Gastrointestinal Effects of

NSAIDs and COX-2 Specific

Inhibitors

Byron Cryer, M.D.

University of Texas Southwestern Medical School and
Dallas VA Medical Center
NSAIDs: What Are the Risks?
• GI Tract
 Ulcers, perforations, bleeding, obstruction strictures,
enteropathy
• Kidney
 Sodium and fluid retention
 Hyperkalemia
 Acute renal failure
 Hypertension
• Platelet
 Inhibition of aggregation leading to increased potential for
bleeding
 Spectrum of NSAID-Induced
GI Mucosal Injury
Upper GI Small Intestine Colon
• GERD • Ulcers • Colitis
• Subepithelial petechial
• Strictures • Ulcers
hemorrhages
• Erosions • Diaphragms • Strictures
• Ulcers • Enteropathy • Diverticular bleed
– Stomach > duodenum
or perforation
• Bleeding
• Collagenous
– Stomach  duodenum
colitis
• Perforations/obstruction
• Relapse of IBD
 Peptic Ulcer Hospitalization Rates

100 40 Uncomplicated
Uncomplicated
80
30
Rate 60
per 20
100,000 40 Hemorrhage Hemorrhage

10
20
Perforation Perforation

0 0
70 75 80 85 90 70 75 80 85 90
Year Year
Gastric Ulcer Duodenal Ulcer

Kurata JH. Semin Gastrointest Dis 1993:4

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

 Total hospitalizations/year: 107,000

 Total costs of hospitalization (~$12,500/hospitalization):
~$1.4 billion
 Deaths/year: 16,500
 Each $1 spent on NSAIDs resulted in an additional $0.35 in
costs to manage adverse effects
 Average cost to treat an episode of NSAID-induced
gastropathy was $2,172 (in 1992)

Singh. Am J Med. 1998;105(suppl 1B):31S-38S.

Johnson et al. Pharmacoeconomics. 1997;12:76-88.
Assessment of NSAID GI Injury
• Healthy volunteers
 Intermediate markers of injury (prostaglandins)
 Fecal red blood cell loss
 Short-term endoscopy study

• Arthritis Patients
 Long-Term Endoscopy studies:
 Endoscopic ulcers, mostly asymptomatic
 Clinical events:
 Symptomatic ulcers
 GI Bleeding
 Perforation
 Obstruction
 Incidence of Endoscopic
NSAID-Induced Ulceration

Mean Range
NSAID Gastropathy > 90 %
Gastric Ulcer 15 % 10 to 30%
Duodenal Ulcer 5% 4 to 10 %

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

Endoscopic Photograph of Gastropathy
Endoscopic Photograph
of Gastric Ulcer
 Prevalence of Endoscopic
NSAID-Induced Ulceration

Mean Range
Gastric Ulcer 15 % 10 to 30%
Duodenal Ulcer 5% 4 to 10 %
Clinically Significant Ulcers 2% 1 to 4%
 Reducing the Risk of GI Complications
with NSAIDS
• Identify risk factors

• Use of gastroprotective drugs

• Safer NSAIDS

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

 List of NSAIDs Available by Prescription
NON-SALICYLATES SALICYLATES COX-2 INHIBITORS
Diclofenac (Voltaren) Aspirina (Zorprin, Easprin) Celecoxib (Celebrex)
Diclofenac/Misoprostol (Arthrotec)b Diflunisal (Dolobid) Valdecoxib (Bextra)
Fenoprofen (Nalfon) Salsalate (Disalcid, Salflex)
Flurbiprofen (Ansaid) Choline salicylate (Trilisate)
Ibuprofen (Motrin)a Magnesium salicylate (Magan)
Indomethacin (Indocin)
Ketoprofen (Orudis)a In Development
Meclofenamate Etoricoxib
Mefenamic acid (Ponstel) Parecoxibc
Nabumetone (Relafen) Lumiracoxib
Naproxen (Naprosyn, Anaprox)a
Oxaprozin (Daypro) Previously Available
Piroxicam (Feldene) Rofecoxib (Vioxx)
Sulindac (Clinoril)
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 Reference

 Reducing the Risk of GI Complications
with NSAIDS
Identify risk factors
– Age (>65 years)
– History of GI ulceration
– History of upper GI ulcer complication
– Concomitant drugs (e.g. corticosteroids,
coumadin)
• Prescribed + Low-Dose Aspirin
– Multiple NSAIDS • Prescribed + OTC NSAIDs
– Cardiovascular disease

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

 Gastroprotection

• Use lowest effective NSAID dose

• Misoprostol

• Proton pump inhibitors

 Gastroprotection:
Misoprostol (MUCOSA trial)
% of patients with serious upper GI complications at 6 months
p=0.049
1.0
0.9

0.8 40% reduction in GI

complications
0.6
0.6

0.4

0.2

0.0

Placebo + NSAID Misoprostol + NSAID

(n=4439) (n=4404)
Silverstein et al. Ann Intern Med 1995;123:241–249
 Gastroprotection:
Proton Pump Inhibitors
% of patients with recurrent upper GI bleeding at 6 months
p=0.005

20 18.8

15
76% reduction in
10 upper GI bleeding

4.4
5

H. pylori eradication Omeprazole + NSAID

+ NSAID (n=75)
(n=75)
Chan et al. N Engl J Med 2001;344:967–973
 Reducing the Risk of GI Complications
with NSAIDS
• Identify risk factors

• Use of gastroprotective drugs

• Safer NSAIDS

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

 List of NSAIDs Available by Prescription
NON-SALICYLATES SALICYLATES COX-2 INHIBITORS
Diclofenac (Voltaren) Aspirina (Zorprin, Easprin) Celecoxib (Celebrex)
Diclofenac/Misoprostol (Arthrotec)b Diflunisal (Dolobid) Valdecoxib (Bextra)
Fenoprofen (Nalfon) Salsalate (Disalcid, Salflex)
Flurbiprofen (Ansaid) Choline salicylate (Trilisate)
Ibuprofen (Motrin)a Magnesium salicylate (Magan)
Indomethacin (Indocin)
Ketoprofen (Orudis)a In Development
Meclofenamate Etoricoxib
Mefenamic acid (Ponstel) Parecoxibc
Nabumetone (Relafen) Lumiracoxib
Naproxen (Naprosyn, Anaprox)a
Oxaprozin (Daypro) Previously Available
Piroxicam (Feldene) Rofecoxib (Vioxx)
Sulindac (Clinoril)
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 Reference

 Mechanism of Action of NSAIDs:
New Concept
CO2H

Arachidonic acid
COX-1 Non-specific NSAIDs COX-2
“Constitutive” “Inducible”
COX-2 NSAIDs

GI Mucosa Platelet
Prostaglandins
Prostaglandins Thromboxane

Mediate pain,
GI mucosal
Hemostasis inflammation, and fever
Protection
Bakhle et al. Med Inflamm. 1996;5:305-323.
Vane et al. Inflamm Res. 1995;44:1-10.
 GI Outcomes Trials: Design
VIGOR (n=8076) CLASS (n=7982)
Drug Rofecoxib 50 mg QD Celecoxib 400 mg BID
(2x max chronic dose) (2x max chronic dose)

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

Comparator Naproxen 500 mg BID Ibuprofen 800 mg TID

Diclofenac 75 mg BID

Low dose ASA No Yes (21 %)

Duration Median 9 months Median 9 months

Maximum 13 months Maximum 13 months
6 months reported

Bombardier et al. N Engl J Med. 2000;343:1520-1528 Silverstein et al. JAMA. 2000; 284:1247-1255.
 CLASS Trial: Upper GI Complications
Alone and With Symptomatic Ulcers
= celecoxib
6

= NSAIDs (ibuprofen + diclofenac) 5

p = 0.02
4 49 / 1384
p = 0.09
All Patients 3

20 / 1384
30 / 1441

Annualized Incidence %
2

1
11 / 1441
0
6

5 p = 0.02
4

Patients Not Taking Aspirin 3

p = 0.04 32 / 1101
2
14 / 1101 16 / 1143
1
5 / 1143
0

p = 0.49
6 17 / 283
5 14/ 298
4 p = 0.92
Patients Taking Aspirin 3
6 / 283
2
6 / 298
1

0
Ulcer Complications Symptomatic Ulcers and
Silverstein et al. JAMA 2000; 284:1247-1255 Ulcer Complications
 CLASS Trial
Time to Complicated Ulcer: Entire Study (13 months)
2

Log-rank P values:
Celecoxib vs NSAIDs 0.450
Celecoxib vs diclofenac 0.640
(%) 1 Celecoxib vs ibuprofen 0.414

Ibuprofen 800 mg TID

Diclofenac 75 mg BID

Celecoxib 400 mg BID

0
0 80 160 180 240 320

Days
FDA Presentation. 2/7/01.
 GI Outcomes Trials: Design
VIGOR (n=8076) CLASS (n=7982)
Drug Rofecoxib 50 mg QD Celecoxib 400 mg BID
(2x max chronic dose) (2x max chronic dose)

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

Comparator Naproxen 500 mg BID Ibuprofen 800 mg TID

Diclofenac 75 mg BID

Low dose ASA No Yes (21 %)

Duration Median 9 months Median 9 months

Maximum 13 months Maximum 13 months
6 months reported

Bombardier et al. N Engl J Med. 2000;343:1520-1528 Silverstein et al. JAMA. 2000; 284:1247-1255.
 VIGOR:
Upper GI Events at 9 Months*
Events per 100 patient years
6 P<0.001
Rofecoxib 50 mg qd (n=4047)
5 4.5
Naproxen 500 mg bid (n=4029)

3
P=0.005
2.1
2
1.4

1 0.6

0
Confirmed upper Complicated confirmed upper GI
GI events events
*Median follow-up period.
Bombardier et al. N Engl J Med. 2000;343:1520-1528
Are Coxibs the Only Approach GI Safety?
Other possible alternatives:
 “Second generation” Coxibs
 Non-Specific NSAID + Co-Therapy
 NSAIDs in development:
 NO-NSAIDs

 PC-NSAIDs

 Older “Safer” NSAIDs

 Non-Acetylated Salicylates

 Nabumetone

 Diclofenac

 Etodolac
 In Vitro Selectivity: COX-2/COX-1 Ratio
lumiracoxib
etoricoxib
rofecoxib
valdecoxib > 50-fold COX-2 selective
etodolac
nimesulide
diclofenac 5- 50-fold COX-2 selective
celecoxib
meloxicam

fenoprofen < 5-fold COX-2 selective

ibuprofen
tolmetin
naproxen
aspirin
indomethacin
ketoprofen
Warner et al. FASEB J. 2004:18:790-804 flurbiprofen
ketorolac
-3 -2 -1 0 1 2 3
Increasingly COX-2 Selective Increasingly COX-1 Selective

Range of COX Selectivity for COX-1 and COX-2

(log10 IC50 COX-2/COX-1)
 Rates of Clinically Significant Upper GI Events
A Patients Not Taking Aspirin
p < 0.05

Annualized incidence, %
p < 0.05
1.2 16/1597
Etodolac
1.0 Naproxen
19/2526
0.8
0.6
5/2210 3/1373
0.4

0.2
0
All Patients NSAID Naïve Patients
B Patients Taking Aspirin

p = 0.68
Annualized incidence, %

p = 0.97
2.5
6/329 Etodolac
2.0 8/520 9/583
5/367 Naproxen
1.5

1.0

0.5
0
All Patients NSAID Naïve Patients
Weideman RA et al. Gastroenterology 2004;127:1322-1328
 List of NSAIDs Available by Prescription
NON-SALICYLATES SALICYLATES COX-2 INHIBITORS
Diclofenac (Voltaren) Aspirina (Zorprin, Easprin) Celecoxib (Celebrex)
Diclofenac/Misoprostol (Arthrotec)b Diflunisal (Dolobid) Valdecoxib (Bextra)
Fenoprofen (Nalfon) Salsalate (Disalcid, Salflex)
Flurbiprofen (Ansaid) Choline salicylate (Trilisate) Not Widely Appreciated
Ibuprofen (Motrin)a Magnesium salicylate (Magan) Etodolac (Lodine)
Indomethacin (Indocin) Meloxicam (Mobic)
Ketoprofen (Orudis)a
Meclofenamate In Development
Mefenamic acid (Ponstel) Etoricoxib
Nabumetone (Relafen) Parecoxibc
Naproxen (Naprosyn, Anaprox)a Lumiracoxib
Oxaprozin (Daypro)
Piroxicam (Feldene) Previously Available
Sulindac (Clinoril) Rofecoxib (Vioxx)
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 Reference

 Low Dose Aspirin:
What Are the GI Risks?
 Daily Aspirin Dose and
Admission for Ulcer Bleeding

Aspirin Dose Odds Ratio (95% Cl)

75 mg (n=27) 2.3 (1.2-4.4)
150 mg (n=22) 3.2 (1.7-6.5)
300 mg (n=62) 3.9 (2.5-6.3)

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

 Effect of Aspirin Doses on
Gastrointestinal COX Inhibition
10 mg ASA
81 mg ASA
120 325 mg ASA
Baseline
100

80
Percent of
Baseline 60 *
40
* * * * *
20

0
Stomach Duodenum Rectum
(
* p < 0.05 vs. Baseline )
Cryer B and Feldman F. Gastroenterology 1999;117:17-25.
Risk of UGI bleeding with Different Formulations
of Low-Dose Aspirin (< 325mg)
Relative Risk
Plain ASA
4
3.6
3.2 Coated ASA

2.6 2.6 2.6

2.4 Buffered ASA

550 cases of UGIB

admitted to hospital
with melena or
confirmed
hematemesis
0
Gastric bleeding Duodenal bleeding

Kelley et al, Lancet 1996; 348; 1413

Risk of Combining Low-Dose Aspirin
with NSAIDs

• National cohort study in Denmark

• 27,694 people on aspirin 100-150 mg qd
Increased incidence
Treatment regimen over general 95% CI
population
Low-dose aspirin 2.6 2.2 - 2.9

Low-dose aspirin + NSAIDs 5.6 4.4 - 7.0

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

 CLASS Trial: Upper GI Complications
Alone and With Symptomatic Ulcers
= celecoxib
6

= NSAIDs (ibuprofen + diclofenac) 5

p = 0.02
4 49 / 1384
p = 0.09
All Patients 3

20 / 1384
30 / 1441

Annualized Incidence %
2

1
11 / 1441
0
6

5 p = 0.02
4

Patients Not Taking Aspirin 3

p = 0.04 32 / 1101
2
14 / 1101 16 / 1143
1
5 / 1143
0

p = 0.49
6 17 / 283
5 14/ 298
4 p = 0.92
Patients Taking Aspirin 3
6 / 283
2
6 / 298
1

0
Ulcer Complications Symptomatic Ulcers and
Silverstein et al. JAMA 2000; 284:1247-1255 Ulcer Complications
 Rates of Clinically Significant Upper GI Events
A Patients Not Taking Aspirin
p < 0.05

Annualized incidence, %
p < 0.05
1.2 16/1597
Etodolac
1.0 Naproxen
19/2526
0.8
0.6
5/2210 3/1373
0.4

0.2
0
All Patients NSAID Naïve Patients
B Patients Taking Aspirin

p = 0.68
Annualized incidence, %

p = 0.97
2.5
6/329 Etodolac
2.0 8/520 9/583
5/367 Naproxen
1.5

1.0

0.5
0
All Patients NSAID Naïve Patients
Weideman RA et al. Gastroenterology 2004;127:1322-1328
 12-Week Effects of Low-dose ASA
and Rofecoxib on Ulcer Formation
Placebo Rofecoxib 25 mg QD + ASA 81 mg QD
ASA 81 mg QD Ibuprofen 800 mg TID

20% *
* 17.1%
Ulcer Incidence

16.1%
15%

10%
7.3%
5.8%
5%

0%
N= 381 387 377 374

* P <0.001 vs. both ASA and placebo

† P 0.002 vs. placebo
Laine et al. Gastroenterology 2004; 127(2):395.
Sept. 30, 2004:
“Merck pulls popular pain drug
due to risks of heart attacks”
Are Coxibs the Only Approach GI Safety?
Other possible alternatives:
 “Second generation” Coxibs
 Non-Specific NSAID + Co-Therapy
 NSAIDs in development:
 NO-NSAIDs

 PC-NSAIDs

 Older “Safer” NSAIDs

 Non-Acetylated Salicylates

 Nabumetone

 Diclofenac

 Etodolac
 Efficacy of PPI in Recurrence of
NSAID-Associated Ulcers
537 patients; (-) H pylori, long-term NSAID users,
Patients Remaining Ulcer Free, %

100 prior gastric ulcer

80

60

40
P<.001 misoprostol, Misoprostol 200 mcg qid
lansoprazole 15 mg, Lansoprazole 30 mg qd
20 lansoprazole 30 mg Lansoprazole 15 mg qd
vs placebo Placebo qd
0
0 4 8 12
Duration of Therapy (weeks)

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

 COX-2 Inhibitor or Non-specific NSAID + PPI
to reduce GI Complications ?
“High-Risk” NSAID users

Lai et al Naproxen 1 + Lansoprazole (n=57) or celecoxib (n=58)

Chan et al. Diclofenac 2 + Omeprazole (n =66) or celecoxib (n=64)

6 months 6 months

GI Complications (%) GI Complications (%)

1 naproxen 500 to 750 mg daily

2 diclofenac 75 mg BID

Lai et al. Gastroenterology 2001 (abstract) 1Chan et al. N Engl J Med. 2002;347:2104
 Prevention of Recurrent Ulcer Bleeding in
High-Risk Patients
INITIAL STUDY GROUP 1 FOLLOW-UP STUDY GROUP 2

Celecoxib 200 mg BID + placebo

35 Diclofenac 75 mg BID + 35
p = NS
Omeprazole 20 mg QD
% re-bleed at 6-months

incidence of ulcer (%)

30 30

6-month cumulative
26
25 25
19
20 20

15 p = NS 15

10 10
6.4
4.9
5 5

0 0
n= 143 144 n= 116 106

Patients with prior ulcer bleed on NSAID; ulcer healed and H. 1Chan et al. N Engl J Med. 2002;347:2104.
pylori – negative or eradicated prior to randomization 2Chan et al. Gastroenterology. 2004;103404.
Conclusions Regarding Upper GI Effects
of NSAIDs
 Untoward GI effects of NSAIDs result in
considerable morbidity, mortality and costs.
 COX-2 inhibitors were develop to reduced
NSAIDS’ GI toxicity.
 However, COX-2 inhibitors have been widely used
by patients not at high risk of NSAIDS’ GI effects.
 Limitations of COX-2 Inhibitors:
 No great need for COX-2s in patients at low GI risk
 No GI benefit in patients concurrently taking aspirin
 CV concerns may exist for some patients
 Conclusions Regarding
Upper GI Effects of NSAIDs
(continued)
 Strategies to reduce risk of GI effects of NSAIDS
should focus on patients at greatest GI risk.
 For such patients, COX-2 inhibitors are an
attractive option from the GI perspective.
 However, for patients taking low-dose aspirin or
when CV concerns exist clinicians may consider
other strategies to reduce NSAIDs’ GI effects.