NSAIDs ASA GI protection

Prof. Chutima PramoolsinsapDivision of Gastroenterology and Tropical Medicine

Ramathibodi Hospital

Practical Approach in Managing NSAID Risks: GI and CV

1st Emergency Medicine Update 2550สมาคมเวชศาสตร์�ฉุ กเฉุ�นแห่�งปร์ะเทศไทย

1 September 2007

Content

Overview: Aspirin and NSAIDs GI adverse effects of NSAIDs

Mechanism Risk factors

Cardiovascular (CV) risks associated with NSAIDs Prevention strategy with NSAIDs based on GI and

CV patient risk factors Summary

Pharmacological Effects Analgesic Antipyretic Anti-inflammatory Anti-platelet Familial Adenomatous Polyposis Alzheimer’s Some are uricosuric

Adverse effects• Platelet dysfunction • Gastritis / PUD +bleeding • Cardiovascular• Acute Renal Failure • Sodium+ water retention• Edema• Analgesic nephropathy• Prolongation of gestation and inhibition of labor• Hypersenstivity

Nonsteroidal Anti-inflammatory Drugs (NSAIDs)

Major Diseases Attributable to Disability-Adjusted Life Years (DALYs) Lost of Thai People by Sex, 2002

Bureau of Policy and Strategy. Burden of Disease and Injuries in Thailand, 2002

Police Information System Centre, Royal Thai Police.

Death and Injury Rates from Road Traffic

Accidents, Thailand, 1984-2002

M F M F M F M F

Year 1960 1980 2000 2020

Growing proportion of the Thai elderly

It is estimated that the number of Thai people > 60 years will increase from 4.02 million (7.36 % of total population) in 1990 to become 10.78 million (15.28%of the total population) in 2020

J Med Assoc Thai 2005; 88 (9): 1257-60

Disease/Symptom of Thai Elders

Total Age (yrs)

60-64 65-69 70-74 > 75

Body ache, backache 75.1 72.7 74.7 77.8 77.3

Joint pain (degeneration) 47.5 42.8 46.7 49.8 54.9

Insomnia 38.7 34.1 38.1 42.0 44.9

Vertigo 36.8 34.4 35.6 38.7 41.2

Eye diseases 33.2 27.5 31.1 37.3 42.8

Dementia 29.8 22.3 26.5 33.2 45.2

Hyper/ hypotension 20.0 17.7 20.3 21.9 21.6

Proportion of Thai elders with most common diseases/symptoms by age group,2002

Surveys on Elderly People in Thailand 2002, National Statistical Office.

Nonsteroidal Anti-Inflammatory Drugs (NSAIDs)

WHO 2005: worldwide 10-50% suffer from musculoskeletal disorders

Pharmaceutical market value for pain relief = $23 billion in 2004.

Worldwide: 70 million people/day prescribed NSAIDs

230 million people/day take OTC NSAIDs

Inflammopharmacology. 2005;13(4):343-70.

Willow leaf extracts for musculoskeletal conditions

Aspirin first synthesised

NSAIDs – a Long History of Analgesia and Toxicity

400 B.C. Greek physician 1899 1938 1950 1970 1982 1992 1998 Hippocrates

Non-selective NSAIDs identified and developed. COX-2

selective NSAIDs discovered

First COX-2 selective NSAIDs approved

first endoscopic evidence thataspirin caused gastric mucosal damage.

Lancet 1938;ii:1222 5

Mechanism of action for aspirin

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

The 9 chemical groupings of NSAIDs

2http://www.fda.gov/cder/drug/infopage/COX /NSAIDmedguide.htm

Range of COX-1 and COX-2 selectivity of NSAIDs

COX = cyclooxy-genase; IC50 = concentration of NSAID that inhibits COX by 50%,

Pharmacological Effects Analgesic Antipyretic Anti-inflammatory Anti-platelet Familial ddenomatous polyposis Alzheimer’s Some are uricosuric

Adverse effects• Platelet dysfunction • Gastritis / PUD +bleeding • Cardiovascular• Acute Renal Failure • Sodium+ water retention• Edema• Analgesic nephropathy• Prolongation of gestation and inhibition of labor• Hypersenstivity

Nonsteroidal Anti-inflammatory Drugs (NSAIDs)

Gastrointestinal adverse

effects and NSAIDs

GI Side effects of NSAIDs

Dyspepsia Esophagitis Esophageal strictures Gastric and duodenal petechiae, ero

sions, ulceration, bleeding, and perforation

Type C gastritis Small and large bowel ulceration, bl

eeding, and perforation Exacerbation of colitis

Acidicenvironment

Bicarbonate layer

Ionic gradient

GastricacidNSAIDs Pepsin

Surfaceepithelial cells

MucuslayerNeutral

environment

Mucosalblood supply

Alkaline environment

Prostaglandin production

Bicarbonate production

Mucus production

Gastric acid plays a central role inNSAID-associated gastroduodenal damage

NSAIDs

normal gastric mucosa

16 minutes after administration of aspirin

Direct effect

Gastric acid plays a central role inNSAID-associated gastroduodenal damage

Acidicenvironment

Bicarbonate layer

Ionic gradient

GastricacidNSAIDs Pepsin

Surfaceepithelial cells

MucuslayerNeutral

environment

Mucosalblood supply

Alkaline environment

Prostaglandin production

Bicarbonate production

Mucus production

NSAIDs

Systemic effect

NSAIDs increase neutrophil–endothelial adhesion

NSAIDs

Decreased prostaglandin, increased tumour necrosis factor

Increased neutrophil–endothelial adhesion

Capillary obstruction

Ischaemic/hypoxic cell injury

Endothelial and epithelial injury

Mucosal ulcerationWallace et al 1997

Neutrophil release ofproteases and oxygen-derived free radicals

NSAID induced GI damage

3 main types of GI lesions:

Superficial damage i.e. mucosal hem

orrhages and erosions

Endoscopically documented non-sy

mptomatic (‘silent’) ulcers

Symptomatic ulcers causing complic

ations i.e.GI hemorrhage.

NSAID ingestion and GI injury

JIACM 2003; 4(4): 315-22

GI symptoms

Endoscopic ulcers

Clinical ulcers

Serious GI events

Relativeseverity

Relativefrequency

NSAID-related GI Effects

Spectrum of lesions / side effects induced by NSAIDs

Lesion / side effects Frequency Clinical Relevance

Erosions > 50% LowEndoscopic Ulcers 10-30%

Dyspepsia >30%

Symptomatic Ulcers 2-4%UGI Complications 1-1.5%LGI Complications ≊0.8%

High

Lanas A, Hunt R, Ann Meds 2006.

MUCOSA CLASS VIGOR TARGET

(N=4439) (N=3981) (N=4029) (N=9127)

Arthritis RA OA(73%); RA OA

RA (27%)

NSAID (N) 10 specified Ibuprofen naproxen Ibuprofen

NSAIDs diclofenac naproxen

Low-dose aspirin Not stated 20% 0 24%

Median follow-up 6 mo 9 mo 9 mo 12 mo

Upper GI complications 1.5% 1.0% 1.4% 1.3%

(annualized incidence)

Upper GI clinical events 2.7% 2.8% 4.5% 2.8%

(annualized incidence)

Incidences of Upper GI Complications and Clinical Events (Complications plus Symptomatic Ulcers) From

NSAID-only Arms of GI Outcome Studies

J Cardiovasc Pharmacol 2006; 47(1):S60-6

0

1

2

3

4

5% of patients

Clopidogrel in Unstable Angina to Prevent Recurrent Events (CURE) Trial Life-threatening or major bleeding

By aspirin dose, n=6293By aspirin dose, n=6293

<100 mg

1.91.9

n=990

100–150 mg

2.22.2

n=2857

151–300 mg

3.33.3

n=1385

>300 mgn=1061

3.83.8

Eur Heart J 2002;4:Suppl, 510

CURE: Aspirin plus clopidogrelAll bleeding episodesAll bleeding episodes

1.91.92.32.3

3.93.9

3.03.0 3.23.2

5.05.0

0

1

2

3

4

5

100 mg 110–162 mg 200 mg

% of patients

n=5259 n=3115 n=4172

AspirinClopidogrel + aspirin

p<0.001

Eur Heart J 2002;4:Suppl, 510

Relative risk (RR) and 95% confidence interval of upper GI bleeding for individual NSAIDs

Non-use ReferenceCelecoxib 1.0 (0.4-2.1)Aceclofenac 2.6 (1.5-4.6)Diclofenac 3.1 (2.3-4.2)Ibuprofen 4.1 (3.1-5.3)Naproxen 7.3 (4.7-11.4)Lomoxicam 7.7 (2.4-24.4)Ketoprofen 8.6 (2.5-29.2)Indomethacin 9.0 (3.9-20.7)Meloxicam 9.8 (4.0-23.8)Piroxicam 12.6 (7.8-20.3)Ketorolac 14.1 (5.2-39.9)

Low

High

Individual NSAID Relative Risk (95% CI)

Lanas A et al. Gut (2006)

*Adjusted for age, sex, calendar semester, ulcer history, nitrates, anticoagulants, antiplatelets, acid-suppressing drugs, coxib and aspirin use.

Cases (n = 2777) and Controls (n = 5532)

3.03.0

4.04.0

1.91.9

11

22

33

44

55

66

77

Ad

just

ed

Ra

te R

ati

oA

dju

ste

d R

ate

Ra

tio

00Non-useNon-use celecoxibcelecoxib rofecoxibrofecoxib diclo+misodiclo+miso NSAIDsNSAIDs

Mamdani et al. BMJ 2002;325(7365):624-7Mamdani et al. BMJ 2002;325(7365):624-7

1.01.01.01.0

Risk of Hospitalization for Upper GI Bleeding with COXIBs

>55% womenMean age >75 yrs>1% with Hx of GI bleed >16% Use of gastroprotective agent>12% Use of aspirin

100,000 (2.2)*100,000 (2.2)* 18,908 (3.6)*18,908 (3.6)* 14,583 (7.3)*14,583 (7.3)* 5,087 (9.6)*5,087 (9.6)* 5,391 (12.6)*5,391 (12.6)*

*n (no. upper GI bleeds per 1000 person-yrs)*n (no. upper GI bleeds per 1000 person-yrs)

Risk Factors for NSAID-Induced Gastropathy

Definite: • Age • Prior history of ulcer • Duration of NSAID therapy • Concomitant corticosteroid therapy • Concomitant warfarin therapy • Concomitant ASA / NSAID • NSAID dose • Serious systemic illness (CHF, RA, CAD, others)

Possible: • Concomitant H. Pylori

infection?

• Smoking

• Alcohol

Risk Factors for NSAID-Associated GI Complications

NSAIDs, nonsteroidal antiinflammatory drugs; SSRIs, selective serotonin reuptake inhibitors.Dalton SO, et al. Arch Intern Med. 2003;163:59–64.

Gabriel SE, et al. Ann Intern Med. 1991;115:787–796;Garcia Rodriguez LA, et al. Lancet. 1994;343:769–772.

Silverstein FE, et al. Ann Intern Med. 1995;123:241–249.

Distribution of Patients with GI ComplicationsFrom NSAIDs by Age and Sex

Am J Gastroenterol 2005;100:1685–93

Risk of UGI Complication for NSAID Users Impact of Ulcer History

0102030405060708090

100110120130140150160

20-60 60-69 70-79 >=80

Men complic ulcer +NSAID Men ulcer + NSAIDs

Men No ulcer +NSAIDs

Inci

den

ce p

er 1

,000

per

son

-yea

rs

Based on Hemandez & Garcia-Rodriguez, BMC Medicine 2006;4:22.

Rates of symptomatic ulcers and ulcer complications with naproxen in patients with rheumatoid arthritis

0.183.1

7.314.5 13.5

18.8

28.8

40

0

10

20

30

40

50

60

Bombadlar C et al. N Engl J Med 343;1520-8(2000): Lenas A. Gastroenterol Gastro 2007.

Number events x 100 patient-years

No NSAID

use

<65

65-

74

>74

Ulcer

Hx

Ulcer

com

plic

atio

ns

>65+

Hx

Ulc

er>6

5+H

x U

lcer

+ste

rold

s

Age

Ann

ualiz

ed I

ncid

ence

%

Ulcer Complications Symptomatic Ulcers andUlcer Complications

0

1

2

3

4

5

6

49 / 1384

30 / 1441

11 / 144120 / 1384

p = 0.02

p = 0.09

All Patients

0

1

2

3

4

5

6

32 / 1101

16 / 11435 / 1143

14 / 1101

p = 0.02

p = 0.04Patients Not Taking Aspirin

0

1

2

3

4

5

6 17 / 283

14/ 298

6 / 298 6 / 283

p = 0.49

p = 0.92Patients Taking Aspirin

CLASS Trial: Upper GI ComplicationsAlone and With Symptomatic Ulcers

Silverstein et al. JAMA 2000; 284:1247-1255

= celecoxib

= NSAIDs (ibuprofen + diclofenac)

Low-dose aspirin excluded

56

17 18

0

5

10

15

20

placebo ASA ASA+ROF Ibuprofen

CumulativeIncidence (%)

*P<0.001 vs placebo and vs aspirinROF = Rofecoxib

Gastroduodenal ulcers at 12 weeks in patients with OA

Aspirin Negates the GI-sparing Effect of COX-2 Inhibitors

Gastroenterology 2004; 127: 395-402.

* *

N=381 N=387 N=377 N=374

%

Low-Dose Aspirin Combined with NSAID or Coxib

Drug R.R 95% CI

Aspirin only 3.6 2.9-4.3

NSAID only 5.0 4.3-5.9

Combined 10.2 6.2-16.7


Coxib only 1.1 0.7-1.9

Combined 9.5 2.5-36.2

Lanas et al. Gut 2006

Risk of UGI Complication for NSAID Users Impact of ASA use

0

10

20

30

40

50

60

70

80

90

100Men + NSAIDs+ASA Men + NSAIDs-no ASA

Men No NSAIDs/ASA

20-60 60-69 70-79 >=80Inci

denc

e pe

r 1,

000

pers

on-y

ears

Based on Hermandez & Garcla-Rodriguez. BMC Medicine 2006;4:22

Non-aspirin antiplatelet agents combined with NSAIDs

Drug R.R 95% CI



Combined 10.2 6.2-16.7

Clopidogrel/Ticlid only 3.1 2.2-4.4


Combined 15.5 4.7-50.4

Lanas et al. Gut 2006

NSAID-Induced Small Bowel LesionsNSAID-Induced Small Bowel Lesions

Endoscopic photograph of terminal ileum, d emonstrating inflamed diaphragm in patien

- t receiving long term NSAIDs

Odds ratios for use of NSAIDs in patients with

upper GI bleeding lower GI bleeding

Increase in risk owing to NSAID use for upper GI and lower GI complications

Lanas et al. 10.7 (95% CI,4.5–26.0) 18.4 (95% CI,4.7–51.4) Wilcox et al. 3.2 (95% CI,2.6 –4.0) 2.6 (95% CI,1.7–3.9)

Lanas et al. 6.3 (95% CI,3.1– 12.9) 8.1 (95% CI,2.3–31.9)

Odds ratios for use of NSAIDs and GI perforation

upper GI lower GI

Gastroenterology 2003;124:288–92

Liver Warning over Lumiracoxib

Australia, Aug. 11, 2007 Therapeutic Goods Administration (TGA)

had received 8 reports of serious liver adverse reactions associated with use of lumiracoxib (prexige®) 2 deaths and 2 patients requiring live

r transplants. All these reports have been received sin

ce March 2007, with 6 reports received in the last 6 weeks.

Mortality Study ASA-attributed Complications and Deaths

>5% of people take low-dose ASA (secondary CV prevention)

Almost a third of all NSAID use detected in patients hospitalized with ulcer bleeding is low-dose ASA.

321 GI Bleedings per 100,000 users 18 Deaths per 100,000 users

Lanas et al. Am J Gastroenterol 2005

Mortality Rate Attributed to NSAID/Aspirin-Associated GI Complications

Am J Gastroenterol 2005;100:1685–93

2533.7 59

153.4

253.8

443

0

50

100

150

200

250

300

350

400

450

Spain

UK

USA

Mortality rate per 1 million people

Entire country population NSAID/aspirin users

Cardiovascular Risks AssociatedWith COX-2–Selective Inhibitors

and Nonselective NSAIDs

COX-2 Inhibitors: The “Promise”

Lower incidence of GI side effects when compared to traditional NSAIDs

Potentially attenuate intestinal tumor development COX-2 increased in atherosclerotic plaque

COX-2 may play a role in inflammation that underlies cardiovascular risk

NSAID Effects on Thromboxane and Prostacylin

Serious Thromboembolic CardiovascularAdverse Events in Nonaspirin Users

1. Silverstein FE, et al. JAMA. 2000;284:1247–1255.2. Bombardier C, et al. N Engl J Med. 2000;343:1520–1528.

APPROVe Trial: Confirmed ThromboticCardiovascular Events Over Time

Bresalier RS, et al. N Engl J Med. 2005; 352: 1092-1102.

September 2004, Vioxx (rofecoxib) withdrawal from worldwide market

April 7, 2005, Bextra (valdecoxib) withdrawal

Parecoxib/Valdecoxib: Cardiovascular Complications After Cardiac Surgery

Cardiovascular Risks in NSAID Users

This black box warning statement now appears in the package insert (July 2005) for celecoxib

Black box warning for COX-2–selective drugs. This black box warning statement now appears in the package insert (July 2005) for celecoxib

APC Trial: Concomitant Aspirin Use Does Not Decrease Cardiovascular Risk of COX-2 Selective Inhibitors

MEDAL Program: Confirmed ThromboticCardiovascular Events Over Time

Cannon CP, et al; MEDAL Steering Committee. Lancet. 2006;368:1771–1781.

BMJ 2006;332;1302-1308

Comparison of effects of different selective COX 2 inhibitors versus myocardial infarction

BMJ 2006;332;1302-1308

Comparison of effects of different selective COX 2 inhibitors versus placebo on stroke

BMJ 2006;332;1302-1308

Comparison of effects of different selective COX2 inhibitors versus placebo on vascular death.

Is conventional NSAIDs safe for cardiovascular events?

Acute Myocardial Infarction NSAID Use: Case-Control Study of MediCal*

FDA Advisory Committee Meeting. Rockville, MD; February 17, 2005.

Singh G, et al. Ann Rheum Dis, 2005: 64(Suppl 3): 263.

Risk of Acute Myocardial Infarction Associated With Current NSAID Use

*Adjusted for other NSAID use, hypertension, congestive heart disease, cerebrovascular disease, hyperlipidemia, diabetes, rheumatoid arthritis, smoking and body mass index.

Circulation. 2006; 113: 1950-1957.

Meta-analysis: Cardiovascular Risk Associated With the Use of COX-2 Selective Inhibitors a

nd Nonselective NSAIDs

17 case-control and 6 cohort studies reporting on CV events (mostly myocardial infarction) with COX-2 selective inhibitors, NSAIDs or both with nonuse/remote use of the agents as the reference exposure.

JAMA. 2006; 296: 1633-1644.

Black Box Warning for All NSAIDs

August 1, 2005 FDA gives black box warning to all NSAIDs

Cardiovascular risk GI risk

Black box warning for "traditional" NSAID group

This example is from the package insert (January 2006) of diclofenac,

BMJ 2006;332;1302-1308

Comparison of effects of selective COX-2 inhibitors versus traditional NSAIDs on myocardial infarction,

BMJ 2006;332;1302-1308

Comparison of effects of selective COX-2 inhibitors versus traditional NSAIDs on stroke

BMJ 2006;332;1302-1308

Comparison of effects of selective COX-2 inhibitors versus traditional NSAIDs on vascular death.

Protective Strategies in Preventing NSAIDs-induced Ulcers and

Ulcer Complications

Reduce the impact of risk factors

Avoid inhibition or restore mucosal prostagladin levels

Misoprostol (cytotec®)

Coxibs

Reduce acid H2-receptor antagonist (H2RA) Proton pump inhibitors (PPI)

Protective Strategies in Preventing NSAIDs-

induced Ulcers and Ulcer Complications

H2-receptor antagonist, (H2RA)

Block the action of histamine on parietal cells, decreasing acid production

H2RA drugs cimetidine (Tagamet) ranitidine (Zantac) famotidine (Famoc) nizatidine (Axid)

Proton pump inhibitors (PPIs)

Omeprazole (Losec®) Lansoprazole (Prevacid®) Pantoprazole (Controloc®) Rabeprazole (Pariet®) Esomeprazole (Nexium®) The currently available 3 PPIs which have an IV formulat

ion: Omeprazole, Pantoprazole, Esomeprazole

Misoprostol (cytotec®)

PGE1 analogue Stimulates increased mucus secretion Increases mucosal blood flow

Side effects Diarrhea, abdominal pain, nausea, flatulence, headache, dysp

epsia, vomiting, and constipation Contraindications: Should not use in pregnant women because

Increases uterine tone and contractions which may cause partial or complete abortions

Birth defects

Directly targets COX-2, Reduces risk of peptic ulceration Does not seem to affect other adver

se-effects of NSAIDs (i.e.renal failure)

Increase in the risk for heart attack, thrombosis and stroke by a relative increase in thromboxane.

Selective COX-2 Inhibitors

September 2004, Vioxx (rofecoxib) withdrawal

April 7, 2005, Bextra (valdecoxib) withdrawal

Risk of adverse upper G.I. events associated with NSAIDs according to use of ulcer healing drugs.

UK study: 9407 incident cases and 88,867 matched controls.

BMJ 2005;331;1310-1316Values are adjusted odds ratios*

Not prescribed Prescribed

Drug prescribed <90 ulcer healing ulcer healing Interaction ratio‡ P value for

Days before index drugs in past drugs in past (95% Cl) interaction

date† 90 days 90 days

Celecoxib 1.44 1.06 0.73 (0.46 to 1.16) 0.18

Rofecoxib 2.33 1.06 0.45 (0.32 to 0.65) <0.001

Other selective 2.40 1.29 0.54 (0.36 to 0.81) <0.001

NSAIDs

Ibuprofen 1.65 0.90 0.55 (0.43 to 0.70) <0.001

Diclofenac 2.17 1.49 0.69 (0.56 to 0.84) <0.001

Naproxen 2.73 0.83 0.31 (0.19 to 0.49) <0.001

Other non selective 2.03 1.16 0.57 (0.42 to 0.77) <0.001

NSAIDs

Aspirin 1.87 0.81 0.43 (0.38 to 0.49) <0.001

Prevention of NSAID-induced ulcer

0

20

40

60

80

100

Pantoprazole

Placebo

Endoscopic remission rates for patients with endoscopically normal or hyperaemic gastric mucosa at baseline [a subset of patients with grade 0 of Lanza classification, who were

treated with either pantoprazole 40 mg od or placebo for up to 12 weeks

0 4 8 12

P=0.036

92%

82%

75%

55%

BIanchi Parro G, et a. Digest Liver Dis 2000

En

do

sco

pic

rem

issi

on

rat

e (%

)

Time (wks)

Efficacy of pantoprazole in the primary prevention of NSAID-induced gastroduodenal damage

Patient population Treatment Treatment n Remission rate (%)duration

Rheumatic 6 months Pantoprazole 20 mg od 257 89disease;

Continuous NSAID; Misoprostol 200 mg bid 258 70high risk (p<0.001)

Rheumatic 6 months Pantoprazole 20 mg od 196 90Disease;

Continuous NSAID; Pantoprazole 40 mg od 199 93high risk

Omeprazole 20 mg o.d. 200 89 (NS)

SINGH, G. Int J Clin Pract 2005

112 RCTS (74,666 participants) 138 deaths and 248 serious GI events On comparing gastroprotective strategies vs placebo

No evidence of effectiveness of H2 receptor antagonists for any primary outcomes

Proton pump inhibitors Reduce risk of symptomatic ulcers (RR 0.09, 95% CI 0.02 - 0.47)

Misoprostol Reduces risk of serious GI (RR 0.57, 95% CI 0.36 - 0.91) Reduces symptomatic ulcers (RR 0.36, 95% CI 0.20 - 0.67)

Systematic review : Effectiveness of five strategies

for the prevention of GI toxicity induced by NSAIDs

BMJ 2004; 329: 948

The effectiveness of five strategies for the prevention of gastrointestinal toxicity induced by NSAIDs: systemat

ic review

COX-2 selectives Reduce risk of symptomatic ulcers (0.41, 95% CI; 0.26-0.65) No reduce the risk of endoscopic ulcers (at least 3 mm diameter).

COX-2 specifics Reduce risk of symptomatic ulcers (0.49, 95% CI; 0.38-0.62) Reduce risk of serious GI complications (0.55, 95% CI; 0.38-.80)

BMJ 2004329948; :

Misoprostol All doses of misoprostol significantly reduced the risk of endosco

pic ulcers. Misoprostol 800 ug/day was superior to 400 ug/day for prevention

of endoscopic GU (RR=0.17, and RR=0.39 respectively, p=0.0055) A dose response relationship was not seen with DU Misoprostol caused diarrhea at all doses, although significantly m

ore at 800 ug/day than 400 ug/day (p=0012). Misoprostol was the only prophylactic agent documented to reduc

e ulcer complications.

Prevention of NSAID-induced gastroduodenal ulcers

ochrane Database of Systematic Reviews 2007 Issue 3

Prevention of NSAID-induced gastroduodenal ulcers

Standard doses of H2RAs

Effective at reducing the risk of endoscopic DU (RR=0.36;

95% CI: 0.18-0.74) but not GU (RR=0.73; 95% CI: 0.50-1.09)

Double dose H2RAs and PPIs were effective at reducing the risk of

endoscopic DU and GU (RR=0.44; 95% CI:0.26-0.74 and RR =0.40;

95% CI: 0.32-0.51 respectively for gastric ulcer, and were better toler

ated than misoprostol.

Cochrane Database of Systematic Reviews 2007 Issue 3

PPIs reduce the relative risk of Ulcer bleeding in patients taking NSAIDs

0 0.5 1 2 3 4 5 6 7 8 9 10 27

Adjusted RR (95% IC)

Non-ASA NSAIDs 5.0 +PPI

ASA (>500 mg/day) +PPI

Lanas et al. AJG 2007

• >70% GI risk reduction with PPI• Reduction similar among different NSAIDs

8.7

0.30

0.14

Effect of PPIs,H2-RA and nitrates on the RR of ulcer bleeding in patients taking Low-dose ASA or Clopidogrel

0 0.5 1 2 3 4 5 6 7 8 9 10 27

Adjusted RR (95% IC)

Low dose ASA 3.6 +PPI 0.32 +H2-RA 0.40

+Nitrate 0.69

Clopidogrel 3.1 +PPI 0.19 +H2-RA 0.83

+Nitrate 0.88

Lanas et al. AJG 2007

PPI plus COX-2 inhibitor

16.5 17.1

0.9

6.84.1 4.8

0

5

10

15

20

25

COX-2-selective NSAIDs Non-selective NSAIDs

Pa

tie

nts

(%

)

Placebo Esomeprazole 20 mg Esomeprazole 40 mg

Ulcer incidence at 6 months by NSAID type

**P<.01, ***P<.001, ****P<.0001 vs. placebo.

** ******

****

134 141125 318 326334n=

Scheiman et al. DDW 2004

Coxibs versus standard-NSAIDs : Effect on serious upper GI events

Adjusted relative risk (95% IC)

0 0.5 1 2 3 4 5

Type of event 51% reduction

Symptomatic 0.49 (0.38-0.62)Ulcers

Upper GI 45% reductionComplications 0.55 (0.38-0.80)

Hooper L et al. BMJ 320:948-58 (2004)

Management of UGIB from NSAID-induced Ulcers

Approach to UGI Bleeding

Assess severity Resuscitate Establish the site of bleeding Endoscopic intervention Reassess severity Medical treatment Indications for surgery

Assessing severity: Rockall criteria

Criterion Score Age <60 years 0

60-79 yrs1>80 years2

Shock None 0Pulse & sBP >100 1sBP <100 2

Co-morbidity None 0Cardiac / any major 2Renal / liver / malig. 3

Total initial score (max = 7)Mortality 50.0%

High risk Low risk Pharmacologic therapy

Endoscopy available

Yes No

Endoscopy feasible

Yes

Endoscopic Hemostasis

OthersVariceal bleedingUlcer bleeding

Success

No

Consult surgeon or refer

Fail

Antisecretory therapy

Refer

Pharmacological therapy and monitoring Rebleed Re-endoscopy

Fail

Guideline of UGIB Management

Endoscopic Stigmata of Ulcer Hemorrhage

Active arterial bleeding

Visible Vessel

Adherent clot

Flat spot

Clean base ulcer

Endoscopic Appearance

Prevalence (%)

Rebleed RateRebleed Rate

with Endoscopic treatment (%)

Active arterial bleeding

12 90 15-30

Visible Vessel 22 50 15-30

Adherent clot 10 33 5

Oozong without stigmata

14 10 Not available

Flat spot 10 7 Not available

Clean base ulcer 32 3 Not available

Endoscopic Stigmata of Ulcer Hemorrhage: Prevalence, Risks of Rebleeding and Reduced Risk of Rebleeding

following Endoscopic Therapy

Endoscopy 1997; 29 : 827-33


Endoscopy available

Yes No

Endoscopy feasible

Yes



Success

No


Fail


Refer


Fail


Endoscopic modalities available for management of Non-variceal UGIB

Injection Adrenaline

(1:10,000) Fibrin glue Human thrombin Sclerosants Alcohol

Thermal Heater probe Bicap probe Gold probe Argon plasma

coagulation Laser therapy

Mechanical Hemoclips Banding Endoloops Staples/sutures


Endoscopy available

Yes No

Endoscopy feasible

Yes



Success

No


Fail


Refer


Fail


Pharmacotherapy for Nonvariceal Bleeding

48-72 hrs after endoscopic therapy, patient should receive acid-suppressive drug to maintain gastric pH >6.

In patients who do not require endoscopic therapy, oral PPI therapy is adequate.

In patients with arterial spurt or visible vessel require endoscopic therapy and a continuous infusion of high -dose intravenous PPI therapy.

Stop aspirin and NSAID . H pylori therapy should be test and treat if presented.

Brunner, et al. Aliment Pharmacol Ther 1995

Omeprazole 80 mg loading dose+ 40 mg q. 8 hours Omeprazole 80 mg loading dose + CI 4 mg/ hour

Effective PPI Dosage & Administration

Intermittent Bolus V.S. Continuous Infusion

00

88

66

44

22

00 88 1616 2424 3232 4040 4848

Med

ian

Intr

agas

tric

pH

Time [h]

Van Rensburg, et al. Gastroenterology 1997. (Abstract)

80 mg bolus then 8 mg/hour n = 14; median pH 6.3, 68% range

IV Pantoprazole In Patients With UGIB After Endoscopic Hemostasis

Recommendation: An intravenous bolus followed by continuous-infusion proton-pump inhibitor is effective in decreasing rebleeding in patients who have undergone successful endoscopic therapy.

Recommendation: A;Evidence: I

Consensus Recommendations for Managing Patients with Nonvariceal UGIB.

•Consensus Recommendations for Managing Patients with Nonvariceal Upper Gastrointestinal Bleeding. Ann Intern Med 2003;139(10):843-57.•A Canadian clinical practice algorithm for the management of patients with nonvariceal upper gastrointestinal bleeding. Can J Gastroenterol 2004;18(10):605-609.


Endoscopy available

Yes No

Endoscopy feasible

Yes



Success

No


Fail


Refer


Fail


Proton pump inhibitor treatment for acute peptic ulcer bleeding

No evidence to suggest that results on mortality and rebleeding were dependent on study quality, route of PPI administration, type of control treatment or application of initial endoscopic haemostatic treatment.

PPIs significantly reduced surgery compared with placebo but not when compared with H2RA.

Among patients with active bleeding or non-bleeding visible vessel, PPI treatment reduced mortality (OR 0.53; 95% CI 0.31 to 0.91), rebleeding and surgery.

Cochrane Database of Systematic Reviews 2006 Issue 3

H. pylori and NSAIDs

70.2

56.1 58.6

23.5

64.5

23

0

10

20

30

40

50

60

70

80

H.pylori, NSAID Use and the Risk of PU Bleeding

Prevalence (%)

PU bleeding + - + - + -

OR 1.79

95% CI; 0.97-3.32

OR 4.85

95% CI; 3.77-6.23OR 6.13

95% CI; 3.93-9.56

Lancet 2002

HP+ NSAID usesHP+NSAID use

HP- No NSAID

H pylori and NSAIDs independently and significantly increase risk of PU bleeding

Recommendations for H pylori eradication in Maastricht III Consensus

Recommendations Level of evidence

Grade of recommendation

In patients receiving long term NSAIDs and who have peptic ulcer and/or ulcer bleeding, PPI maintenance treatment is better than H. pylori eradication in preventing ulcer recurrence and/or bleeding

Ib A

H. pylori eradication is of value in chronic NSAID users but is insufficient to prevent NSAID related ulcer disease completely

Ib A

In naı¨ve users of NSAIDs, H, pylori eradication may prevent PU and or bleeding

Ib A

1b; Individual RCT with narrow confidence interval

Gut. 2006;55:1717-24

H pylori and Low dose ASA

H. pylori infection increases complications for patients taking low-dose aspirin.

Risk for UGI bleeding with low-dose aspirin and H. pylori infection (OR = 4.7; 95% CI, 2.0-10.9) compared with aspirin alone but much lower than previous ulcer history (OR = 15.2; 95% CI, 3.8-60.1).

Recommendation: Patients who are receiving long term aspirin who bleed should be tested for H. pylori and, if positive, receive eradication therapy.

SummaryPractical Approach in

Managing NSAID Risks: GI and CV

Strategy in patients who need NSAIDs

Step 1 : Evaluate presence of risk factor : Estimate the GI & CV risk

Step 2 : Minimize the risk according to these factors

Step 3 : Use the most appropriate therapeutic strategy

The most important risk factors

Age Most Frequent

Low-dose ASA >20% of patients

Ulcer History Highest RR

Factor Reason

Definition of GI risksGI risk Complication Rate NNT Cost of

100 pt-yrs prevention

Low <1.5 >120 ≈120,000ε

Intermediate 2-10 10-100 3,000-20,000ε

High >20 <10 <3,000ε

Lanas et al. APT 2004;20:321-31.

Assess Cardiac Risk First

When choosing an NSAID Assess cardiac risk factors first because of concern about CV

safety of COX-2 inhibitors Naproxen may have cardioprotective

Consider whether patient would be benefit from aspirin therapy No GI benefit of COX-2 inhibitors for patients who take aspirin

For patients with GI risk factors Consider non-NSAID therapies For patients requiring NSAIDs, consider adding a PPI

Assess the presence of high-risk factors for serious NSAID-induced GI adverse

events i.e elderly people,, if necessary, keep the dose as low as possible.

Comorbidity (ie renal and hepatic disease) needs to be considered when prescribe

NSAIDs.

Prescribe with caution in patients with underlying GI disease or risk factors for CVS

disease.

Beware drug interactions of NSAIDs / COX-2 inhibitors

Patients with history of chronic or allergic skin conditions,

A standard NSAID may be preferred to a COXIB (rarely COXIBs reported

to be associated with increased risk of serious skin reactions)

Majority of cases occur in the first month of use

Minimizing risk of NSAIDs users

Coxibs are contraindicated in: ischemic heart disease cerebrovascular disease peripheral arterial disease moderate or severe heart failure.

In people with risk factors for heart disease the balance of GI and CV risk should be considered before prescribing a coxib.

People requiring low dose aspirin should generally not be prescribed a coxib because GI benefit has not been clearly demonstrated in this group.

Practical Points for COX-2 selective NSAIDs Uses

If high risk of NSAID-induced GI adverse effects and requires concomitant use of low-dose aspirin prophylaxis and an NSAID: Do not stop aspirin. Re-consider use paracetamol with or without codeine. If NSAID is considered necessary, cautious to prescribe an

NSAID with less COX-2 selectivity (e.g. naproxen, but not ibuprofen) together with a gastroprotective agent.

Avoid concomitant use of aspirin with ibuprofen.

Low-dose Aspirin and NSAID

Strategies to Reduce NSAID-induced Mucosal Injury and Platelet Dysfunction

Avoid NSAIDs or minimize dosage Alternative COX-2 inhibitors Proton pump inhibitors (PPIs)

PPIs are more effective than H2RA in preventing NSAID-induced ulcer

PPIs are better tolerate than misoprostol Prostaglandin analogue – misoprostol

NSAID required?

High risk Low risk

-No prophylaxis-Monitor clinical signs and symptoms -Use non-NSAIDs analgesic-Use low dose, short acting NSAIDs-Limit duration of therapy-Avoid using combination of NSAIDs-Avoid to combine with corticosteriod or anticoagulant

Risk assessment for NSAID-induced ulcer

-Cotherapy with

Gastroprotective drugs

-Selective COX-2 inhibitors

Yes

Recommendations for the use of NSAIDs according to GI and

cardiovascular risk.Cardiovascular risk*

Gastrointestinal risk**

Low Moderate Severe

Low NSAID NSAID + PPI/misoprostol or COX2 inhibitor

COX2 inhibitor + PPI

High NSAID*** + PPI or misoprostol

NSAID***+ PPI or misoprostol

Avoid NSAIDs or COX2 inhibitors *High cardiovascular risk: requirement for low-dose aspirin for primary prevention

(calculated 10-year cardiovascular risk >10%) or secondary prevention of serious cardiovascular events.

**Gl risk: low (no risk factors), moderate (1-2 risk factors), or high (> 2 risk factors, previous ulcer complications, or concomitant use of corticosteroids or anticoagulants). All patients with a history of ulcers who require NSAIDs should be tested for H. pylori and if infection is present, eradication therapy should be given.

*** Naproxen is preferred NSAID in patients with a high cardiovascular risk.

Nat Clin Pract Gastroenterol Hepatol. 2006;3(10):563-73.

Thank you

Technology

NSAIDs ASA GI protection