NSAID-associated gastric mucosal damage

NSAIDs – a long history of analgesia and toxicity

First recorded use of willow leaf extracts for musculoskeletal conditions found on Sumerian stone tablets.

Aspirin first synthesised in 1899.

First pathological evidence of gastric damage from aspirin in 1938.

New non-aspirin, non-selective NSAIDs identified in the 1950s and developed in the 1970s.

COX-2 selective NSAIDs discovered in 1992.

First COX-2 selective NSAIDs approved in 1998.

Arachidonic acid

COX-1(constitutive)

COX-2(induced by inflammatory stimuli)

Non-selective NSAIDs

• Gastrointestinal cytoprotection• Platelet activity

• Inflammation• Pain• Fever

Prostaglandins Prostaglandins

COX-2 selective NSAIDs

Vane & Botting 1995

NSAIDs inhibit the COX enzyme, which exists in two forms

Wallace et al 2000

Gastric mucosal damage requires inhibition of both COX-1 and COX-2

Gastric damage score (%)

0

5

10

15

* p<0.05

Vehicle Celecoxib SC-560 Indo-methacin

Celecoxib+

SC-560

**

Systemic effects of NSAIDs decrease the defences of the gastric mucosa

Prostaglandins regulate a variety of defence mechanisms:

– increased secretion of mucus, mucopolysaccharide and bicarbonate ions

– decreased permeability of epithelial cells

– increased restitution of the epithelial layer.

Gastric blood flow is significantly decreased by indomethacin in a rat model

Wallace et al 2000

110

Gastric blood flow (% of basal)

indomethacin,10 mg/kg

vehicle

* p<0.05

** p<0.01

10 20 30 40 50 60

90

70

50

00

Time after administration (minutes)

***

**

** **

NSAIDs increase neutrophil–endothelial adhesion

NSAIDs

Decreased prostaglandin,

increased tumour necrosis factor

Increased neutrophil–endothelial adhesion

Capillary obstruction Neutrophil release ofproteases and oxygen-

derived free radicals

Ischaemic/hypoxic cell injury

Endothelial and epithelial injury

Mucosal ulcerationWallace et al 1997

COX-2 selective NSAIDs promote leucocyte adherence to the endothelium in a rat model

Wallace et al 2000

* p<0.05 versus vehicle

celecoxib, 1.0 µmol/L

SC-560, 1.0 µmol/L

celecoxib, 3.0 µmol/L

indomethacin, 7.0 µmol/L

vehicle, 1.0 µmol/L

0 15 30 45 600

20

15

10

5

*

* *

*

*

*

Adherent leucocytes/100 µm

Time (minutes)

NSAID damage to the gastric mucosa.Scanning electron micrographs of normal gastric mucosa (left) andmucosal surface (right) 16 minutes after administration of aspirin.

Baskin et al 1976

Topical irritant effects from NSAIDs

Gastric acid plays a central role inNSAID-associated gastroduodenal damage

Acidicenvironment

Bicarbonate layer

Ionic gradient

GastricacidNSAIDs Pepsin

Surfaceepithelial cells

Mucuslayer

Neutralenvironment

Mucosalblood supply

Alkaline environment

Prostaglandin production

Bicarbonate production

Mucus production

NSAIDs

NSAID-associated gastroduodenal damage is pH-dependent

Elliott et al 1996

intraduodenal indomethacin, 40 mg/kg

intraduodenal salineTotal haemorrhagic mucosal area(%)

Gastric luminal pH

02.0 4.0 5.5 7.0

1

2

3

4

5

Plachetka et al 2003

Probability of NSAID-associated gastroduodenal damage is related to gastric acidity

0

20

40

60

80

Probability of no pathology (%)100

50000 4000300020001000Integrated gastric acidity (mmol•hour/L)

Upper GI side-effects

NSAID use is associated with upper GI side-effects

NSAIDs, including COX-2 selective NSAIDs, are associated with an increased risk of upper GI symptoms.

NSAIDs, including COX-2 selective NSAIDs, are associated with peptic ulceration.

Complications of NSAID use – bleeding, perforated or obstructed peptic ulcers – are a major cause of morbidity and mortality.

Langman et al 1999; Silverstein et al 2000;Wolfe et al 1999

Cumulative incidence of upper GI symptoms is approximately 25% with both non-selective and

COX-2 selective NSAIDs

†Acid reflux, dyspepsia, epigastric discomfort, heartburn, nausea or vomiting. Langman et al 1999

non-selective NSAIDsn=1564

Cumulative incidence of upper GI symptoms† over 6 months (%)

0

10

20

30

rofecoxibn=3357

* p<0.05

*

Simon et al 1999

†Dyspepsia, diarrhoea, abdominal pain, nauseaand flatulence.

Incidence of upper GI symptoms in patients free from ulcer is similar with non-selective and COX-

2 selective NSAIDsPatients with upper GI symptoms† (%)

All doses taken twice daily

0

5

10

15

20

25

30

35

Celecoxib,100 mgn=240

Celecoxib,200mgn=235

Celecoxib,400 mgn=217

Naproxen,500mgn=225

NSAID users have increased prevalence of heartburn, acid reflux and epigastric pain

Harvey et al 2003

n=4902

Prevalence (%)

heartburnacid refluxepigastric pain

0

10

20

30

40

50

None Aspirin NSAIDsexcluding

aspirin

Aspirin+ otherNSAIDs

Hallas & Bytzer 1998

2.4

ACE inhibitors

NSAID ingestion is one of the few drug-related risk factors for dyspepsia

0.40.0 0.8 1.2 1.6 2.0

NSAIDs

Calcium blockers

Corticosteroids

Methylxanthines

Adjusted rate ratio (CI) of prescription preceding the use of an anti-ulcer drug

Poor health-related quality of life among patients free from ulcer taking NSAIDs, including COX-2

selective NSAIDs

Data on file, NASA 1 & SPACE 1;Gralnek et al 2000; van der Molen et al 1997;

Ware & Sherbourne 1992

US populationn=2474asthman=110diabetes mellitusn=541NSAIDs (NASA 1)n=500NSAIDs (SPACE 1)n=579

0

20

40

60

80

100Mean SF-36 score

Physic

al

functi

oning

Role ph

ysica

l

Bodily

pain

Genera

l hea

lth

Mental

healt

h

Role em

otion

al

Vitality

Social

functi

oning

Upper GI side-effects impact negatively on patients’ lives and can lead to withdrawal from

treatment

Productivity at work and daily activities are reduced amongst NSAID users:

– 13% reduced productivity at work (n=27)

– 26% reduced daily activities (n=61).

More than half of all patients who switch NSAIDs do so because of side-effects.

44% of prescribers select the NSAID dose to minimise side-effects – at the expense of pain relief.

Knott 2000; Steinfeld et al 2002; Wahlqvist et al 2003

NSAID users are at risk of reflux esophagitis

Reflux esophagitis LA Grades A–D.

Photos reproduced with permission from Professor G Tytgat

Avidan et al 2001

Reflux esophagitis: the presence of definite mucosal breaks or metaplasia of the esophagus, visible under endoscopy.

Among patients taking non-selective NSAIDs for osteoarthritis, the prevalence rate of erosive esophagitis was 21%.

A B

C D

NSAID-associated peptic ulceration

The majority of patients develop some gastric erosions after each doseof a non-selective NSAID.

Approximately 15–30%of NSAID users develop endoscopically evident ulcers at any one time – these will be generally silent.

COX-2 selective NSAIDs reduce the incidence of peptic ulcers compared with non-selective NSAIDs, but patients with risk factors or those who also use low-dose aspirin remain at risk.

Photo reproduced from the Interactive Atlas of Gastroenterology

Hawkey & Skelly 2002; Laine 1996; Silverstein et al 2000

Hawkey et al 1997

NSAID-associated dyspepsia may predict peptic ulcer disease

ASTRONAUT

Relative risk of developing an ulcer/multiple erosions in those with moderate/severe dyspepsia

OMNIUM

0

2

4

6

8

10

Healing Maintenance

1.8

3.9

5.3

7.8

Cheatum et al 1999

Prevalence of peptic ulceration is dependent on the relative NSAID toxicity

Patients with peptic ulcers (%)500 10 30 4020

FenoprofenDiclofenacNaproxenSulindac

IbuprofenIndomethacin

PiroxicamFlurbiprofen

EtodolacKetoprofen

Aspirin>1 NSAID

Other NSAIDs

Laine et al 2004

Risk of peptic ulceration is similar between non-selective and COX-2 selective NSAIDs with

concomitant low-dose aspirinplacebon=410

aspirinn=406

rofecoxib + aspirinn=399

ibuprofenn=400

Cumulative incidence of ulcers (%)

*** p<0.001 versusplacebo + aspirin

02

4

6

8

10

12

14

16

18***

***

Upper GI complications

Fourfold increased risk of serious upper GI events from non-aspirin NSAID use

Hernãndez-Díaz & Garcia Rodriguez 2000

Griffin 1991Laporte 1991Holvoet 1991Nobili 1992Keating 1992Henry 1993Kaufman 1993Savage 1993Garcia Rodriguez 1994Langman 1994Lanza 1995Traversa 1995Hallas 1995Matikainen 1996Perez Gutthann 1997MacDonald 1997Wilcox 1997Garcia Rodriguez 1998

Relative risk of upper GI bleeding or perforation

0

1

2

3

4

5

6

7

8

Study

Weil et al 1995

Aspirin, alone or with another NSAID, increases the risk of upper GI complications

Relative risk

Aspirin,75 mg

once daily

Aspirin,150 mg

once daily

Aspirin,300 mg

once daily

NSAIDs Aspirin + otherNSAIDs

0

1

2

3

4

5

6

7

8

Henry et al 1996

Risk of GI complications is dependent on the relative NSAID toxicity

Estimated relative risk of haemorrhage or perforation

Azap

ropa

zone

50.0

0.5

Piro

xicam

Keto

prof

enIn

dom

etha

cinNa

prox

enAs

pirin

Sulin

dac

Diflu

nisal

Diclo

fena

cIb

upro

fen

Bombardier et al 2000

†Perforation, obstruction, bleedingor symptomatic peptic ulcer.

Rofecoxib carries a lower overall risk of upper GI events than naproxen

naproxen, 500 mg twice dailyrofecoxib, 50 mgonce daily

Duration of follow-up (months)

Cumulative incidence of a confirmed upper GI event† (%)5

3

4

2

0

1

0 42 1086 12

n=8076

Jüni et al 2002

No long-term advantage of celecoxib overnon-selective NSAIDs in terms of ulcer

complications

diclofenac

celecoxib

ibuprofen

Duration of follow-up (months)

Cumulative proportion of ulcer complications (%)

0 3 6 9

1.0

0.8

0.6

0.4

0.2

0.012

Hawkey & Skelly 2002

Risk of ulcer complications with celecoxib remains high among patients with other risk

factors

More than one risk factor

ibuprofen, 800 mg three times daily, or diclofenac, 75 mg twice daily

celecoxib, 400 mg twice daily

Patients with ulcer complications (%)

2

0

1

No risk factor

n=8059

Hawkey & Skelly 2002

†Perforation, obstruction, bleeding or symptomatic peptic ulcer.

With rofecoxib, the risk of upper GI side-effects is higher among patients with other risk factors

3

naproxen, 500 mg twice daily

rofecoxib, 50 mg once daily

Patients with upper GI events†

(%)6

4

2

0No risk factor More than

one risk factor

5

1

High-risk patients with previous GI disease remain at risk of upper GI bleeding with COX-2

selective NSAIDs

Nørgard et al 2004

Adjusted odds ratio for upper GIbleeding

Prescription within 30 days of hospital admission

0.0

0.5

1.0

1.5

2.0

2.5

3.0

3.5

Celecoxib Rofecoxib Non-aspirin,non-selective

NSAIDs

n=3686

Silverstein et al 2000

Annualised incidence (6-month data) (%)Upper GI ulcercomplications

Upper GI ulcer complications +

symptomatic peptic ulcers

Celecoxib + aspirin 2.01 4.7

NSAID + aspirin 2.12 6.0

Celecoxib alone 0.44

p<0.05

1.40

p<0.05

NSAID alone 1.27 2.91

Concomitant aspirin therapy increases the rate of upper GI ulcer complications with celecoxib

Risk factors

Patient-related factors:– age >60 years– history of peptic ulcer disease/upper GI

complications.

Drug-related factors– use of a relatively toxic NSAID– use of a high dose of NSAID (or two NSAIDs

used concurrently) – concurrent use of an anticoagulant– concurrent use of a corticosteroid.

Seager & Hawkey 2001

Risk factors for upper GI complications occurring with NSAIDs

Weil et al 2000

Risk factors for peptic ulcer bleeding

Odds ratio0 1 2 3 4 8

Current smoking

Diabetes

Heart failure

Dyspepsia in past year

Previous peptic ulcer

Warfarin use

Oral corticosteroid use

NSAID use

5 6 7

NSAID-associated dyspepsia is a risk factor for NSAID-associated ulcer complications

Risk factor Adjusted odds ratio 95% CIAge

60 years 1.0 Reference group61–75 years 5.7 (2.6–12.6)75 years 12.7 (5.5–29.4)

Male 1.0 Reference groupFemale 0.5 (0.3–1.0)Dyspepsia 2.0 (1.0–4.2)NSAID-associated dyspepsia

8.7 (4.0–18.9)

Ulcer history 2.0 (0.9–4.6)Duration of treatment

3 months 1.0 Reference group3–12 months 0.3 (0.1–0.9)1 year 0.2 (0.1–0.4)

Current smokers 1.9 (1.0–3.6)Hansen et al 1996

Risk of upper GI events may be silent

50–60% of NSAID-associated peptic ulcers, presenting for the first time as a complication, have been silent previously.

Most patients with endoscopic lesions do not develop dyspepsia:

– 9% of patients with abnormal endoscopy had dyspeptic symptoms (n=45).

Larkai et al 1987; Singh 1998

Gutthann et al 1997

female non-usersmale non-usersfemale usersmale usersHospitalisations/1000 person-years

15 20 25 30 35 40 45 50 55 60 65 70 75 80 85+

20

15

10

5

0

25

Age (years)

NSAID-associated complications are a particular problem in the elderly

Huang et al 2002

H. pylori infection and NSAID use synergistically increase the risk of peptic ulcer disease

Patients with peptic ulcer (%) NSAID users

controls100

80

40

20

0

60

H. pylori-positiven=180

H. pylori-negativen=205

H. pylori-positiven=127

H. pylori-negativen=149

Chan et al 2002

Uncertainty over the benefit of eradication ofH. pylori before initiating NSAID therapy –

eradication is beneficial

eradication6-month probability of ulcer (%)

placebo

0

10

20

30

40

Any ulcer Complicated ulcers

**

** ** p<0.01

Uncertainty over the benefit of eradication ofH. pylori before initiating NSAID therapy – PPI

therapy is as beneficial as eradication

Labenz et al 2002

* p<0.05** p<0.01

Patients with peptic ulcer (%)

triple therapy+ placebo

n=161

triple therapy+ PPIn=173

PPIsn=155

placebon=171

0

1

2

3

4

5

6

7

* *

**

Hospitalisations and mortality

Armstrong & Blower 1987; Singh 1998; Wolfe et al 1999

NSAIDs are associated with the risk of serious upper GI complications, hospitalisation and

mortality

Non-selective NSAIDs account for approximately 20–25% of all reported drug adverse events.

80% of peptic ulcer-related deaths occur in non-selective NSAID users.

In the USA, NSAID use accounts for approximately 107,000 hospitalisations and 16,500 deaths per year.

Wolfe et al 1999

†1997 US mortality data for seven selected disorders.

NSAID-associated deaths: the ‘silent epidemic’

NSAID toxicityLeukaemia AIDS

Multiple myelomaAsthma

Cervical cancer

Hodgkin’s disease0

5000

10,000

15,000

20,000

25,000

Number of deaths†

The annual costs of medical care forNSAID-associated upper GI complications are conservatively estimated to exceed US$2 billion.

Excess cost for the care of gastroduodenal disease in non-selective NSAID users increases with dose:

– <1 standard dose per day: US$56

– 1–2 standard doses per day: US$120

– >2 standard doses per day: US$157.

Singh & Triadafilopoulos 1999; Smalley et al 1996

Excess costs of treating NSAID-associated upper GI side-effects

Factor by which drug costs must be multiplied to reflect the cost of care

Country Naproxen Diclofenac PiroxicamUK 1.40–1.44 1.42–1.47 1.84–1.93France 1.36 1.65 1.67

Canada 1.31 1.22–1.67 1.95Country All NSAIDsCanada 1.66 (1.61–7.49)USA 1.45USA 2.99 (non-aspirin)

NSAID-associated upper GI side-effects substantially increase the total cost of care

Bidaut-Russell & Gabriel 2001

Management

Managing NSAID-associated upper GI side-effects

Options for therapy:– dose reduction or switch to a less toxic NSAID

– prostaglandin analogue to replace gastroprotective prostaglandins

– H2-receptor antagonist or PPI to reduce the acidity of the stomach.

Guidelines recommend that patients withat least one GI risk factor receive either a non-selective NSAID with a co-prescribed GI-supportive therapy or a COX-2 selective NSAID.

American College 2002; Dubois 2004; NICE 2001

PPIs control acid secretion by directly inhibiting the proton pump

Inhibition of acid secretion

Parietalcell

Canalicularspace

Proton pump

Inhibition of proton pump

Activation

Concentration

PPI(inactive)

Gastric glandH+

Blood

H2-receptor antagonists inhibit signal transduction to the proton pump

H+

Acid secretion

Signal transduction to activate proton pump

Parietal cell

Histamine receptorHistamine receptor antagonist

Histamine

Inhibition of histamine receptor

Gastric gland

Blood

Proton pump

PPIs, H2-receptor antagonists and prostaglandin analogues in treating NSAID-associated

heartburn

Hawkey et al 1998; Yeomans et al 1998; Wilson et al 2001

0 7 14 21 28

Patients with heartburn (%)60

40

20

0

misoprostol, 200 µg four times daily

omeprazole, 20 mg once daily

60

40

20

00 7 14 21 28

Duration of treatment (days)

Patients with heartburn (%) ranitidine, 150 mg twice daily

omeprazole, 20 mg once daily

Duration of treatment (days)

PPIs, H2-receptor antagonists and prostaglandin analogues in ulcer healing

Hawkey et al 1998; Yeomans et al 1998

–40 –30 –20 –10 0 10 20 30 40

Omeprazole, 20 mg once dailyOmeprazole, 40 mg once daily

Omeprazole, 20 mg once dailyRanitidine, 150 mg twice daily

Omeprazole, 20 mg once dailyMisoprostol, 200 µg four times daily

Therapeutic gain (%) for the first-named drug (95% CI)

PPIs and H2-receptor antagonists in ulcer prophylaxis

Yeomans et al 1998

gastric ulcer

duodenal ulcer

Omeprazole, 20 mg once daily

Ranitidine,150 mg twice daily

40

30

20

10

0

Patients developing an ulcer (%)