Management NSAID induced GI complication: the role of PPI Prof Dr. Lukman Hakim Z, SpPD-KGEH
Jun 03, 2015
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)