative Risk of MI in Men Taking ASA + Intermittent or Regular NSAID Use+ Intermittent or Regular NSAID Use

Relative Risk of MI in Men Taking ASA Relative Risk of MI in Men Taking ASA + Intermittent or Regular NSAID Use+ Intermittent or Regular NSAID Use

DrugDrug Relative Risk of MIRelative Risk of MI 95% CI95% CI

Placebo alone Placebo alone 1.00 1.00 NA NA

ASA alone ASA alone 0.56 0.56 0.44-0.72 0.44-0.72

ASA plus “intermittent” NSAID use ASA plus “intermittent” NSAID use 0.69 0.69 0.46-1.05 0.46-1.05

ASA plus “regular” NSAID useASA plus “regular” NSAID use 1.57 1.57 0.70-3.56 0.70-3.56

Kurth et al. Circulation. 2003;108:1191-1195.

Effect of Ibuprofen on Effect of Ibuprofen on Cardioprotective Effect of AspirinCardioprotective Effect of Aspirin

Effect of Ibuprofen on Effect of Ibuprofen on Cardioprotective Effect of AspirinCardioprotective Effect of Aspirin

Participants - patients who took ASA < 325 mgs/day and survived ≥ I month after D/C with CVD (n=7107).

Groups: 1. ASA alone (n=6285) 2. ASA + Ibuprofen (mean = 1210 mg/d) (n=187) 3. ASA + Diclofenac (mean = 117 mgs/d) (n=206) 4. ASA + other NSAID (n=429)

Cox’s regression models with time-dependent variables

MacDonald TM and Wei L. Lancet 2003; 361:573-4

Mortality from CARDIOVASCULAR causesMortality from CARDIOVASCULAR causes

GroupGroup Number of Number of deathsdeaths

Mortality rate/ Mortality rate/ 1000 person-yrs1000 person-yrs

Hazard ratioHazard ratio p valuep value

Aspirin alone Aspirin alone (n=6285)(n=6285)

13501350 58.558.5 1.001.00 --

Aspirin + Aspirin + ibuprofen ibuprofen (n=187)(n=187) 3939 61.661.6 1.731.73 0.0305*0.0305*

Aspirin + Aspirin + diclofenac diclofenac (n=206)(n=206) 4444 62.062.0 0.800.80 0.37490.3749

Aspirin + other Aspirin + other NSAIDs NSAIDs (n=429)(n=429) 114114 70.070.0 1.031.03 0.83370.8337

MacDonald TM and Wei L. Lancet 2003; 361:573-4

FDA boxed warning for the potential of increased risk of CV events and GI bleeding associated with all prescription NSAIDs, including Celebrex.

For all prescription NSAIDs, FDA has requested a contraindication for use in patients who have recently undergone CABG surgery.

In light of the increased CV risk for all prescription NSAIDs, as well as the increased reporting rate of rare skin reactions with Bextra, the FDA requested Bextra’s withdrawal from the market.

OTC manufacturers asked to include potential CV, GI and skin reaction risks in their labels

April 7,2005: FDA AnnouncementApril 7,2005: FDA AnnouncementApril 7,2005: FDA AnnouncementApril 7,2005: FDA Announcement

ANKYLOSING ANKYLOSING SPONDYLITISSPONDYLITISANKYLOSING ANKYLOSING SPONDYLITISSPONDYLITIS

TREATMENT OF TREATMENT OF ANKYLOSING SPONDYLITISANKYLOSING SPONDYLITIS

TREATMENT OF TREATMENT OF ANKYLOSING SPONDYLITISANKYLOSING SPONDYLITIS

NSAIDsNSAIDs

Physical TherapyPhysical Therapy

SulfasalazineSulfasalazine

TNFTNF Inhibitors Inhibitors

Celecoxib for Ankylosing Celecoxib for Ankylosing SpondylitisSpondylitis

Celecoxib for Ankylosing Celecoxib for Ankylosing SpondylitisSpondylitis

• Randomized, double-blind, placebo-controlled study of Celecoxib 200mgs qd and 400mgs qd.

• Randomized, active- (NSAID), placebo-controlled multicenter, 6-week study of Celecoxib 100mgs BID and Ketoprofen 100mgs BID.

Celecoxib Versus Ketoprofen in ASCelecoxib Versus Ketoprofen in AS Celecoxib Versus Ketoprofen in ASCelecoxib Versus Ketoprofen in AS

Pain Intensity Functional Impairment

Mea

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25

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12

10

8

6

4

2

0

-1

12

6

Celecoxib 100 mg bid (n=80)Celecoxib 100 mg bid (n=80)Placebo (n=76)Placebo (n=76) Ketoprofen 100 mg bid (n=90)Ketoprofen 100 mg bid (n=90)

Dougados et al. Arthritis Rheum. 2001.

P =.007P =.001

P =.051

P =.043-2

Celecoxib Versus Naproxen in ASCelecoxib Versus Naproxen in ASCelecoxib Versus Naproxen in ASCelecoxib Versus Naproxen in AS

Pain Intensity* Functional Impairment*

Mea

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35

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0

9.9

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36.3

30.430

10

30

35

20

15

5

0

4.0

21.1

27.9†

22.5

10

16

12

10

6

0

-2

-3.3

8.5

15.8‡

12.1

4

14

8

2

-4

Celecoxib 200 mg qd (n=137)

Placebo (n=156)

Naproxen 500 mg bid (n=157)


Disease Activity*

Mea

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I*P <.001 for all active treatments vs placebo

†P <.05 vs celecoxib 200 mg qd ‡P <.01 vs celecoxib 200 mg qd

Celecoxib Versus Naproxen in ASCelecoxib Versus Naproxen in AS::Safety AnalysesSafety Analyses

Celecoxib Versus Naproxen in ASCelecoxib Versus Naproxen in AS::Safety AnalysesSafety Analyses

53

7.1

1.3

54.0

2.2 0.7

53

5.6

0.6

50

5.71.9

0

10

20

30

40

50

60

70

% o

f P

ati

en

ts


Placebo (n=156)

Naproxen (n=157)


1 AE Withdrawal due to AE 1 SAE

Data on file.

THANK YOUTHANK YOUTHANK YOUTHANK YOU

a risk-benefit analysis of the use of nsaids in the management of arthritis anne-barbara mongey, md,...

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