MANAGEMENT OF NSAID GASTROPATHY

Marcellus Simadibrata Kolopaking MD PhD

Department of Medical EducationDivision Gastroenterology Department of Internal MedicineFaculty of Medicine University IndonesiaDr.Cipto Mangunkusumo Hospital Jakarta

Introduction

NSAIDs are used throughout the world.

NSAIDs are associated with significant upper GI side-effects NSAID gastropathy

Epidemiology

United States: + 15 – 20 million people long-term NSAID users.

Incidence serious GI complications with NSAID use :1 - 3 % per year. Exposure of 10 million patients 100,000 -300,000 potentially fatal GI complications annually.

Epidemiology

Indonesia hospital base data of NSAID adverse effect :

Makassar 71%

Jakarta 62.7%

Surabaya 61%

Malang 21% (NSAID 22.6%, Jamu 65.3%, NSAID + Jamu 12.1%)

No population data

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 enzim COX (siklooksigenase) enzyme which has

the role in prostaglandin production

NSAIDs are associated with significant upper GI side-effects

Classical NSAIDs account for approximately 20-25% of all reported drug adverse events.

It has been estimated that 15-40% of patients taking NSAIDs experience upper GI symptoms.

The majority(50%) of patients develop some gastric erosions after each dose of a classical NSAID, up to 100% patients will demonstrate subepithelialhemorrhage, and 10-25% of chronic users will develop a peptic ulcer.

Hazleman 1989; Wolfe et.al. 1986

Hirschowitz 1994; Langman et.al. 1999; Silverstein et.al. 2000; Singh et.al. 1996

Brown & Yeomans 1999; Eliott et.al. 1994; Laine 1996

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

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

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

Potentially life-threatening upper GI complications occur in 1-4% of classical NSAID users each year.

In the USA, NSAID use has accounted for approximately 107.000 hospitalisations and 16.500 deaths per year

Armstrong & Blower 1987

Singh 1998

Wolfe et.al. 1999

Table 1. Risk For Serious Gastrointestinal Complications

Related To Use Of Nonsteroidal Antiinflammatory Drugs

NUMBER 95%

OF ODDS CONFIDENCE

CATEGORY STUDIES* RATIO INTERVAL

Overall 16 2.74 2.54–2.97

Patient > 60 years old 8 5.52 4.63–6.60

Patient < 60 years old 3 1.65 1.08–2.53

Gastrointestinal bleeding 9 2.39 2.11–2.70

Gastrointestinal surgery 3 7.75 5.83–10.31

Gastrointestinal cause of death 4 4.79 3.64–6.22

*Data derived from metaanalysis of 16 casecontrol and cohort studies.

Modified from Gabriel S. Jaakkimainen L. Bombardier C. Risk for serious gastrointestinal

complications related to use of nonsteroidal antiinflammatory drugs. A metaanalysis. Ann

intern Med 1991; 115: 787.

Patient’s Risk Factor for GI complications

High risk:

- History of peptic ulcer with complication

- Multiple(>2) risk factors

Moderate risk:

- Age > 65 yo

- High dose NSAID therapy

- History of ulcer without complication

- Uses of aspirin, corticosteroid or anticoagulat

Low risk:

- Without risk factor

Konsensus Gastropati OAINS 2010

Patient’s Risk Factor for GI complications

High risk:

- History of peptic ulcer with complication

- Multiple(>2) risk factors

Moderate risk:

- Age > 65 yo

- High dose NSAID therapy

- History of ulcer without complication

- Uses of aspirin, corticosteroid or anticoagulat

Low risk:

- Without risk factor

Konsensus Gastropati OAINS 2010

Long-term Risks of Peptic Ulcers Associated With Helicobacter pyloriInfection and NSAIDs

Study design/methods.

183 cases with peptic ulcers and 730 controls (1:4)

Results.

H pylori infection is associated with an elevated risk of peptic ulcers (OR: 1.95, 95% CI: 1.38-2.74).

Compared to no NSAIDs, any NSAID use (OR: 1.54, 95% CI: 1.06-2.23) increases the risk of peptic ulcers.

There is also a significant interaction between NSAIDs and H pylori (P = .047 for interaction of H pylori and increasing quartiles of NSAID use).

Conclusion.

H pylori infection and NSAID use increase the risks of peptic ulcers. The ulcer risk associated with NSAID use among H pylori-negative subjects is greater than that for those with H pylori infection.

Lew et.al. http://cme.medscape.com/viewarticle/490253_12

Definition of NSAID Gastropathy NSAID gastroduodenopathy: acute mucosal

lesion of the gaster & duodenum due to Nonsteroidal antiinflammatorydrugs(NSAID): hyperemia, erosions & ulcer

Peptic ulcer: ulceration of the gaster & duodenum related to acid – pepsin & other agresive factors

Pathophysiology of NSAID Gastropathy

- NSAID/ASA topical: GI mucosal damage

systemic: decreased prostaglandin COX-1

- Adenosine diphopsphate receptor antagonist(clopidogrel)

inhibit gastric ulcer healing inhibit platelet/VEGF

release

Konsensus gastropati OAINS 2010

ETIOLOGY OF NSAID GASTROPATHY

Etiology : NSAID agresive factor

Imbalance of agresive factor and defensive factor

Agressive factors Defensive factors

-Gastric acid -Mucosal blood flow

-Pepsin -Surface epithelial cell

-Bile reflux -Prostaglandin

-Niotine -Phospholipid/surfactan

-NSAID -Mucus

-Corticosteroid -Bicarbonat

-Helicobacter pylori -Motility

-Stress -Mucosal impermeability to H+

-Chemical -Intracell pH regulation

Normal balance of aggressive factors & defensive factors in normal stomach

Hiraishi H et al., Mebio 1994;11(19):86 (Japanese)

Phospholipase

LipoxygenaseCyclooxygenase

NSAIDs

Phospholipid

Arachidonic acid

Decrease of PGs

Decrease mucosal defense

Mucus reductionDecrease of HCO3

- secretionMicrocirculation injury

Gastric mucosal injury

Increase of LTs

Increase free radicals

Ischemia-reperfusion

Neutrophil activation

H+ dependent pathway

Accumulation in cells

Directly damage cells

Vasospasm

LTC4

LTD4

LTB4

Liposoluble

Inhibition

Free radicals play an important role in NSAIDs-induced gastric mucosal injuries

Aspirinand other

NSAIDs

PROTECTIVEFACTORS

Mucus layer

Ionic gradient

Bicarbonate layer

Prostaglandins

Surface epithelialcells

Mucosal bloodsupply

H. pyloriPepsinGastric

acid

AGGRESSIVE FACTORS

Aspirin andother NSAIDs

Prostaglandinproduction

Bicarbonateproduction

Mucusproduction

Acidicenvironment

Neutral environment

Gastric acid plays a central role inNSAID-associated gastroduodenal damage

CLINICAL MANIFESTATION OF NSAID GASTROPATHY

No symptom

Dyspepsia: epigastric pain, epigastricdiscomfort, bloating, early satiety, vomitus, nausea, belching etc

Fatigue

Upper GI bleeding

Stricture/stenosis

Acute abdomen: perforation

SUPPORTING EXAMINATION

Pheripheral blood examination, liver function test, kidney function test, fecal occult blood test.

H.pylori infection: serology, biopsy culture of the gastric mukosa, histopathology, CLO test, 14 C urea breath test, stool antigen

Esophago-gastroduodenoscopy

Barium meal X-ray(OMD)

Diagnosis of NSAID Gastropathy History of NSAID consumption & dyspepsia

Physical examination

Supporting examinations: laboratory, esophagogastroduodenoskopy examination, Barium meal(OMD)

Diagnostic Evaluation

Gastrics with erosions

Endoscopy

Biopsyforceps

Cytologybrush

ENDOSCOPICAL APPEARANCES

Lesions: Hyperemia, erosion & ulcer

Bleeding: active/not, oozing, spurting

Lesions in stomach, duodenum & jejunum

HISTOPATHOLOGICAL ABNORMALITIES

Subepithelial hemorrhage

Epithelial thinning & separation

Mucus thinning & disappearance

Mucosal erosion & ulcer

COMPLICATION OF NSAID GASTROPATHY

Obstruction(5%)

Perforation(<10%)

Upper GI bleeding(15%): continue to hypovolemic shock, anemia

INDONESIAN CONSENSUS RECOMMENDATIONS

1. GI complications of NSAID (ASA and Non ASA NSAID)

As the use of NSAID (Including COX-2 selective and OTC traditional NSAID) in conjunction with cardiac-dose ASA increase the risk of ulcer complications gastroprotective therapy should be prescribed for at risk patients

2. GI Effects of ASA

The use of low-dose ASA for cardioprophylaxis is associated with a two-to four fold increase in in UGI effects

Enteric coated or buffered preparation do not reduce the risk of bleeding

The risk of UGI effects increases with ASA dose escalation for chronic phase of therapy, doses >81 mg should not be routinely prescribed

For patients at risk of adverse effects gastro protective therapy should be prescribed

3. Gastrointestinal Effect of Combined ASA and Anticoagulant Therapy

The combination between ASA & anticoagulant therapy (including unfractionated heparin, LMWH, Warfarin) is associated with extracranial bleeding, and the large proportion is UGI bleeding

Patient should receive concomitant PPI as well

In the long term management of ACS, multipleRCTs show that combination between anticoagulant therapy and antiplatelet is superior to anti platelet alone, but it also increase the risk of GI effect

A meta analysis of 4 RCTs unfractionnated heparin + ASA vs ASA alone for ACS 50% increase of major bleeding

4. GI Effects of Clopidogrel

Substitution of clopidogrel (thienopyridine) is not a recommended strategy to reduce the risk of recurrent ulcer bleeding in high risk patients and is inferior to the combination of ASA plus PPI

Many studies show that combination between PPI and clopidogrel decrease the risk of UGI bleeding compared with clopidogrel alone

Conlicting data exist as to wether PPI diminish the efficacy of clopidogrel

The current trials: PRINCIPLES-TIMI 44 (Prasugrel in comparison to clopidogrel for inhibition of platelet activation and aggregation thrombolysis in myocardial infarction) and TRITON-TIMI 38 (Trial to Assess Improvement in Therapeutic Outcomes by optimizing Platelet Inhibition with Prasugrel-Thrombolysis in Myocardial Infarction)

Assessed the association between PPI use, platelet function and clinical outcomes for patient treated with clopidogrel or prasugrel PPIs do not diminish antiplatelet effect of clopidogrel or prasugrel

5. GI Effects of Combination Between Clopidogrel and Anticoagulant Therapy

The combination of clopidogrel and warfarin therapy greater risk of bleeding, compared with monotherapy alone

use of combination antiplatelet and anticoagulant therapy should be considered only in cases which the benefits are likely to outweigh the risk

6. Treatment and Prevention of NSAID Gastropathy

PPI are the preferred agents for the therapy and prophylaxis of NSAID (including ASA) GI-injury

Goal of treatment :

To relief the symptoms

To heal the lession

To prevent ulcer and complication

To prevent ulcer reccurence

Prevention

NSAID + PPI/Misoprostol

Less side effect NSAID

Misoprostol (synthetic prostaglandin analogue)

effective in the prevention of NSAID Gastropathy, but it has more side effects as abdominal cramp and diarrhea

Patient with NSAID or antiplatelet (ASA or clopidogrel) consumption

Evaluate gastrointestinal risk factors

Gastrointestinal bleeding

Dual antiplatelet therapyAnticoagulant therapy

History of complicated ulcerHistory of ulcer without bleeding

Upper and/or Low GI Endoscopy (if facility available)

More than 1 risk factor:Age ≥ 65 yoCorticosteroid consumptionDyspepsia or GERD

PPI+rebamipide/misoprostol*** PPI/rebamipide/misoprostol***

Upper GI Ulcer

H. Pylori test(UBT, HpSA)

If (+) therapy

PPI/rebamipide/misoprostol***

TREATMENT AND PREVENTION OF NSAID GASTROENTEROPATHY

Yes

Yes

Yes

Yes No

No

PATIENT RISKS FOR GASTROINTESTINAL COMPLICATIONS

• High risk:

1. History of complicated ulcer

2. Multiple of risks(>2)

• Moderate risk:

1. Age > 65 yo

2. High dose NSAID treatment

3. History of non complicated ulcer

4. Consumption: Aspirin, corticosteroid, anticoagulan

• Low risk:

1. Without risk factor

National consensus 2011 on the management of NSAIDGastroenteropathy in Indonesia. Jakarta

SUMMARY OF THE RECOMMENDATION PREVENTION OF NSAID GASTROENTEROPATHY

Gastrointestinal Risks

Mild Moderate Severe

CV Risks

low*

NSAID +

rebamipide/

misoprostol***

NSAID + PPI/

rebamipide /

misoprostol***

Alternative

therapy or COX2

inhibitor +PPI /

rebamipide /

misoprostol***

CV Risks

high**

Naproxen +

PPI/rebamipide/

misoprostol***

Naproxen +

PPI/rebamipide/

misoprostol***

Avoid NSAID or

COX2 inhibitor,

Alternative therapy

*Cardiovascular Risks (CV) low: do not need low dose aspirin / clopidogrel** Cardiovascular Risks(CV) high: need low dose aspirin / clopidogrel*** Misoprostol frequently caused side effects diarrhea and abdominal cramp.

Many RCTs showed:

Lansoprazole is more effective than ranitidine

Lansoprazole is more effective than omperazole

in the prevention and treatment of NSAID gastropathy and in the prevention of ulcer reccurency

Effectivity of other PPI in the management of NSAID gastropathy required further data

Figure. Healing rate of NSAID-associated gastric ulcer

Maeda dkk. 1998. Therapeutic Research

22/52 (42.3)

4 8

50

100

Hea

ling

rat

e

Weeks

: H2 blocker (52 lesions): H2 blocker + cytoprotective drugs(52 lesions): PPI (62 lesions)

(%)

31/62 (50.0)

50/62 (80.6)

32/52 (61.5)

( ) : %

33/103 (32.0)

70/103 (68.0)

Figure. Healing rate of NSAID-associated gastric ulcer (Omeprazole vs Lansoprazole)

Maeda dkk. 1998. Therapeutic Research

4 8

50

100H

ealin

g r

ate

Weeks

: Omeprazole (25 lesions): Lansoprazole (37 lesions)

(%)

20/37 (54.1)

11/25 (44.0)

32/37 (86.5)

18/25 (72.0)

( ) : %

Figure. Cumulative rates of healing at 4 and 8 weeks during treatment with ranitidine hydrochloride, 150 mg twice daily; 15 mg once daily; or lansoprazole, 30 mg once daily, among intent-to-treat patients

Naurang. et al. 2000. Arch Intern Med

4 8

50

100

(%) H

eale

d

Week

: Ranitidine Hydrochloride: Lansoprazole, 15 mg: Lansoprazole, 30 mg

(%)

40

90

30

80

20

70

10

60

Gastric ulcers

Pharmacokinetic and acid inhibition profiles

Efficacy

Indications and formulations

Potential for drug interactions

Tolerability/safety

Choosing a PPI to manage acid related diseases:

factors to be considered

Tolman et al, J Clin Gastroenterol 1997; 24: 65–70.Howden et al, Clin Pharmacokinet 1991; 20: 38–49.

Hassan-Alin et al, Eur J Clin Pharmacol 2000; 56: 665–70.

Omeprazole has up to 40% bioavailability after first dose

l Progressive increase in bioavailability (to about 60%) and antisecretory effect to day 5

Lansoprazole bioavailability is 85% after first dose

Esomeprazole bioavailability is 64% after first dose; half-life similar to omeprazole

Bioavailability of PPIs

Bio

ava

ila

bil

ity

(%

)

Tolman et al, J Clin Gastroenterol 1997; 24: 65–70.Fitton & Wiseman, Drugs 1996; 51: 460–82.

Hassan-Alin et al, Gastroenterology 2000; 118: A16.Swan et al., Aliment Pharmacol Ther 1999; 13(Suppl 3): 11–7.

Howden, Clin Pharmacokinet 1991; 20: 38–49.

PPI bioavailability after the first dose

8090

80

70

60

50

40

30

20

10

0

Lansoprazole Pantoprazole Esomeprazole Rabeprazole Omeprazole

77

64

52

40

Tolman et al., J Clin Gastroenterol 1997; 24: 65–70.

Me

an

24

-h g

ast

ric

pH

5

Pre-regimen Day 1 Day 5

4

2

0

**

**

Lansoprazole 30 mg once daily

Omeprazole 20 mg once daily

Double-blind crossover study in 14 healthy volunteers

**p<0.002 after first and fifth doses

Speed of onset of PPI-induced

acid suppression

3

1

Thoring et al., Scand J Gastroenterol 1999; 34: 341–5.

n=15, crossover study healthy volunteers

300

200

0

Tim

e t

o r

ea

ch p

H >

4 (m

inu

tes)

130

250

Lansoprazole30 mg

100

Omeprazole20 mg

Time to acid suppression:

lansoprazole vs omeprazole

Mean time

to pH 4

(hours:minutes)

Difference (minutes) p-value

Lansoprazole 30 mg 1:29

-7 0.70

Esomeprazole 40 mg 1:22

Lansoprazole 15 mg 1:50

16 0.48

Esomeprazole 20 mg 2:06

Eriksson et al., Scand J Gastroenterol 2001; 36(Suppl 233): 49.

Equivalent speed of onset of acid

suppression: lansoprazole and esomeprazole

Esomeprazole 40 mg IV satu kali sehari lebih cepat dan lebih efektif mengontrolkeasaman lambung dibandingkan pantoprazole 40 mg IV

Drug tested Lansoprazole Omeprazole Esomeprazole Pantoprazole Rabeprazole

Phenytoin No Yes No No No

Warfarin No Yes No No No

Diazepam No Yes Yes No No

Prednisone No No NT NT NT

Oral contraceptive No No NT No NT

Propranolol No No NT NT NT

Metoprolol NT NT NT No NT

Theophylline No No NT No No

Parsons et al., Eur Gastro Hepatol 1996; 8(Suppl 1): S15–20; Fitton & Wiseman, Drugs 1996; 51: 460–82. Freston, Am J

Gastroenterol 1997; 92(Suppl 4): S51–5; Humphries et al., Gut 1996; 39(Suppl 3): 297.

Pan et al., Gastroenterology 1999; 116: A276; Nexium Prescribing Information, 2001.

Henry et al., Eur J Clin Pharmacol 1987; 33: 369–73; Karol et al., J Clin Pharmacol 2000; 40: 301–8.

NT = not tested

Interactions between PPIs

and other drugs

7. Role of H. pylori

Testing for and eradicating H. pylori in patient with history of ulcer disease is recommended before starting NSAID/Antiplatelet therapy

Both H. pylori infection and NSAID use independently and significantly increase the risk of peptic ulcer and ulcer bleeding

H. pylori infection and NSAID use are synergistic for peptic ulcer development and ulcer bleeding

Huang et al., Lancet 2002; 359: 14–22.

Intragastric pH with high-dose iv PPI therapy

Clinical pharmacology studies H. pylori-negative healthy volunteers

24 hour iv infusion

1Röhss K, et al. Intl J Clin Pharm Ther 2007;45:345–54; 2Metz DC, et al. Aliment Pharmacol Ther 2006;23:985–95

n Median/mean Time pH>624-hour pH (0–24 hours)

Esomeprazole80 mg + 8 mg/hour1 25 5.8 12.6

Pantoprazole80 mg + 8 mg/hour2 36 5.0 5.5–6.7

* This is not “ a head to head” study

8. Discontinuation of Antiplatelet Therapy Because of Bleeding

decision for discontinuation of ASA in the setting of acute ulcer bleeding must be made on an individual basis, based upon cardiac risk and GI risk assessment to discern potential thrombotic and hemorraghic complication

There is no evidence that non-ASA anti platelet drug such as clopidogrel will reduce bleeding risk in the presence of active ulcers

9. Endoscopy in patients on mono or dual antiplatelet therapy

Endoscopic therapy may be performed in high risk cardiovascular patients on dual antiplatelet therapy, and collaboration between the cardiologist and endoscopist should be balance the risk of bleeding with thrombosis, with regard to the timing of cessation of antiplatelet therapy

Conclusion

NSAID Gastroduodenopathy is one of important problems in daily clinical practice.

There are some risk factors which correlated to NSAID ulcers complications.

The treatment and prevention of NSAID gastropathy Proton Pump Inhibitor.

The most effective and safe PPI for the treatment and prevention of NSAID gastropathy is Esomeprazole.