Management NSAID induced GI complication: the role of PPI

Prof Dr. Lukman Hakim Z, SpPD-KGEH

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

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.

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

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

Cheatum et al 1999

Prevalence of peptic ulceration is dependent on the relative NSAID toxicity

Patients with peptic ulcers (%)

500 10 30 4020

Fenoprofen

DiclofenacNaproxenSulindac

IbuprofenIndomethacin

PiroxicamFlurbiprofen

EtodolacKetoprofen

Aspirin>1 NSAID

Other NSAIDs

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

Patient-related factors:

– age >60 years

– history of peptic ulcer disease/upper GIcomplications.

Drug-related factors

– use of a relatively toxic NSAID(low dose aspirin or high dose NSAID therapy

– use of a high dose of NSAID (or two NSAIDsused concurrently)

– concurrent use of an anticoagulant

– concurrent use of a corticosteroid

Other disease– cardiovascular disease

– Helicobacter pylori infection

Lanza et al. Am J Gastroenterol 2009; 104:728 – 738

Risk factors for upper GI complications occurring with NSAIDs

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

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

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

NSAID-associated gastroduodenal damage is pH-dependent

Elliott et al 1996

intraduodenal indomethacin, 40 mg/kg

intraduodenal saline

Total 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)

Management

Algorithm for prevention of nonsteroidal antiinflammatory (NSAID)-related gastroduodenal

toxicity

NSAID useplus comorbid risks?

NO YES

• Use lower-risk NSAIDs with minimal duration and dosage

• Ask about surreptitious OTC NSAID and aspirin use

• Treat known H. pylori infection, but routine testing not indicated

• Assess cardiovascular risks

Average Risk for Gastroduodenal Complication

• All average-risk measures plus strongly consider—

• Assess for and treat H. pylori infection if present

• Institute gastroprotection with misoprostol or a proton pump inhibitor

• COX-2 selective agent if low cardiovascular risk

• COX-2 selective agent + PPI in those with a history of GI bleeding (very high risk)

High Risk for Gastroduodenal Complication

Schlansky B and hwang JH. J Gastroenterol 2009; 44[Suppl XIX]:44–52

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

Methode to prevent peptic ulcer and mucosal injury in patients taking NSAID

co-therapy with a PPI, high-dose (2 × ) H 2 RA, or the synthetic prostaglandin E1 analog, misoprostol

substitution of a COX-2 inhibitor for a traditional NSAID.

• Although co-therapy with a standard-dose H 2 RA may prevent duodenal ulcers,

it has not been shown to prevent NSAID-related gastric ulceration.• Enteric coating or buffering of NSAIDs and co-therapy with sucralfate have

not been shown to be effective in preventing NSAID-related gastric or duodenal

ulceration

Lanza et al. Am J Gastroenterol 2009; 104:728 – 738

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 receptor

Histamine 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)

Acid suppressor vs CytoprotectorAcid suppressor vs CytoprotectorMisoprostol is as effective as PPIMisoprostol is as effective as PPI

More adverse event shown in More adverse event shown in Misoprostol vs PPIMisoprostol vs PPI

Esomeprazole treatment provides significantlygreater gastric acid suppression than other PPI

0 4 8 12 16 20 24

p=0.0003

p=0.0001

Esomeprazole 40 mg Esomeprazole 40 mg

Pantoprazole 40 mg Pantoprazole 40 mg

Lansoprazole 30 mg

Time with 24 hour intragastric pH above 4

3-way crossover study, Day 5 data, patients NSAID treatment (include COX-2 selective)

hours

Goldstein et al. Aliment Pharmacol Ther 2006; 23, 1189–1196

17.8

15.9

14.6 n=90

Esomeprazole - fast and effective healing of gastric ulcers in patients taking NSAIDs, including COX-2

selective NSAIDs

*79.0

Patients healed at 4 weeks%

* p<0.05 vs ranitidine**p<0.01 vs ranitidine

Chi-squared test

Ranitidine 150 mgtwice daily

esomeprazole 20 mgonce daily

0

20

40

60

80

100

Goldstein et al. Am J Gastroenterol 2005;100:2650 - 2657

66.7

Esomeprazole – first PPI proven to be effective in preventing ulcers in at risk patients taking NSAIDs,

including COX-2 selective NSAIDs(PLUTO study, life table analysis)

COX-2 selective

Patients in group

Cumulative proportion of patients with gastric and/or duodenal ulcers at 6 months%

Non-selectiveTotal

35

19.1

24

0

150

10.6

168

5.9

185

12.3

192

5.2

Scheiman et al. Am J Gastroenterol 2006;101:701–710)

Placebo

Esomeprazole 20 mg once daily

p<0.05vs. placebo

Log-rank test

*

*

*

0

5

10

15

20

Summary

Current management approach of adding PPIs to reduce NSAIDs’ ulcer risks is an effective approach

Esomeprazole proven to be more effective for healing and preventing gastric ulcer in patients with NSAID (incl COX-2 selective than other PPI)