NSAID Upper G/I NSAID Upper G/I Adverse Effects Adverse Effects

Minimizing Risks Minimizing Risks

The 1The 1stst Palestinian PalestinianG/I ConferenceG/I Conference

May 20-22-2010May 20-22-2010

NSAIDs NSAIDs –– a long history a long history of analgesia & toxicityof analgesia & toxicity

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

Aspirin first synthesised in 1899.Aspirin first synthesised in 1899. First pathological evidence of gastric damage First pathological evidence of gastric damage

from aspirin in 1938.from aspirin in 1938. New non-aspirin, non-selective NSAIDs New non-aspirin, non-selective NSAIDs

identified in the 1950s and developed in the identified in the 1950s and developed in the 1970s.1970s.

COX-2 selective NSAIDs discovered in 1992.COX-2 selective NSAIDs discovered in 1992. First COX-2 selective NSAIDsFirst COX-2 selective NSAIDs approved in approved in

1998.1998.

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 NSAIDs inhibit the COX enzyme, which exists in two enzyme, which exists in two

formsforms

Wallace et al 2000

Gastric mucosal damage Gastric mucosal damage requires inhibition of both requires inhibition of both

COX-1 and COX-2COX-1 and COX-2Gastric damage score (%)

0

5

10

15

* p<0.05

Vehicle Celecoxib SC-560 Indo-methacin

Celecoxib+

SC-560

**

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 Topical irritant effects from NSAIDsfrom 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

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

Upper GI side-Upper GI side-effectseffects

NSAID use is associated NSAID use is associated with upper GI side-effectswith upper GI side-effects NSAIDs, including COX-2 selective NSAIDs, including COX-2 selective

NSAIDs, are associated with an NSAIDs, are associated with an increased risk of upper GI symptoms.increased risk of upper GI symptoms.

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

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

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

Simon et al 1999†Dyspepsia, diarrhoea, abdominal pain, nauseaand flatulence.

Incidence of upper GI symptoms in Incidence of upper GI symptoms in patients free from ulcer is similar patients free from ulcer is similar

with non-selective and COX-2 with non-selective and COX-2 selective NSAIDsselective 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

Hallas & Bytzer 1998

2.4

ACE inhibitors

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

for dyspepsiafor dyspepsia

0.40.0 0.8 1.2 1.6 2.0

NSAIDs

Calcium blockers

Corticosteroids

Methylxanthines

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

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

selective NSAIDsselective 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

func

tionin

g

Role p

hysic

al

Bodily

pain

Gener

al he

alth

Men

tal h

ealth

Role e

mot

ional

Vitality

Social

func

tionin

g

Upper GI side-effects impact Upper GI side-effects impact negatively on patientsnegatively on patients’’ lives and lives and

can lead to withdrawal from can lead to withdrawal from treatmenttreatment Productivity at work and daily activities Productivity at work and daily activities

are reduced amongst NSAID users:are reduced amongst NSAID users: 13% reduced productivity at work (n=27)13% reduced productivity at work (n=27) 26% reduced daily activities (n=61).26% reduced daily activities (n=61).

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

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

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

NSAID users are at risk of NSAID users are at risk of reflux esophagitisreflux esophagitis

Reflux esophagitis LA Grades A–D.

Photos reproduced with permission from Professor G Tytgat

Avidan et al 2001

Reflux esophagitis: Reflux esophagitis: the presence of the presence of

definite mucosal definite mucosal breaks or metaplasia breaks or metaplasia

of the esophagus, of the esophagus, visible under visible under

endoscopyendoscopy..

Among patients Among patients taking non-selective taking non-selective

NSAIDs for NSAIDs for osteoarthritis, the osteoarthritis, the prevalence rate of prevalence rate of

erosive esophagitis erosive esophagitis was 21%was 21%..

A B

C D

NSAID-associated peptic NSAID-associated peptic ulcerationulceration

The majority of patients The majority of patients develop some gastric develop some gastric

erosions after each doseerosions after each doseof a non-selective NSAIDof a non-selective NSAID..

Approximately 15Approximately 15––30%30%of NSAID users develop of NSAID users develop

endoscopically evident ulcers endoscopically evident ulcers at any one time at any one time –– these will these will

be generally silentbe generally silent..

COX-2 selective NSAIDs COX-2 selective NSAIDs reduce the incidence of reduce the incidence of

peptic ulcers compared with peptic ulcers compared with non-selective NSAIDs, but non-selective NSAIDs, but

patients with risk factors or patients with risk factors or those who also use low-dose those who also use low-dose

aspirin remain at riskaspirin remain at risk..

Photo reproduced from the Interactive Atlas of Gastroenterology

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

Hospitalisations per1000 person/years

Femalenon-users

Male non-users

Female users

Male users

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

20

15

10

5

0

25

Pérez Gutthann et al. Epidemiology 1997;8:18-24

Annual Rates of Hospitalisation for Ulcer Complications

Saskatchewan, Canada 1982-86

Hawkey et al 1997

NSAID-associated dyspepsia NSAID-associated dyspepsia may predict peptic ulcer may predict peptic ulcer

diseasedisease

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

Laine et al 2004

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

selective NSAIDs with concomitant selective NSAIDs with concomitant low-dose aspirinlow-dose aspirin

placebon=410

aspirinn=406

rofecoxib + aspirinn=399

ibuprofenn=400

Cumulative incidence of ulcers (%)

*** p<0.001 versusplacebo + aspirin

0

2

4

6

8

10

12

14

16

18***

***

Upper GI Upper GI complicationscomplications

Weil et al 1995

Aspirin, alone or with another Aspirin, alone or with another NSAID, increases the risk of NSAID, increases the risk of

upper GI complicationsupper GI complicationsRelative 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

Bombardier et al 2000†Perforation, obstruction, bleedingor symptomatic peptic ulcer.

Rofecoxib carries a lower Rofecoxib carries a lower overall risk of upper GI overall risk of upper GI events thanevents than naproxennaproxen

naproxen, 500 mg twice daily

rofecoxib, 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

Hawkey & Skelly 2002

Risk of ulcer complications with Risk of ulcer complications with celecoxibcelecoxib

remains high among patients with remains high among patients with other risk factorsother 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

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

bleeding with COX-2 selective bleeding with COX-2 selective NSAIDsNSAIDs

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

Risk FactorsRisk Factors

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

complications.complications. Drug-related factorsDrug-related factors

use of a relatively toxic NSAIDuse of a relatively toxic NSAID use of a high dose of NSAID (or two NSAIDsuse of a high dose of NSAID (or two NSAIDs

used concurrently) used concurrently) concurrent use of an anticoagulantconcurrent use of an anticoagulant concurrent use of a corticosteroid.concurrent use of a corticosteroid. H pylori infection.H pylori infection.

Seager & Hawkey 2001

Risk factors for upper GI Risk factors for upper GI complications occurring with complications occurring with

NSAIDsNSAIDs

Weil et al 2000

Risk factors for peptic Risk factors for peptic ulcer bleedingulcer bleeding

Odds ratio

0 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

Risk of upper GI events Risk of upper GI events may be silentmay be silent

5050––60% of NSAID-associated 60% of NSAID-associated peptic ulcers, presentingpeptic ulcers, presenting for the for the first time as a complication,first time as a complication, have have been silent previously.been silent previously.

Most patients with endoscopic Most patients with endoscopic lesions do not develop dyspepsia: lesions do not develop dyspepsia: 9% of patients with abnormal 9% of patients with abnormal

endoscopy had dyspeptic endoscopy had dyspeptic symptoms (n=45).symptoms (n=45).

Larkai et al 1987; Singh 1998

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

NSAIDs are associated with the NSAIDs are associated with the risk of serious upper GI risk of serious upper GI

complications, hospitalisation and complications, hospitalisation and mortalitymortality

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

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

In the USA, NSAID use accounts for In the USA, NSAID use accounts for approximately 107,000 approximately 107,000 hospitalisationshospitalisations and 1 and 16,500 deaths 6,500 deaths per year.per year.

Strategies to Strategies to Prevent and Prevent and

Treat NSAID Treat NSAID

complicationscomplications

Mortality from bleeding ulcers: 5-10%

Management of NSAID-induced

peptic ulcer disease

Management of NSAID-induced

peptic ulcer diseaseDiscontinue use of NSAIDs or Discontinue use of NSAIDs or

substitute with less toxic agentssubstitute with less toxic agentsl Low-toxicity NSAIDs or COX-2 inhibitorsLow-toxicity NSAIDs or COX-2 inhibitors

Suppress acid secretionSuppress acid secretionl Normal-dose PPI therapyNormal-dose PPI therapy

l High-dose HHigh-dose H22RA therapyRA therapy

Use mucosal protectantsUse mucosal protectantsl Misoprostol (Misoprostol (substantial side-effects, )substantial side-effects, )

Seager & Hawkey, BMJ 2001; 323: 1236–9.Silverstein et al., Ann Intern Med 1995; 123: 241–9.Graham et al., Ann Intern Med 1993; 119: 257–62.Yeomans et al., N Engl J Med 1998; 338: 719–26.

32

AntacidsAntacids

l Limited efficacy, especially in preventing Limited efficacy, especially in preventing gastric ulcergastric ulcer

HH22RAsRAs

l Effective in preventing DU >GU; Effective in preventing DU >GU; some drug interactions, well toleratedsome drug interactions, well tolerated

PPIsPPIs

l More effective than HMore effective than H22RAs for healing RAs for healing

NSAID-induced ulcers, well toleratedNSAID-induced ulcers, well tolerated

Seager & Hawkey, BMJ 2001; 323: 1236–9.Goldstein et al., Gut 1999; 25(Suppl V): A101.Yeomans et al., N Engl J Med 1998; 338: 719–26.

Acid suppression in NSAID-induced peptic ulcer

Acid suppression in NSAID-induced peptic ulcer

The simplest ways to The simplest ways to avoid or reduce NSAID avoid or reduce NSAID

risksrisks ……....

DonDon’’t use an NSAID or COX-2 t use an NSAID or COX-2 inhibitor inhibitor –– use something else (e.g. use something else (e.g. paracetamol)paracetamol)

Use the lowest effective dose of the Use the lowest effective dose of the NSAID or COX-2 inhibitorNSAID or COX-2 inhibitor

But this often doesn’t work

1982 20001992

0.5

1

1.5

2

NSAID- G/I NSAID- G/I complicationcomplication

Fries etal .2004

Endoscopic Photograph Endoscopic Photograph of Gastropathyof Gastropathy

Endoscopic PhotographEndoscopic Photographof Gastric Ulcerof Gastric Ulcer

Cardiovascular Cardiovascular benefits and GI benefits and GI

risks of low-dose risks of low-dose AspirinAspirin

Low-dose Aspirin (75-Low-dose Aspirin (75-325MG) for prevention of 325MG) for prevention of

CV eventsCV events 2 prevention (established CV disease)2 prevention (established CV disease) - Decreases CV events and mortality - Decreases CV events and mortality (RCTs)(RCTs)

* RRR= 19%, ARR=1.49% per yr. * RRR= 19%, ARR=1.49% per yr. - CV benefit generally outweighs harm - CV benefit generally outweighs harm

(bleeding). (bleeding). • 1 prevention (no overt CV disease).1 prevention (no overt CV disease). - Decreases CV events, but not mortality - Decreases CV events, but not mortality (RCTs)(RCTs) * RRR= 12%, ARR= 1.49% per yr.* RRR= 12%, ARR= 1.49% per yr. - Increased bleeding may outweigh CV benefit. - Increased bleeding may outweigh CV benefit. - Use if increased risk for future cardiac events.- Use if increased risk for future cardiac events. * >10% risk of CHD in 10 yrs (AHA). * >10% risk of CHD in 10 yrs (AHA).

Potential implication of a Potential implication of a Low incidence of Aspirin-Low incidence of Aspirin-

induced ulcersinduced ulcers Anti-platelet effect may be more Anti-platelet effect may be more

important than mucosal injury as important than mucosal injury as cause of GI complications. cause of GI complications.

- Aspirin may complicate pre-existing Aspirin may complicate pre-existing GI injury.GI injury.

- Aspirin an infrequent cause of Aspirin an infrequent cause of endoscopic ulcers but higher endoscopic ulcers but higher proportion are complicated. proportion are complicated.

ACCF/ACG/AHA Consensus ACCF/ACG/AHA Consensus Document Document

management of low-dose management of low-dose Aspirin GI injuryAspirin GI injury

PPIs preferred agents for the therapy and PPIs preferred agents for the therapy and prophylaxis of aspirin-associated GI injury.prophylaxis of aspirin-associated GI injury.

Risk factors necessitating PPI therapy.Risk factors necessitating PPI therapy.- Ulcer history (complicated or uncomplicated.Ulcer history (complicated or uncomplicated.- GI bleeding. GI bleeding. - Concomitant anticoagulant or antiplatelets.Concomitant anticoagulant or antiplatelets.- Two or more of the following 3 Two or more of the following 3 ““riskrisk”” factors: factors: • Age >_ 60, steroids, dyspepsia or GERD symptoms Age >_ 60, steroids, dyspepsia or GERD symptoms

Cardiovascular Cardiovascular Benefits And GI Risks Benefits And GI Risks

Of ClopidogrelOf Clopidogrel

Aspirin + Clopidogrel vs. Aspirin + Clopidogrel vs. Aspirin Conclusions Form Aspirin Conclusions Form

Double Double –– Blind RCTS for CV Blind RCTS for CV DiseaseDisease

In patients with acute coronary In patients with acute coronary syndrome or atria fibrillation syndrome or atria fibrillation Clopidogrel plus aspirin produces Clopidogrel plus aspirin produces small but significant relative risk small but significant relative risk reductions of reductions of –– 10-20% in CV events 10-20% in CV events compared to aspirin alone. compared to aspirin alone.

ACC/AHA GUIDELINES ACC/AHA GUIDELINES Clopidogrel + AspirinClopidogrel + Aspirin

>- 1month after a bare metal stent.>- 1month after a bare metal stent. >- 1 year after a drug-eluting stent.>- 1 year after a drug-eluting stent. >- 1month and ideally one year >- 1month and ideally one year

following unstable angina or following unstable angina or NSTEMI managed without NSTEMI managed without intervention.intervention.

Long-term (e.g., 1year) following Long-term (e.g., 1year) following STEMISTEMI

ACCF/ACG/AHA Consensus ACCF/ACG/AHA Consensus DocumentDocument

Patients taking dual antiplatelet Patients taking dual antiplatelet therapy should receive a PPI.therapy should receive a PPI.

Recommendation of PPI based on:Recommendation of PPI based on:- RCTs in low-dose aspirin users. RCTs in low-dose aspirin users. - 1 case-control study of peptic ulcer 1 case-control study of peptic ulcer

bleeding among Clopidogrel or bleeding among Clopidogrel or ticlopidine users. ticlopidine users.

* RR of current PPI use=0.21(0.1-0.5). * RR of current PPI use=0.21(0.1-0.5).

PPI-Clopidogrel Interaction PPI-Clopidogrel Interaction

fact or fictionfact or fiction 3 observational studies show 3 observational studies show

associationassociation- OR/RR: 1.25-1.5.OR/RR: 1.25-1.5.• Due to confounding, when RRs < 1.5-2 canDue to confounding, when RRs < 1.5-2 can’’t t

conclude whether observed statistical association is conclude whether observed statistical association is valid.valid.

- All 5 PPIs showed positive association. All 5 PPIs showed positive association. • 5 observational studies do not show 5 observational studies do not show

significant association .significant association .• Laine 2010 Laine 2010

Potential PPL-Clopidogrel Potential PPL-Clopidogrel interctioninterction

U.S.FDA:U.S.FDA:--’’’’Concomitant use of drugs that inhibit Concomitant use of drugs that inhibit

CYP2C19(e.g.omeprazole) should be CYP2C19(e.g.omeprazole) should be discourageddiscouraged’’’’

-EMEA: -EMEA: -Discourages -Discourages ‘’‘’concomitant use of PPi concomitant use of PPi

and Clopidogrel and Clopidogrel –– containing containing medicines unless absolutely medicines unless absolutely necessarynecessary’’’’ . .

Laine 2010Laine 2010

PPL-C Clopidogrel PPL-C Clopidogrel interactioninteraction

Totality of evidence currently Totality of evidence currently insufficient to conclude whether valid insufficient to conclude whether valid statistical association or make judgment statistical association or make judgment of causality of causality

Nonetheless, healthcare providers must Nonetheless, healthcare providers must make decisions for their patients based make decisions for their patients based on the available evidence.on the available evidence.

Laine 2010Laine 2010