GI Effects of NSAIDs and COX-2 Specific Inhibitors - 2005-4090S1_02_FDA -Cryer

Gastrointestinal Effects of Gastrointestinal Effects of NSAIDs and COX-2 Specific NSAIDs and COX-2 Specific InhibitorsInhibitors

Byron Cryer, M.D.Byron Cryer, M.D.

University of Texas Southwestern Medical School andUniversity of Texas Southwestern Medical School and

Dallas VA Medical CenterDallas VA Medical Center

NSAIDs: What Are the Risks?NSAIDs: What Are the Risks?

• GI TractGI Tract Ulcers, perforations, bleeding, obstruction strictures, enteropathy Ulcers, perforations, bleeding, obstruction strictures, enteropathy

• KidneyKidney Sodium and fluid retention Sodium and fluid retention HyperkalemiaHyperkalemia Acute renal failure Acute renal failure HypertensionHypertension

• PlateletPlatelet Inhibition of aggregation leading to increased potential for Inhibition of aggregation leading to increased potential for

bleedingbleeding

Spectrum of NSAID-InducedSpectrum of NSAID-InducedGI Mucosal InjuryGI Mucosal Injury

Upper GIUpper GI• • GERD GERD • • Subepithelial petechialSubepithelial petechial

hemorrhages hemorrhages• • ErosionsErosions• • UlcersUlcers

– – Stomach > duodenumStomach > duodenum

• • BleedingBleeding

– – Stomach Stomach duodenum duodenum

• • Perforations/obstruction

Small IntestineSmall Intestine

•• UlcersUlcers

• • StricturesStrictures

• • DiaphragmsDiaphragms

• • EnteropathyEnteropathy

ColonColon

•• ColitisColitis

• • UlcersUlcers

• • StricturesStrictures

• • Diverticular bleedDiverticular bleed

or perforation or perforation

• • CollagenousCollagenous

colitis colitis

• • Relapse of IBDRelapse of IBD

Peptic Ulcer Hospitalization RatesPeptic Ulcer Hospitalization Rates

Kurata JH. Kurata JH. Semin Gastrointest DisSemin Gastrointest Dis 1993:4 1993:4

RateRate per per

100,000100,000

Gastric UlcerGastric Ulcer Duodenal UlcerDuodenal Ulcer

70 75 80 85 900

20

40

60

80

100

Uncomplicated Uncomplicated

HemorrhageHemorrhage

Perforation Perforation

70 75 80 85 900

20

40

YearYear YearYear

30

10

Uncomplicated Uncomplicated

HemorrhageHemorrhage

Perforation Perforation

Singh. Singh. Am J MedAm J Med. 1998;105(suppl 1B):31S-38S.. 1998;105(suppl 1B):31S-38S.Johnson et al. Johnson et al. Pharmacoeconomics.Pharmacoeconomics. 1997;12:76-88. 1997;12:76-88.

NSAID-Induced Gastropathy:NSAID-Induced Gastropathy:Morbidity, Mortality and Costs in the U.S.Morbidity, Mortality and Costs in the U.S.

Total hospitalizations/year: 107,000Total hospitalizations/year: 107,000

Total costs of hospitalization (Total costs of hospitalization ($12,500/hospitalization): $12,500/hospitalization): $1.4 billion$1.4 billion

Deaths/year: 16,500Deaths/year: 16,500

Each $1 spent on NSAIDs resulted in an additional $0.35 in Each $1 spent on NSAIDs resulted in an additional $0.35 in costs to manage adverse effects costs to manage adverse effects

Average cost to treat an episode of NSAID-induced Average cost to treat an episode of NSAID-induced gastropathy was $2,172 (in 1992)gastropathy was $2,172 (in 1992)

Assessment of NSAID GI InjuryAssessment of NSAID GI Injury• Healthy volunteersHealthy volunteers

Intermediate markers of injury (prostaglandins)Intermediate markers of injury (prostaglandins) Fecal red blood cell lossFecal red blood cell loss Short-term endoscopy studyShort-term endoscopy study

• Arthritis PatientsArthritis Patients Long-Term Endoscopy studiesLong-Term Endoscopy studies::

Endoscopic ulcers, mostly asymptomaticEndoscopic ulcers, mostly asymptomatic

Clinical events:Clinical events: Symptomatic ulcersSymptomatic ulcers GI BleedingGI Bleeding PerforationPerforation ObstructionObstruction

Incidence of EndoscopicIncidence of EndoscopicNSAID-Induced UlcerationNSAID-Induced UlcerationIncidence of EndoscopicIncidence of Endoscopic

NSAID-Induced UlcerationNSAID-Induced Ulceration

MeanMean RangeRangeNSAID GastropathyNSAID Gastropathy > 90 %> 90 %

Gastric UlcerGastric Ulcer 15 % 15 % 10 to 30%10 to 30%

Duodenal UlcerDuodenal Ulcer 5 % 5 % 4 to 10 % 4 to 10 %

MeanMean RangeRangeNSAID GastropathyNSAID Gastropathy > 90 %> 90 %

Gastric UlcerGastric Ulcer 15 % 15 % 10 to 30%10 to 30%

Duodenal UlcerDuodenal Ulcer 5 % 5 % 4 to 10 % 4 to 10 %

Wolfe MM et al. N Engl J Med 1999;340:1888-1899Wolfe MM et al. N Engl J Med 1999;340:1888-1899

Endoscopic Photograph of GastropathyEndoscopic Photograph of Gastropathy

Endoscopic PhotographEndoscopic Photographof Gastric Ulcerof Gastric Ulcer

Prevalence of EndoscopicPrevalence of EndoscopicNSAID-Induced UlcerationNSAID-Induced UlcerationPrevalence of EndoscopicPrevalence of EndoscopicNSAID-Induced UlcerationNSAID-Induced Ulceration

MeanMean RangeRangeGastric UlcerGastric Ulcer 15 % 15 % 10 to 10 to

30%30%

Duodenal UlcerDuodenal Ulcer 5 % 5 % 4 to 10 4 to 10 %%

Clinically Significant UlcersClinically Significant Ulcers 2% 2% 1 to 4% 1 to 4%

MeanMean RangeRangeGastric UlcerGastric Ulcer 15 % 15 % 10 to 10 to

30%30%

Duodenal UlcerDuodenal Ulcer 5 % 5 % 4 to 10 4 to 10 %%

Clinically Significant UlcersClinically Significant Ulcers 2% 2% 1 to 4% 1 to 4%

Reducing the Risk of GI Complications Reducing the Risk of GI Complications with NSAIDSwith NSAIDS

• Identify risk factorsIdentify risk factors

• Use of gastroprotective drugsUse of gastroprotective drugs

• Safer NSAIDSSafer NSAIDS


List of NSAIDs Available by PrescriptionList of NSAIDs Available by PrescriptionNON-SALICYLATESNON-SALICYLATES SALICYLATES COX-2 INHIBITORS SALICYLATES COX-2 INHIBITORSDiclofenac (Voltaren)Diclofenac (Voltaren) AspirinAspirinaa (Zorprin, Easprin) (Zorprin, Easprin) Celecoxib (Celebrex)Celecoxib (Celebrex)Diclofenac/Misoprostol (Arthrotec)Diclofenac/Misoprostol (Arthrotec)bb Diflunisal (Dolobid)Diflunisal (Dolobid) Valdecoxib (Bextra)Valdecoxib (Bextra)Fenoprofen (Nalfon) Fenoprofen (Nalfon) Salsalate (Disalcid, Salflex)Salsalate (Disalcid, Salflex) Flurbiprofen (Ansaid) Flurbiprofen (Ansaid) Choline salicylate (Trilisate)Choline salicylate (Trilisate)Ibuprofen (Motrin)Ibuprofen (Motrin)aa Magnesium salicylate (Magan)Magnesium salicylate (Magan)Indomethacin (Indocin) Indomethacin (Indocin) Ketoprofen (Orudis)Ketoprofen (Orudis)aa In DevelopmentIn DevelopmentMeclofenamate Meclofenamate EtoricoxibEtoricoxibMefenamic acid (Ponstel) Mefenamic acid (Ponstel) ParecoxibParecoxibcc Nabumetone (Relafen)Nabumetone (Relafen) LumiracoxibLumiracoxibNaproxen (Naprosyn, Anaprox)Naproxen (Naprosyn, Anaprox)aa

Oxaprozin (Daypro)Oxaprozin (Daypro) Previously AvailablePreviously AvailablePiroxicam (Feldene)Piroxicam (Feldene) Rofecoxib (Vioxx)Rofecoxib (Vioxx)Sulindac (Clinoril)Sulindac (Clinoril)Tolmetin (Tolectin)Tolmetin (Tolectin) a Also available as over-the-counter preparations in the U.S.

b Combination tablet of NSAID/synthetic prostaglandin E1

c Parenterally administered

2004 Physician’s Desk Reference2004 Physician’s Desk Reference


Identify risk factorsIdentify risk factors–Age (>65 years)Age (>65 years)

–History of GI ulcerationHistory of GI ulceration

–History of upper GI ulcer complicationHistory of upper GI ulcer complication

–Concomitant drugs (e.g. corticosteroids, Concomitant drugs (e.g. corticosteroids, coumadin)coumadin)

–Multiple NSAIDS Multiple NSAIDS

–Cardiovascular diseaseCardiovascular disease

• Prescribed + Low-Dose AspirinPrescribed + Low-Dose Aspirin

• Prescribed + OTC NSAIDsPrescribed + OTC NSAIDs


GastroprotectionGastroprotection

• Use lowest effective NSAID doseUse lowest effective NSAID dose

• MisoprostolMisoprostol

• Proton pump inhibitorsProton pump inhibitors

Gastroprotection:Gastroprotection:Misoprostol (MUCOSA trial)Misoprostol (MUCOSA trial)

0.9

0.6

0.0

0.2

0.4

0.6

0.8

1.0

Silverstein et al. Ann Intern Med 1995;123:241–249

% of patients with serious upper GI complications at 6 months% of patients with serious upper GI complications at 6 months

Placebo + NSAIDPlacebo + NSAID(n=4439)(n=4439)

p=0.049

Misoprostol + NSAIDMisoprostol + NSAID(n=4404)(n=4404)

40% reduction in GI 40% reduction in GI complicationscomplications

Gastroprotection:Gastroprotection: Proton Pump Inhibitors Proton Pump Inhibitors

18.8

4.4

0

5

10

15

20

Chan et al. N Engl J Med 2001;344:967–973

% of patients with recurrent upper GI bleeding at 6 months% of patients with recurrent upper GI bleeding at 6 months

Omeprazole + NSAIDOmeprazole + NSAID(n=75)(n=75)

H. pyloriH. pylori eradication eradication + NSAID+ NSAID

(n=75)(n=75)

p=0.005

76% reduction in 76% reduction in upper GI bleedingupper GI bleeding


• Identify risk factorsIdentify risk factors

• Use of gastroprotective drugsUse of gastroprotective drugs

• Safer NSAIDSSafer NSAIDS


List of NSAIDs Available by PrescriptionList of NSAIDs Available by PrescriptionNON-SALICYLATESNON-SALICYLATES SALICYLATES COX-2 INHIBITORS SALICYLATES COX-2 INHIBITORSDiclofenac (Voltaren)Diclofenac (Voltaren) AspirinAspirinaa (Zorprin, Easprin) (Zorprin, Easprin) Celecoxib (Celebrex)Celecoxib (Celebrex)Diclofenac/Misoprostol (Arthrotec)Diclofenac/Misoprostol (Arthrotec)bb Diflunisal (Dolobid)Diflunisal (Dolobid) Valdecoxib (Bextra)Valdecoxib (Bextra)Fenoprofen (Nalfon) Fenoprofen (Nalfon) Salsalate (Disalcid, Salflex)Salsalate (Disalcid, Salflex) Flurbiprofen (Ansaid) Flurbiprofen (Ansaid) Choline salicylate (Trilisate)Choline salicylate (Trilisate)Ibuprofen (Motrin)Ibuprofen (Motrin)aa Magnesium salicylate (Magan)Magnesium salicylate (Magan)Indomethacin (Indocin) Indomethacin (Indocin) Ketoprofen (Orudis)Ketoprofen (Orudis)aa In DevelopmentIn DevelopmentMeclofenamate Meclofenamate EtoricoxibEtoricoxibMefenamic acid (Ponstel) Mefenamic acid (Ponstel) ParecoxibParecoxibcc Nabumetone (Relafen)Nabumetone (Relafen) LumiracoxibLumiracoxibNaproxen (Naprosyn, Anaprox)Naproxen (Naprosyn, Anaprox)aa

Oxaprozin (Daypro)Oxaprozin (Daypro) Previously AvailablePreviously AvailablePiroxicam (Feldene)Piroxicam (Feldene) Rofecoxib (Vioxx)Rofecoxib (Vioxx)Sulindac (Clinoril)Sulindac (Clinoril)Tolmetin (Tolectin)Tolmetin (Tolectin) a Also available as over-the-counter preparations in the U.S.




Mechanism of Action of NSAIDs: New Concept

COX-2“Inducible”

Prostaglandins

COX-1“Constitutive”

Prostaglandins

Mediate pain, inflammation, and fever

Arachidonic acid

CO2H

Non-specific NSAIDs

GI mucosal

ProtectionHemostasis

Bakhle et al. Med Inflamm. 1996;5:305-323.Vane et al. Inflamm Res. 1995;44:1-10.

COX-2 NSAIDs

Thromboxane

GI Mucosa Platelet

GI Outcomes Trials: DesignGI Outcomes Trials: Design

Celecoxib 400 mg BIDCelecoxib 400 mg BID(2x max chronic dose)(2x max chronic dose)

Rofecoxib 50 mg QDRofecoxib 50 mg QD(2x max chronic dose)(2x max chronic dose)

DrugDrug

Yes (21 %)Yes (21 %)NoNoLow dose ASALow dose ASA

Ibuprofen 800 mg TIDIbuprofen 800 mg TIDDiclofenac 75 mg BIDDiclofenac 75 mg BID

Naproxen 500 mg BIDNaproxen 500 mg BIDComparatorComparator

OA (72 %), RA (28 %)OA (72 %), RA (28 %)RARAPatientsPatients

CLASS (n=7982)CLASS (n=7982)VIGOR (n=8076)VIGOR (n=8076)

DurationDuration Median 9 monthsMedian 9 monthsMaximum 13 monthsMaximum 13 months

Median 9 monthsMedian 9 monthsMaximum 13 monthsMaximum 13 months6 months reported6 months reported

Silverstein et al. Silverstein et al. JAMAJAMA. 2000; 284:1247-1255.. 2000; 284:1247-1255.Bombardier et al. Bombardier et al. N Engl J Med.N Engl J Med. 2000;343:1520-1528 2000;343:1520-1528

Ann

ualiz

ed I

ncid

ence

%

Ulcer ComplicationsUlcer Complications Symptomatic Ulcers andSymptomatic Ulcers andUlcer ComplicationsUlcer Complications

0

1

2

3

4

5

6

49 / 138449 / 1384

30 / 144130 / 1441

11 / 144111 / 144120 / 138420 / 1384

p = 0.02p = 0.02

p = 0.09p = 0.09All PatientsAll Patients

0

1

2

3

4

5

6

32 / 110132 / 1101

16 / 114316 / 11435 / 11435 / 1143

14 / 110114 / 1101

p = 0.02p = 0.02

p = 0.04p = 0.04Patients Not Taking AspirinPatients Not Taking Aspirin

0

1

2

3

4

5

6 17 / 28317 / 283

14/ 29814/ 298

6 / 2986 / 298 6 / 2836 / 283

p = 0.49p = 0.49

p = 0.92p = 0.92

Patients Taking AspirinPatients Taking Aspirin

CLASS Trial: Upper GI ComplicationsCLASS Trial: Upper GI ComplicationsAlone and With Symptomatic UlcersAlone and With Symptomatic Ulcers

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

= celecoxib= celecoxib= NSAIDs (ibuprofen + diclofenac)= NSAIDs (ibuprofen + diclofenac)

0

1

2

(%)

Days

0 80 240 320

CLASS Trial Time to Complicated Ulcer: Entire Study (13 months)

FDA Presentation. 2/7/01.

Log-rank P values:

Celecoxib vs NSAIDs

0.450

Celecoxib vs diclofenac

0.640

Celecoxib vs ibuprofen

0.414

180160

Ibuprofen 800 mg TID

Diclofenac 75 mg BID

Celecoxib 400 mg BID

GI Outcomes Trials: DesignGI Outcomes Trials: Design

Celecoxib 400 mg BID(2x max chronic dose)

Rofecoxib 50 mg QD(2x max chronic dose)

Drug

Yes (21 %)NoLow dose ASA

Ibuprofen 800 mg TIDDiclofenac 75 mg BID

Naproxen 500 mg BIDComparator

OA (72 %), RA (28 %)RAPatients

CLASS (n=7982)VIGOR (n=8076)VIGOR (n=8076)

Duration Median 9 monthsMaximum 13 months

Median 9 monthsMaximum 13 months6 months reported

Silverstein et al. JAMA. 2000; 284:1247-1255.Bombardier et al. N Engl J Med. 2000;343:1520-1528

VIGOR: Upper GI Events at 9 Months*

2.1

0.6

4.5

1.4

0

1

2

3

4

5

6

Complicated confirmed upper GI events

Confirmed upper GI events

Events per 100 patient years

PP<0.001<0.001

PP=0.005=0.005

*Median follow-up period.Bombardier et al. N Engl J Med. 2000;343:1520-1528

Rofecoxib 50 mg qd (n=4047)

Naproxen 500 mg bid (n=4029)

Are Coxibs the Only Approach GI Safety?Are Coxibs the Only Approach GI Safety?

“ “Second generation” Coxibs Second generation” Coxibs Non-Specific NSAID + Co-TherapyNon-Specific NSAID + Co-Therapy NSAIDs in development:NSAIDs in development:

NO-NSAIDsNO-NSAIDs PC-NSAIDsPC-NSAIDs

Older “Safer” NSAIDsOlder “Safer” NSAIDs Non-Acetylated SalicylatesNon-Acetylated Salicylates NabumetoneNabumetone DiclofenacDiclofenac EtodolacEtodolac

Other possible alternatives:Other possible alternatives:

-3-3 -2-2 -1-1 00 11 22 33

ketorolacketorolac

In Vitro Selectivity: COX-2/COX-1 Ratio

Warner et al. FASEB J. 2004:18:790-804 flurbiprofenflurbiprofen

ibuprofenibuprofentolmetintolmetin

naproxennaproxenaspirinaspirin

indomethacinindomethacinketoprofenketoprofen

fenoprofenfenoprofen

etoricoxibetoricoxibrofecoxibrofecoxib

valdecoxibvaldecoxib

celecoxibcelecoxib

nimesulidenimesulidediclofenacdiclofenac

etodolacetodolac

meloxicammeloxicam

> 50-fold COX-2 selective> 50-fold COX-2 selective

5- 50-fold COX-2 selective5- 50-fold COX-2 selective

< 5-fold COX-2 selective< 5-fold COX-2 selective

Range of COX Selectivity for COX-1 and COX-2Range of COX Selectivity for COX-1 and COX-2(log(log10 10 ICIC5050 COX-2/COX-1) COX-2/COX-1)

Increasingly COX-2 SelectiveIncreasingly COX-2 Selective Increasingly COX-1 SelectiveIncreasingly COX-1 Selective

lumiracoxiblumiracoxib

0.20.2

0.40.4

0.60.6

0.80.8

1.01.0

All PatientsAll Patients NSAID Naïve PatientsNSAID Naïve Patients00

1.21.2

Patients Not Taking AspirinPatients Not Taking Aspirin

0.50.5

1.01.0

1.51.5

2.02.0



2.52.5

p = 0.68p = 0.68

p < 0.05p < 0.05

p = 0.97p = 0.97

p < 0.05p < 0.05

5/22105/2210

19/252619/2526

3/13733/1373

16/159716/1597

6/3296/3299/5839/583

5/3675/3678/5208/520

An

nu

aliz

ed i

nc

iden

ce,

%A

nn

ual

ized

in

cid

ence

, %

An

nu

aliz

ed i

nc

iden

ce,

%A

nn

ual

ized

in

cid

ence

, %

AA

BB

EtodolacEtodolacNaproxenNaproxen


Rates of Clinically Significant Upper GI Events Rates of Clinically Significant Upper GI Events

Weideman RA et al. Gastroenterology 2004;127:1322-1328Weideman RA et al. Gastroenterology 2004;127:1322-1328

List of NSAIDs Available by PrescriptionList of NSAIDs Available by PrescriptionNON-SALICYLATESNON-SALICYLATES SALICYLATES COX-2 INHIBITORS SALICYLATES COX-2 INHIBITORSDiclofenac (Voltaren)Diclofenac (Voltaren) AspirinAspirinaa (Zorprin, Easprin) (Zorprin, Easprin) Celecoxib (Celebrex)Celecoxib (Celebrex)Diclofenac/Misoprostol (Arthrotec)Diclofenac/Misoprostol (Arthrotec)bb Diflunisal (Dolobid)Diflunisal (Dolobid) Valdecoxib (Bextra)Valdecoxib (Bextra)Fenoprofen (Nalfon) Fenoprofen (Nalfon) Salsalate (Disalcid, Salflex)Salsalate (Disalcid, Salflex)Flurbiprofen (Ansaid) Flurbiprofen (Ansaid) Choline salicylate (Trilisate)Choline salicylate (Trilisate) Not Widely AppreciatedNot Widely Appreciated Ibuprofen (Motrin)Ibuprofen (Motrin)aa Magnesium salicylate (Magan)Magnesium salicylate (Magan) Etodolac (LodineEtodolac (Lodine))Indomethacin (Indocin) Indomethacin (Indocin) Meloxicam (Mobic)Meloxicam (Mobic)Ketoprofen (Orudis)Ketoprofen (Orudis)aa Meclofenamate Meclofenamate In DevelopmentIn DevelopmentMefenamic acid (Ponstel) Mefenamic acid (Ponstel) EtoricoxibEtoricoxibNabumetone (Relafen)Nabumetone (Relafen) ParecoxibParecoxibcc

Naproxen (Naprosyn, Anaprox)Naproxen (Naprosyn, Anaprox)aa LumiracoxibLumiracoxibOxaprozin (Daypro)Oxaprozin (Daypro)Piroxicam (Feldene)Piroxicam (Feldene) Previously AvailablePreviously AvailableSulindac (Clinoril)Sulindac (Clinoril) Rofecoxib (Vioxx)Rofecoxib (Vioxx)Tolmetin (Tolectin)Tolmetin (Tolectin) a Also available as over-the-counter preparations in the U.S.




Low Dose Aspirin:Low Dose Aspirin: What Are the GI Risks? What Are the GI Risks?

Daily Aspirin Dose andDaily Aspirin Dose andAdmission for Ulcer BleedingAdmission for Ulcer Bleeding

Aspirin DoseAspirin Dose

75 mg (n=27)75 mg (n=27)

150 mg (n=22)150 mg (n=22)

300 mg (n=62)300 mg (n=62)

Odds Ratio (95% Cl)Odds Ratio (95% Cl)

2.3 (1.2-4.4)2.3 (1.2-4.4)

3.2 (1.7-6.5)3.2 (1.7-6.5)

3.9 (2.5-6.3)3.9 (2.5-6.3)

Weil J et al. BMJ. 1995;310:827-830.

Effect of Aspirin Doses on Effect of Aspirin Doses on Gastrointestinal COX InhibitionGastrointestinal COX Inhibition

Percent of Percent of

BaselineBaseline

( p < 0.05 vs. Baseline )( p < 0.05 vs. Baseline )**StomachStomach DuodenumDuodenum RectumRectum

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

BaselineBaseline

00

2200

4400

6600

8800

110000

112200

1100 mmgg AASSAA

8811 mmgg AASSAA

332255 mmgg AASSAA

Cryer B and Feldman F. Gastroenterology 1999;117:17-25.Cryer B and Feldman F. Gastroenterology 1999;117:17-25.

Risk of UGI bleeding with Different Formulations Risk of UGI bleeding with Different Formulations of Low-Dose Aspirin (< 325mg)of Low-Dose Aspirin (< 325mg)

00

443.63.6

2.62.62.42.4

2.62.62.62.6

Relative RiskRelative Risk

Gastric bleedingGastric bleeding Duodenal bleedingDuodenal bleeding

3.23.2

Plain ASAPlain ASA

Coated ASACoated ASA

Buffered ASABuffered ASA

550 cases of UGIB 550 cases of UGIB admitted to hospital admitted to hospital with melena or with melena or confirmed confirmed hematemesishematemesis

Kelley et al, Lancet 1996; 348; 1413Kelley et al, Lancet 1996; 348; 1413

• National cohort study in DenmarkNational cohort study in Denmark

• 27,694 people on aspirin 100-150 mg qd27,694 people on aspirin 100-150 mg qd

Treatment regimenTreatment regimenIncreased incidenceIncreased incidence

over generalover generalpopulation population

95% CI95% CI

Low-dose aspirin

Low-dose aspirin + NSAIDs

2.6

5.6

2.2 - 2.9

4.4 - 7.0

Sorensen et al, Am J Gastroenterol 2000; 95; 2218

Risk of Combining Low-Dose Aspirin Risk of Combining Low-Dose Aspirin with NSAIDswith NSAIDs

Ann

ualiz

ed I

ncid

ence

%

Ulcer ComplicationsUlcer Complications Symptomatic Ulcers andSymptomatic Ulcers andUlcer ComplicationsUlcer Complications

0

1

2

3

4

5

6

49 / 138449 / 1384

30 / 144130 / 1441

11 / 144111 / 144120 / 138420 / 1384

p = 0.02p = 0.02

p = 0.09p = 0.09All PatientsAll Patients

0

1

2

3

4

5

6

32 / 110132 / 1101

16 / 114316 / 11435 / 11435 / 1143

14 / 110114 / 1101

p = 0.02p = 0.02

p = 0.04p = 0.04Patients Not Taking AspirinPatients Not Taking Aspirin

0

1

2

3

4

5

6 17 / 28317 / 283

14/ 29814/ 298

6 / 2986 / 298 6 / 2836 / 283

p = 0.49p = 0.49

p = 0.92p = 0.92


CLASS Trial: Upper GI ComplicationsCLASS Trial: Upper GI ComplicationsAlone and With Symptomatic UlcersAlone and With Symptomatic Ulcers

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

= celecoxib= celecoxib= NSAIDs (ibuprofen + diclofenac)= NSAIDs (ibuprofen + diclofenac)

0.20.2

0.40.4

0.60.6

0.80.8

1.01.0


1.21.2

Patients Not Taking AspirinPatients Not Taking Aspirin

0.50.5

1.01.0

1.51.5

2.02.0



2.52.5

p = 0.68p = 0.68

p < 0.05p < 0.05

p = 0.97p = 0.97

p < 0.05p < 0.05

5/22105/2210

19/252619/2526

3/13733/1373

16/159716/1597

6/3296/3299/5839/583

5/3675/3678/5208/520

An

nu

aliz

ed i

nc

iden

ce,

%A

nn

ual

ized

in

cid

ence

, %

An

nu

aliz

ed i

nc

iden

ce,

%A

nn

ual

ized

in

cid

ence

, %

AA

BB



Rates of Clinically Significant Upper GI Events Rates of Clinically Significant Upper GI Events

Weideman RA et al. Gastroenterology 2004;127:1322-1328Weideman RA et al. Gastroenterology 2004;127:1322-1328

12-Week Effects of Low-dose ASA 12-Week Effects of Low-dose ASA and Rofecoxib on Ulcer Formationand Rofecoxib on Ulcer Formation

* P* P <0.001 vs. both ASA and placebo <0.001 vs. both ASA and placebo† † PP 0.002 vs. placebo 0.002 vs. placebo Laine et al.Laine et al. Gastroenterology 2004; 127(2):395. Gastroenterology 2004; 127(2):395.

5.8%7.3%

16.1%17.1%

0%

5%

10%

15%

20%

Ulc

er In

cid

en

ceU

lcer

Inc

ide

nce

** **

381381 387387 377377 374374N =N =

PlaceboPlacebo

ASA 81 mg QDASA 81 mg QD Ibuprofen 800 mg TIDIbuprofen 800 mg TID

Rofecoxib 25 mg QD + ASA 81 mg QDRofecoxib 25 mg QD + ASA 81 mg QD

““Merck pulls popular pain drugMerck pulls popular pain drug due to risks of heart attacks” due to risks of heart attacks”

Sept. 30, 2004: Sept. 30, 2004:

Are Coxibs the Only Approach GI Safety?Are Coxibs the Only Approach GI Safety?

“ “Second generation” Coxibs Second generation” Coxibs Non-Specific NSAID + Co-TherapyNon-Specific NSAID + Co-Therapy NSAIDs in development:NSAIDs in development:

NO-NSAIDsNO-NSAIDs PC-NSAIDsPC-NSAIDs

Older “Safer” NSAIDsOlder “Safer” NSAIDs Non-Acetylated SalicylatesNon-Acetylated Salicylates NabumetoneNabumetone DiclofenacDiclofenac EtodolacEtodolac

Other possible alternatives:Other possible alternatives:

Efficacy of PPI in Recurrence of Efficacy of PPI in Recurrence of NSAID-Associated UlcersNSAID-Associated Ulcers

Graham et al. Graham et al. Arch Intern MedArch Intern Med. 2002;162:169.. 2002;162:169.

537 patients; (-) 537 patients; (-) H pyloriH pylori, long-term NSAID users,, long-term NSAID users,prior gastric ulcerprior gastric ulcer

00 44 88 1212

100100

8080

6060

4040

2020

00

Misoprostol 200 mcg qidMisoprostol 200 mcg qidLansoprazole 30 mg qdLansoprazole 30 mg qdLansoprazole 15 mg qdLansoprazole 15 mg qdPlacebo qdPlacebo qd

Duration of Therapy (weeks)Duration of Therapy (weeks)

PP<.001 misoprostol, <.001 misoprostol, lansoprazole 15 mg,lansoprazole 15 mg,lansoprazole 30 mg lansoprazole 30 mg vs placebovs placebo

Pa

tie

nts

Rem

ain

ing

Ulc

er

Fre

e, %

Pa

tie

nts

Rem

ain

ing

Ulc

er

Fre

e, %

Lai et alLai et al Naproxen Naproxen 11 + Lansoprazole (n=57) + Lansoprazole (n=57) oror celecoxib (n=58)celecoxib (n=58)

Chan et al.Chan et al. Diclofenac Diclofenac 22 + Omeprazole (n =66) + Omeprazole (n =66) oror celecoxib (n=64)celecoxib (n=64)

GI Complications (%)GI Complications (%) GI Complications (%) GI Complications (%)

COX-2 Inhibitor COX-2 Inhibitor oror Non-specific NSAID + PPI Non-specific NSAID + PPIto reduce GI Complications ?to reduce GI Complications ?

Lai et al. Gastroenterology 2001 (abstract)

““High-Risk” NSAID usersHigh-Risk” NSAID users

6 months6 months 6 months6 months

1Chan et al. N Engl J Med. 2002;347:2104

1 naproxen 500 to 750 mg daily2 diclofenac 75 mg BID

4.96.4

0

5

10

15

20

25

30

35

% r

e-b

leed

at

6-m

on

ths

19

26

0

5

10

15

20

25

30

35

6-m

on

th c

um

ula

tive

in

cid

ence

of

ulc

er (

%)

p = NS

p = NS

n = n = 143 144 116 106

Prevention of Recurrent Ulcer Bleeding in Prevention of Recurrent Ulcer Bleeding in High-RiskHigh-Risk Patients Patients

Celecoxib 200 mg BID + placeboDiclofenac 75 mg BID + Omeprazole 20 mg QD

INITIAL STUDY GROUP 1 FOLLOW-UP STUDY GROUP 2

1Chan et al. N Engl J Med. 2002;347:2104.2Chan et al. Gastroenterology. 2004;103404.

Patients with prior ulcer bleed on NSAID; ulcer healed and H. pylori – negative or eradicated prior to randomization

Conclusions Regarding Upper GI Effects Conclusions Regarding Upper GI Effects of NSAIDsof NSAIDs

Untoward GI effects of NSAIDs result in Untoward GI effects of NSAIDs result in considerable morbidity, mortality and costs.considerable morbidity, mortality and costs.

COX-2 inhibitors were develop to reduced COX-2 inhibitors were develop to reduced NSAIDS’ GI toxicity.NSAIDS’ GI toxicity.

However, COX-2 inhibitors have been widely used However, COX-2 inhibitors have been widely used by patients not at high risk of NSAIDS’ GI effects.by patients not at high risk of NSAIDS’ GI effects.

Limitations of COX-2 Inhibitors:Limitations of COX-2 Inhibitors:

No great need for COX-2s in patients at low GI riskNo great need for COX-2s in patients at low GI risk

No GI benefit in patients concurrently taking aspirinNo GI benefit in patients concurrently taking aspirin

CV concerns may exist for some patientsCV concerns may exist for some patients

Conclusions RegardingConclusions Regarding Upper GI Effects of NSAIDs Upper GI Effects of NSAIDs

(continued)(continued)

Strategies to reduce risk of GI effects of NSAIDS Strategies to reduce risk of GI effects of NSAIDS should focus on patients at greatest GI risk.should focus on patients at greatest GI risk.

For such patients, COX-2 inhibitors are an For such patients, COX-2 inhibitors are an attractive option from the GI perspective.attractive option from the GI perspective.

However, for patients taking low-dose aspirin or However, for patients taking low-dose aspirin or when CV concerns exist clinicians may consider when CV concerns exist clinicians may consider other strategies to reduce NSAIDs’ GI effects. other strategies to reduce NSAIDs’ GI effects.

Documents

GI Effects of NSAIDs and COX-2 Specific Inhibitors - 2005-4090S1_02_FDA -Cryer