Gastrointestinal Effects of NSAIDs and COX-2 Specific Inhibitors

1
Gastrointestinal Effects of NSAIDs and COX-2
Specific Inhibitors
Byron Cryer, M.D. University of Texas
Southwestern Medical School and Dallas VA Medical
Center
2
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

3
Spectrum of NSAID-InducedGI Mucosal Injury
Small Intestine Ulcers Strictures
Diaphragms Enteropathy

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

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

4
Peptic Ulcer Hospitalization Rates
100
40
Uncomplicated
Uncomplicated
80
30

Rate per 100,000
60
20
Hemorrhage
40
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 19934
5
NSAID-Induced GastropathyMorbidity, Mortality
and Costs in the U.S.

• Total hospitalizations/year 107,000
• Total costs of hospitalization (12,500/hospitali
  zation) 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. 1998105(suppl
1B)31S-38S. Johnson et al. Pharmacoeconomics.
19971276-88.
6
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

7
Incidence of EndoscopicNSAID-Induced Ulceration

• Mean Range
• NSAID Gastropathy gt 90
• Gastric Ulcer 15 10 to 30
• Duodenal Ulcer 5 4 to 10

Wolfe MM et al. N Engl J Med 19993401888-1899
8
Endoscopic Photograph of Gastropathy
9
Endoscopic Photographof Gastric Ulcer
10
Prevalence of EndoscopicNSAID-Induced Ulceration

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

11
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 19993401888-1899
12
List of NSAIDs Available by Prescription
NON-SALICYLATES SALICYLATES
COX-2 INHIBITORS
Diclofenac (Voltaren) Aspirina (Zorprin,
Easprin) Celecoxib (Celebrex) Diclofenac/Misopros
tol (Arthrotec)b Diflunisal (Dolobid)
Valdecoxib (Bextra) Fenoprofen (Nalfon)
Salsalate (Disalcid, Salflex) Flurbiprofen
(Ansaid) Choline salicylate (Trilisate) Ibuprofe
n (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 Physicians Desk Reference
13
Reducing the Risk of GI Complications with NSAIDS

• Identify risk factors
• Age (gt65 years)
• History of GI ulceration
• History of upper GI ulcer complication
• Concomitant drugs (e.g. corticosteroids,
  coumadin)
• Multiple NSAIDS
• Cardiovascular disease

Wolfe MM et al. N Engl J Med 19993401888-1899
14
Gastroprotection

• Use lowest effective NSAID dose
• Misoprostol
• Proton pump inhibitors

15
GastroprotectionMisoprostol (MUCOSA trial)
of patients with serious upper GI complications
at 6 months
p0.049
Placebo NSAID (n4439)
Misoprostol NSAID (n4404)
Silverstein et al. Ann Intern Med 1995123241249
16
Gastroprotection Proton Pump Inhibitors
of patients with recurrent upper GI bleeding at
6 months
p0.005
76 reduction in upper GI bleeding
H. pylori eradication NSAID (n75)
Omeprazole NSAID (n75)
Chan et al. N Engl J Med 2001344967973
17
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 19993401888-1899
18
List of NSAIDs Available by Prescription
NON-SALICYLATES SALICYLATES
COX-2 INHIBITORS
Diclofenac (Voltaren) Aspirina (Zorprin,
Easprin) Celecoxib (Celebrex) Diclofenac/Misopros
tol (Arthrotec)b Diflunisal (Dolobid)
Valdecoxib (Bextra) Fenoprofen (Nalfon)
Salsalate (Disalcid, Salflex) Flurbiprofen
(Ansaid) Choline salicylate (Trilisate) Ibuprofe
n (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 Physicians Desk Reference
19
Mechanism of Action of NSAIDs New Concept
COX-1Constitutive
COX-2Inducible
Non-specific NSAIDs
COX-2 NSAIDs
GI Mucosa
Platelet
Prostaglandins
Prostaglandins
Thromboxane
Mediate pain, inflammation, and fever
Hemostasis
GI mucosal Protection
Bakhle et al. Med Inflamm. 19965305-323. Vane
et al. Inflamm Res. 1995441-10.
20
GI Outcomes Trials Design
CLASS (n7982)
VIGOR (n8076)
Drug
Celecoxib 400 mg BID (2x max chronic dose)
Rofecoxib 50 mg QD (2x max chronic dose)
Comparator
Ibuprofen 800 mg TID Diclofenac 75 mg BID
Naproxen 500 mg BID
Yes (21 )
No
Low dose ASA
Duration
Median 9 months Maximum 13 months 6 months
reported
Median 9 months Maximum 13 months
Silverstein et al. JAMA. 2000 2841247-1255.
Bombardier et al. N Engl J Med.
20003431520-1528
21
CLASS Trial Upper GI Complications Alone and
With Symptomatic Ulcers
celecoxib
p 0.02
NSAIDs (ibuprofen diclofenac)
49 / 1384
p 0.09
All Patients
30 / 1441
20 / 1384
11 / 1441
p 0.02
p 0.04
Patients Not Taking Aspirin
32 / 1101
16 / 1143
14 / 1101
Annualized Incidence
5 / 1143
p 0.49
17 / 283
14/ 298
p 0.92
Patients Taking Aspirin
6 / 283
6 / 298
Symptomatic Ulcers and Ulcer Complications
Ulcer Complications
Silverstein et al. JAMA 2000 2841247-1255
22
CLASS Trial Time to Complicated Ulcer Entire
Study (13 months)

Log-rank P values Celecoxib vs
NSAIDs 0.450 Celecoxib vs diclofenac 0.640 Celecox
ib vs ibuprofen 0.414
()
Ibuprofen 800 mg TID
Diclofenac 75 mg BID
Celecoxib 400 mg BID
0
80
240
320
180
160
Days
FDA Presentation. 2/7/01.
23
GI Outcomes Trials Design
CLASS (n7982)
VIGOR (n8076)
Drug
Celecoxib 400 mg BID (2x max chronic dose)
Rofecoxib 50 mg QD (2x max chronic dose)
Comparator
Ibuprofen 800 mg TID Diclofenac 75 mg BID
Naproxen 500 mg BID
Yes (21 )
No
Low dose ASA
Duration
Median 9 months Maximum 13 months 6 months
reported
Median 9 months Maximum 13 months
Silverstein et al. JAMA. 2000 2841247-1255.
Bombardier et al. N Engl J Med.
20003431520-1528
24
VIGOR Upper GI Events at 9 Months
Events per 100 patient years
Plt0.001
Rofecoxib 50 mg qd (n4047)
Naproxen 500 mg bid (n4029)
P0.005
Complicated confirmed upper GI events
Confirmed upper GI events
Median follow-up period. Bombardier et al. N
Engl J Med. 20003431520-1528
25
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

26
In Vitro Selectivity COX-2/COX-1 Ratio
lumiracoxib
etoricoxib
rofecoxib
valdecoxib
gt 50-fold COX-2 selective
etodolac
nimesulide
5- 50-fold COX-2 selective
diclofenac
celecoxib
meloxicam
fenoprofen
lt 5-fold COX-2 selective
ibuprofen
tolmetin
naproxen
aspirin
indomethacin
ketoprofen
flurbiprofen
Warner et al. FASEB J. 200418790-804
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)
27
Rates of Clinically Significant Upper GI Events
Patients Not Taking Aspirin
A
p lt 0.05
p lt 0.05
1.2
16/1597
Etodolac
1.0
Naproxen
19/2526
0.8
Annualized incidence,
0.6
5/2210
3/1373
0.4
0.2
0
All Patients
NSAID Naïve Patients
B
Patients Taking Aspirin
p 0.68
p 0.97
2.5
6/329
Etodolac
8/520
9/583
2.0
Naproxen
5/367
1.5
Annualized incidence,
1.0
0.5
0
All Patients
NSAID Naïve Patients
Weideman RA et al. Gastroenterology
20041271322-1328
28
List of NSAIDs Available by Prescription
NON-SALICYLATES SALICYLATES
COX-2 INHIBITORS
Diclofenac (Voltaren) Aspirina (Zorprin,
Easprin) Celecoxib (Celebrex) Diclofenac/Misopros
tol (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 Physicians Desk Reference
29
Low Dose Aspirin What Are the GI Risks?
30
Daily Aspirin Dose andAdmission for Ulcer
Bleeding
Aspirin Dose 75 mg (n27) 150 mg (n22) 300 mg
(n62)
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. 1995310827-830.
31
Effect of Aspirin Doses on Gastrointestinal COX
Inhibition
1
0

m
g

A
S
A
8
1

m
g

A
S
A
1
2
0
3
2
5

m
g

A
S
A
Baseline
1
0
0
8
0
Percent of Baseline

6
0





4
0
2
0
0
Stomach
Duodenum
Rectum

( p lt 0.05 vs. Baseline )
Cryer B and Feldman F. Gastroenterology
199911717-25.
32
Risk of UGI bleeding with Different Formulations
of Low-Dose Aspirin (lt 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
33
Risk of Combining Low-Dose Aspirin with NSAIDs

• National cohort study in Denmark
• 27,694 people on aspirin 100-150 mg qd

Treatment regimen
Increased incidence over general population
95 CI
Low-dose aspirin Low-dose aspirin NSAIDs
2.6
2.2 - 2.9
4.4 - 7.0
5.6
Sorensen et al, Am J Gastroenterol 2000 95 2218
34
CLASS Trial Upper GI Complications Alone and
With Symptomatic Ulcers
celecoxib
p 0.02
NSAIDs (ibuprofen diclofenac)
49 / 1384
p 0.09
All Patients
30 / 1441
20 / 1384
11 / 1441
p 0.02
p 0.04
Patients Not Taking Aspirin
32 / 1101
16 / 1143
14 / 1101
Annualized Incidence
5 / 1143
p 0.49
17 / 283
14/ 298
p 0.92
Patients Taking Aspirin
6 / 283
6 / 298
Symptomatic Ulcers and Ulcer Complications
Ulcer Complications
Silverstein et al. JAMA 2000 2841247-1255
35
Rates of Clinically Significant Upper GI Events
Patients Not Taking Aspirin
A
p lt 0.05
p lt 0.05
1.2
16/1597
Etodolac
1.0
Naproxen
19/2526
0.8
Annualized incidence,
0.6
5/2210
3/1373
0.4
0.2
0
All Patients
NSAID Naïve Patients
B
Patients Taking Aspirin
p 0.68
p 0.97
2.5
6/329
Etodolac
8/520
9/583
2.0
Naproxen
5/367
1.5
Annualized incidence,
1.0
0.5
0
All Patients
NSAID Naïve Patients
Weideman RA et al. Gastroenterology
20041271322-1328
36
12-Week Effects of Low-dose ASA and Rofecoxib on
Ulcer Formation


Ulcer Incidence
381
387
377
374
N
P lt0.001 vs. both ASA and placebo P 0.002 vs.
placebo
Laine et al. Gastroenterology 2004 127(2)395.
37
Merck pulls popular pain drug due to risks of
heart attacks
Sept. 30, 2004
38
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

39
Efficacy of PPI in Recurrence of
NSAID-Associated Ulcers
537 patients (-) H pylori, long-term NSAID
users, prior gastric ulcer
100
80
60
Patients Remaining Ulcer Free,
40
Plt.001 misoprostol, lansoprazole 15
mg, lansoprazole 30 mg vs placebo
Misoprostol 200 mcg qid Lansoprazole 30 mg
qd Lansoprazole 15 mg qd Placebo qd
20
0
12
0
4
8
Duration of Therapy (weeks)
Graham et al. Arch Intern Med. 2002162169.
40
COX-2 Inhibitor or Non-specific NSAID PPI to
reduce GI Complications ?
High-Risk NSAID users
Lai et al Naproxen 1 Lansoprazole (n57) or
celecoxib (n58) Chan et al. Diclofenac 2
Omeprazole (n 66) or celecoxib
(n64) GI Complications () GI
Complications ()
6 months
6 months
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. 20023472104
41
Prevention of Recurrent Ulcer Bleeding in
High-Risk Patients
INITIAL STUDY GROUP 1
FOLLOW-UP STUDY GROUP 2
Celecoxib 200 mg BID placebo Diclofenac 75 mg
BID Omeprazole 20 mg QD
Patients with prior ulcer bleed on NSAID ulcer
healed and H. pylori negative or eradicated
prior to randomization
1Chan et al. N Engl J Med. 20023472104. 2Chan
et al. Gastroenterology. 2004103404.
42
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

43
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.