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

Small Intestine
Ulcers Strictures Diaphragms Enteropathy

Upper GI
GERD Subepithelial petechial hemorrhages Erosions Ulcers Stomach > duodenum Bleeding Stomach duodenum Perforations/obstruction

Colon
Colitis Ulcers Strictures Diverticular bleed or perforation Collagenous colitis Relapse of IBD

Peptic Ulcer Hospitalization Rates

100 80
Uncomplicated

40 30 20
Hemorrhage

Uncomplicated

Rate 60 per 100,000 40

20 0 70

Hemorrhage

10
Perforation Perforation

75

80

85

0 90 70

75

80

85

90

Year Gastric Ulcer

Year 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 Incidence Endoscopic NSAID-Induced Ulceration NSAID-Induced Ulceration Mean

NSAID Gastropathy NSAID Gastropathy Gastric Ulcer Gastric Ulcer Duodenal Ulcer Duodenal Ulcer

Range Range
> 90 % > 90 % 15 % 15 % 5% 5% 10 to 30% 10 to 30% 4 to 10 % 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 Mean Range Range
10 to 30% 10 to 30% 4 to 10 % 4 to 10 % 1 to 4% 1 to 4% Gastric Ulcer 15 % Gastric Ulcer 15 % Duodenal Ulcer 5% Duodenal Ulcer 5% Clinically Significant Ulcers Clinically Significant Ulcers 2% 2%

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
Diclofenac (Voltaren) Diclofenac/Misoprostol (Arthrotec)b Fenoprofen (Nalfon) Flurbiprofen (Ansaid) Ibuprofen (Motrin)a Indomethacin (Indocin) Ketoprofen (Orudis)a Meclofenamate Mefenamic acid (Ponstel) Nabumetone (Relafen) Naproxen (Naprosyn, Anaprox)a Oxaprozin (Daypro) Piroxicam (Feldene) Sulindac (Clinoril)

SALICYLATES
Aspirina (Zorprin, Easprin) Diflunisal (Dolobid) Salsalate (Disalcid, Salflex) Choline salicylate (Trilisate) Magnesium salicylate (Magan)

COX-2 INHIBITORS
Celecoxib (Celebrex) Valdecoxib (Bextra)

In Development Etoricoxib Parecoxibc Lumiracoxib Previously Available Rofecoxib (Vioxx)

Tolmetin (Tolectin)

Also available as over-the-counter preparations in the U.S. b Combination tablet of NSAID/synthetic prostaglandin E1 c Parenterally administered
a

2004 Physicians 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 0.8 0.6 0.4 0.2 0.0 0.6 0.9

40% reduction in GI complications

Placebo + NSAID (n=4439)

Misoprostol + NSAID (n=4404)

Silverstein et al. Ann Intern Med 1995;123:241249

Gastroprotection: Proton Pump Inhibitors

% of patients with recurrent upper GI bleeding at 6 months
p=0.005
20 18.8

15

10 4.4

76% reduction in upper GI bleeding

H. pylori eradication + NSAID (n=75)

Omeprazole + NSAID (n=75)

Chan et al. N Engl J Med 2001;344:967973

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
Diclofenac (Voltaren) Diclofenac/Misoprostol (Arthrotec)b Fenoprofen (Nalfon) Flurbiprofen (Ansaid) Ibuprofen (Motrin)a Indomethacin (Indocin) Ketoprofen (Orudis)a Meclofenamate Mefenamic acid (Ponstel) Nabumetone (Relafen) Naproxen (Naprosyn, Anaprox)a Oxaprozin (Daypro) Piroxicam (Feldene) Sulindac (Clinoril)

SALICYLATES
Aspirina (Zorprin, Easprin) Diflunisal (Dolobid) Salsalate (Disalcid, Salflex) Choline salicylate (Trilisate) Magnesium salicylate (Magan)

COX-2 INHIBITORS
Celecoxib (Celebrex) Valdecoxib (Bextra)

In Development Etoricoxib Parecoxibc Lumiracoxib Previously Available Rofecoxib (Vioxx)

Tolmetin (Tolectin)

Also available as over-the-counter preparations in the U.S. b Combination tablet of NSAID/synthetic prostaglandin E1 c Parenterally administered
a

2004 Physicians Desk Reference

Mechanism of Action of NSAIDs: New Concept

CO2H Arachidonic acid Non-specific NSAIDs COX-2 NSAIDs GI Mucosa Platelet

COX-1 Constitutive

COX-2 Inducible

Prostaglandins GI mucosal Protection

Thromboxane

Prostaglandins

Hemostasis

Mediate pain, inflammation, and fever

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 Patients Comparator Low dose ASA Duration Rofecoxib 50 mg QD (2x max chronic dose) RA Naproxen 500 mg BID No Median 9 months Maximum 13 months Celecoxib 400 mg BID (2x max chronic dose) OA (72 %), RA (28 %) Ibuprofen 800 mg TID Diclofenac 75 mg BID Yes (21 %) Median 9 months Maximum 13 months 6 months reported
Silverstein et al. JAMA. 2000; 284:1247-1255.

Bombardier et al. N Engl J Med. 2000;343:1520-1528

CLASS Trial: Upper GI Complications Alone and With Symptomatic Ulcers

= celecoxib = NSAIDs (ibuprofen + diclofenac)
6 5 4

p = 0.02
p = 0.09 11 / 1441 20 / 1384 49 / 1384 30 / 1441

Annualized Incidence %

All Patients

3 2 1 0

6 5 4 3 2 1 0

p = 0.02 p = 0.04
5 / 1143 14 / 1101 32 / 1101 16 / 1143

Patients Not Taking Aspirin

p = 0.49
6 5 4 3 2 1 0

17 / 283

Patients Taking Aspirin

p = 0.92
6 / 298 6 / 283

14/ 298

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

Ulcer Complications

Symptomatic Ulcers and Ulcer Complications

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

2

(%) 1

Log-rank P values: Celecoxib vs NSAIDs Celecoxib vs diclofenac Celecoxib vs ibuprofen

0.450 0.640 0.414

Ibuprofen 800 mg TID Diclofenac 75 mg BID Celecoxib 400 mg BID

0 0
FDA Presentation. 2/7/01.

80

160 180

240

320

Days

GI Outcomes Trials: Design

VIGOR (n=8076) CLASS (n=7982)
Drug Patients Comparator Low dose ASA Duration Rofecoxib 50 mg QD (2x max chronic dose) RA Naproxen 500 mg BID No Median 9 months Maximum 13 months Celecoxib 400 mg BID (2x max chronic dose) OA (72 %), RA (28 %) Ibuprofen 800 mg TID Diclofenac 75 mg BID Yes (21 %) Median 9 months Maximum 13 months 6 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

Events per 100 patient years 6
5 4 3 2 1 0
2 .1 1 .4 0 .6

P<0.001
4 .5

Rofecoxib 50 mg qd (n=4047) Naproxen 500 mg bid (n=4029)

P=0.005

Confirmed upper GI events

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

Complicated confirmed upper GI events

Are Coxibs the Only Approach GI Safety?

Other possible alternatives:
Second generation Coxibs Non-Specific NSAID + Co-Therapy NSAIDs in development: s NO-NSAIDs s PC-NSAIDs s Older Safer NSAIDs s Non-Acetylated Salicylates s Nabumetone s Diclofenac s Etodolac
s s s

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

lumiracoxib etoricoxib rofecoxib valdecoxib etodolac nimesulide diclofenac celecoxib meloxicam > 50-fold COX-2 selective

5- 50-fold COX-2 selective

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

-3

fenoprofen < 5-fold COX-2 selective ibuprofen tolmetin naproxen aspirin indomethacin ketoprofen flurbiprofen ketorolac

-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
Annualized incidence, %

Patients Not Taking Aspirin

p < 0.05
1.2 1.0 0.8 0.6 0.4 0.2 0 5/2210 3/1373

p < 0.05
19/2526

16/1597

Etodolac Naproxen

B
Annualized incidence, %

All Patients

NSAID Nave Patients

Patients Taking Aspirin

p = 0.97
8/520 9/583

p = 0.68
6/329 5/367

2.5 2.0 1.5 1.0 0.5 0

Etodolac Naproxen

All Patients

NSAID Nave Patients

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

List of NSAIDs Available by Prescription

NON-SALICYLATES
Diclofenac (Voltaren) Diclofenac/Misoprostol (Arthrotec)b Fenoprofen (Nalfon) Flurbiprofen (Ansaid) Ibuprofen (Motrin)a Indomethacin (Indocin) Ketoprofen (Orudis)a Meclofenamate Mefenamic acid (Ponstel) Nabumetone (Relafen) Naproxen (Naprosyn, Anaprox)a Oxaprozin (Daypro) Piroxicam (Feldene) Sulindac (Clinoril)

SALICYLATES
Aspirina (Zorprin, Easprin) Diflunisal (Dolobid) Salsalate (Disalcid, Salflex) Choline salicylate (Trilisate) Magnesium salicylate (Magan)

COX-2 INHIBITORS
Celecoxib (Celebrex) Valdecoxib (Bextra) Not Widely Appreciated Etodolac (Lodine) Meloxicam (Mobic) In Development Etoricoxib Parecoxibc Lumiracoxib Previously Available Rofecoxib (Vioxx)

Tolmetin (Tolectin)

Also available as over-the-counter preparations in the U.S. b Combination tablet of NSAID/synthetic prostaglandin E1 c Parenterally administered
a

2004 Physicians Desk Reference

Low Dose Aspirin: What Are the GI Risks?

Daily Aspirin Dose and Admission for Ulcer Bleeding

Aspirin Dose 75 mg (n=27) 150 mg (n=22) 300 mg (n=62) Odds Ratio (95% Cl) 2.3 (1.2-4.4) 3.2 (1.7-6.5) 3.9 (2.5-6.3)

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

Effect of Aspirin Doses on Gastrointestinal COX Inhibition

120 100

Baseline

10 mg ASA 81 mg ASA 325 mg ASA

Percent of Baseline

80 60 40 20 0

* * *
Stomach

* *
Duodenum
(

*
Rectum

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

* p < 0.05 vs. Baseline )

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

Plain ASA

3.6 3.2 2.6 2.6 2.4 2.6

Coated ASA Buffered ASA 550 cases of UGIB admitted to hospital with melena or confirmed hematemesis

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

Treatment regimen
Low-dose aspirin Low-dose aspirin + NSAIDs

Increased incidence over general population

2.6 5.6

95% CI
2.2 - 2.9 4.4 - 7.0

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

CLASS Trial: Upper GI Complications Alone and With Symptomatic Ulcers

= celecoxib = NSAIDs (ibuprofen + diclofenac)
6 5 4

p = 0.02
p = 0.09 11 / 1441 20 / 1384 49 / 1384 30 / 1441

Annualized Incidence %

All Patients

3 2 1 0

6 5 4 3 2 1 0

p = 0.02 p = 0.04
5 / 1143 14 / 1101 32 / 1101 16 / 1143

Patients Not Taking Aspirin

p = 0.49
6 5 4 3 2 1 0

17 / 283

Patients Taking Aspirin

p = 0.92
6 / 298 6 / 283

14/ 298

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

Ulcer Complications

Symptomatic Ulcers and Ulcer Complications

Rates of Clinically Significant Upper GI Events

A
Annualized incidence, %

Patients Not Taking Aspirin

p < 0.05
1.2 1.0 0.8 0.6 0.4 0.2 0 5/2210 3/1373

p < 0.05
19/2526

16/1597

Etodolac Naproxen

B
Annualized incidence, %

All Patients

NSAID Nave Patients

Patients Taking Aspirin

p = 0.97
8/520 9/583

p = 0.68
6/329 5/367

2.5 2.0 1.5 1.0 0.5 0

Etodolac Naproxen

All Patients

NSAID Nave Patients

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

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

Placebo ASA 81 mg QD Rofecoxib 25 mg QD + ASA 81 mg QD Ibuprofen 800 mg TID

20%

*
16.1%

*
17.1%

Ulcer Incidence

15% 10%
5.8%

7.3%

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: s NO-NSAIDs s PC-NSAIDs s Older Safer NSAIDs s Non-Acetylated Salicylates s Nabumetone s Diclofenac s Etodolac
s s s

Efficacy of PPI in Recurrence of NSAID-Associated Ulcers

Patients Remaining Ulcer Free, %
100 80 60 40 20 0 0 537 patients; (-) H pylori, long-term NSAID users, prior gastric ulcer

P<.001 misoprostol, lansoprazole 15 mg, lansoprazole 30 mg vs placebo

Misoprostol 200 mcg qid Lansoprazole 30 mg qd Lansoprazole 15 mg qd Placebo qd

4 8 Duration of Therapy (weeks)

12

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 Chan et al. Naproxen 1 + Lansoprazole (n=57) or Diclofenac 2 + Omeprazole (n =66) or celecoxib (n=58) celecoxib (n=64)

6 months

6 months

GI Complications (%)
1

GI Complications (%)

naproxen 500 to 750 mg daily 2 diclofenac 75 mg BID

Lai et al. Gastroenterology 2001 (abstract)
1

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

Prevention of Recurrent Ulcer Bleeding in High-Risk Patients

INITIAL STUDY GROUP
% re-bleed at 6-months
35 30 25 20 15 10 5 0 4.9 6.4

FOLLOW-UP STUDY GROUP

35 30 26 19

6-month cumulative incidence of ulcer (%)

Celecoxib 200 mg BID + placebo Diclofenac 75 mg BID + Omeprazole 20 mg QD

p = NS

25 20 15 10 5 0

p = NS

n=

143

144

n=
1

116

106

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

Chan et al. N Engl J Med. 2002;347:2104. Chan et al. Gastroenterology. 2004;103404.

Conclusions Regarding Upper GI Effects of NSAIDs

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

COX-2 inhibitors were develop to reduced 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. attractive option from the GI perspective.

For such patients, COX-2 inhibitors are an However, for patients taking low-dose aspirin or

when CV concerns exist clinicians may consider other strategies to reduce NSAIDs GI effects.