PUD and complications from NSAIDs and antiplatelet agents ......NSAID related dyspepsia→improved compliance Rostom et al. Cochrane Database Syst Rev 2002 clinical compications of

PUD and complications from NSAIDs

and antiplatelet agents: epidemiology,

mechanisms of tissue damage and

gastroprotective strategies

Dimitrios Chistodoulou

Associate Professor of Gastroenterology

University Hospital of Ioannina – Greece

Faculty of Medicine, University of Ioannina - Greece

Disclosures

Advisory and/or Speaking for

BMS

MSD

Novartis

NSAIDs

Analgesic action

Anti-inflammatory action

Antiplatelet action (aspirin)

Prevention of cancer (esophagus, pancreas, large bowel )

Gastric erosions

Peptic ulcer Bleeding

Perforation

Pyloric stenosis

Small and large intestinal lesions

Renal toxicity

Intracranial hemorrhage (aspirin)

Worsening of heart failure

Cardiovascular disease

Benefits

Side effects

Mechanism of NSAID-induced toxicity 1) Inhibition of cycloxygenase

Reduction of prostaglandins(loss of cell protective action, decreased cell regeneration, decreased blood flow)

2) Local action

1.Increased mucocal permeability

2. Toxic effect of bile, bacteria, food components

3. Chemotaxis of neutrophils

Impact of NSAIDs on microcirculation Reduction of local blood flow( PGE, PGI)

Damage of endothelium of microcirculation

NSAIDs

ΙCAMs

CD11/CD18 β2-integrins

Endothelial cells

Λευκοκύτταρα

Chemotaxis ofneutrophils

Proteases Ο-

Tissue damage

TNF-a

Leukotrienes

Aspirin - NSAIDS

PROTECTIVE FACTORS

Mucus layer

Ionic difference

HCO3 layer

Prostaglandins

Epithelial cells

Mucosal blood flow

H. pyloriPepsinGastric

acid

ATTACKING FACTORS

Aspirin –Other NSAIDs

Prostaglandinsproduction

HCO3

productionMucus

production

Acidic environment

Ουδέτερο περιβάλλον

Upper GI complications from NSAIDs: How high is the risk?

To chronic NSAIDs users:

Peptic ulcers at endoscopy in 40% (vs 1-5% with placebo)

Dyspepsia in 15-50%

Singh et al, Int J Clin Pract 2005Wolfe et al, NEJM 1999

Severe clinical complications of peptic ulcers from non-selective NSAIDs

1.5% per year, RR=4

Without warning symptoms: 50-60%

Upper GI Bleeding from low dose aspirin for antiplatelet action:

1.2% per year, RR=2

Intestinally dissolvable equally hazardous

Upper GI complications from NSAIDs: How high is the risk of severe complications?

Lanas, Curr Treat Opt Gastroenterol 2006

In Europe upper gastrointestinal complications from NSAIDS lead to:

160,000 admissions per year

25,000 deaths per year

Upper GI complications from NSAIDs: How high is the risk?

Plesnila-Frank et al, UEGW 2006

Risk factor Further increase of 4fold risk

History of peptic ulcer x5

History of ulcer complications x5-13

Age > 65 x2.5

High dose of non-selective NSAID x2

Kind of non-selective NSAID (safer: ibuprofen, diclofenac)

Two non-selective NSAIDs x2.5

Non-selective NSAID + aspirin x2

Non-selective NSAID + anticoagulants x2.5

Non-selective NSAID + corticosteroids x2

Upper GI complications from NSAIDs: Who are at greater risk?

Go MF, Gastrointest Endosc Clin N Am 2006AGA Consensus, CGH 2006El-Serag et al, Arch Intern Med 2002

Probable risk factors

Coadministration of SSRI x1.5

High dose of aspirin

H. Pylori infection

NSAID-related dyspepsia

Concomitant diseases (heart disease, rheumatoid arthritis

Female gender

Alcohol abuse

Smoking

Loke YK et al, APT 2008Go MF, Gastrointest Endosc Clin N Am 2006Lanas Curr Treat Opt Gastroenterol 2006

Prevention of UGI complications from non-selective NSAIDs

Options

Modification of risk factors

Gastroprotective agent + non-selective NSAID

Eradication of H. pylori

COX-2 selective NSAID

Gastroprotective agent + COX-2 selective NSAID

Look for risk factors

Assess the indication for NSAID use

Use less toxic NSAIDs (ibuprofen, diclofenac)

Reduce dose and duration of treatment

Avoid coadminitration of another NSAID, steroid, anticoagulants

Inform patient for potential complications

Modification of risk factors for upper GI complications

Paracetamol:

dose related risk of upper GI

bleeding

2g daily → RR=2


Protective agent + non-selective NSAID

Misoprostol

Η2RA

ΡΡΙ


Misoprostol + non-selective NSAID

800 mg daily (2x2 ή 1x4) reduce:► ulcers at endoscopy► clinical ulcer complications

Rostom et al. Cochrane Database Syst Rev 2002

But,but in patients with recent upper GI bleeding from NSAIDs

■ recurrence of bleeding in 22% within six months

Chan et al. AP&T 2001

■ reduced compliance• dosage• side effects in 27% (diarrhea, nausea, abdominal pain)



H2RA + non-selective NSAID

Standard dosage (1x2): not effective

Double dosage (2x2): contradictory results

Only endoscopic studies


Rostom et al, Cochrane Database Syst Rev 2002

At standard dosage (1x1) reduce:

■ ulcers at endoscopy

• equally effective with misoprostol

• superior to H2RA

■ NSAID related dyspepsia→ improved compliance


■ clinical compications of ulcers in high-risk patients


PPI + non-selective NSAID

Chan NEJM 2001, Chan NEJM 2002, Chan Gastro 2004, Lai Αm J Med 2005

0%

20%

40%

60%

80%

100%

19%4 - 6%

Recurrence of bleedingwithin 6 months

NSAID + PPI

Patients with recent upper

GI bleeding from NSAIDs


PPI + non-selective NSAID

NSAID

Protective agent + non-selective NSAID

Misoprostol

Η2RAs

ΡΡΙs


Clear advantage

Eradication of H. pylori

Randomized studies■ for endoscopic ulcers

Reduction of ulcers in new NSAID users

- not to already chronic users

Less effective than ΡΡΙsVergara et al. Aliment Pharm Ther 2005

■ for bleeding

Less effective than ΡΡΙs Chan et al. NEJM 2001

Epidemiologial studiesNSAIDs and Hp act synergistically Papatheodoridis et al. Clin Gastr Hepatol 2006


Safer for upper GI than non-selective NSAIDs (RR = 0,5)

If aspirin is co-administered the advantage is lost

Equal safety for upper GI to ΡΡΙ + non-selective NSAID

Risk of cardiovascular complications, mainly acute myocardial

infarction (RR = 1,4): thrombotic and hypertensive action

Bombardier et al. NEJM 2000 Silverstein et al. JAMA 2000

Schnitzer et al. Lancet 2004 Kearney et al. BMJ 2006

Chan et al. NEJM 2002 Chan et al. Gastro 2004

Lai et al. Am J Med 2005

COX-2 inhibitors


Non-selective NSAIDs:

also increase the cardiovasclular risk (exeption: naproxen)

•Hypertensive (all)

• prethrombotic

• reduce antiplatelet action of aspirin

Grosser et al. J Clin Invest 2006

0%

20%

40%

60%

80%

100%

9%0%

COX2 inhibitor + PPI

Chan et al. Gastroenterology 2006 [abstract]

P=0.004

No risk of rebleeding

independently of aspirin

administraion

Patients with recent UGI bleeding

from NSAIDs

(n = 273)

COX-2 inhibitor + ΡΡΙ

Prevention of UGI complications from selective NSAIDs

Rebleeding within 12 months

COX2 inhibitor

Randomized studies:

The addition of PPIfurther reduces endoscopic ulcers

Scheiman et al. Am J Gastroenterol 2006

eliminates risk of rebleeding

Chan et al. Gastroenterology Lancet 2007


Prevention of UGI complications from selective NSAIDs

COX-2 inhibitor + ΡΡΙ safer than non-selective NSAID+PPI


Prevention of UGI complications from non selective NSAIDs

OR: 0.49 (0.25-0.82), P=0.0084

Targownik LE et al, Gastroenterology 2008

Comparison of gastroprotective strategies

Strategy OR of upper GI complication

Non-selective NSAID + low dose misoprostol 0.74

Non-selective NSAID + PPI 0.67

Non-selective NSAID + PPI + misoprostol 0.58

Coxib 0.51

Coxib + PPI 0.36

Targownik LE et al, Gastroenterology 2008

Prevention of upper GI complications from NSAIDs

Non-selective NSAID


Non-selective NSAID + H. pylori eradication

COX-2 inhibitor

Up

per

Gas

tro

inet

sin

alS

afet

y

Non-selective NSAID+ ΡΡΙ =

Lanza FL et al, Am J Gastro 2009

Cost – effectiveness

?

Markov model with 10,000 patients under NSAIDs:lifelong follow-up from the age of 50 years

Leontiadis et al. UK Health Technology Assessment Agency Report 2007

Prevention of UGI complications from non selective NSAIDs

Cost-effectiveness

Hp eradication +PPI

No action PPI

Leontiadis et al. UK Health Technology Assessment Agency Report 2007

Hp eradicaton

Recommended H. Pylori treatment in the Greek population

First-line:

Concomitant therapy

PPI+Amoxicillin 1g + Clarithromycin 500 mg + Metronidazol 500mg, bid for 10 days

Second-line:

Triple therapy with levofloxacin:

PPI+Amoxicillin 1g + Levofloxacin 500mg, bid for 10 days

Georgopoulos SD et al, J Clin Gastroenterol 2013Georgopoulos SD et al, Helicobacter 2013

Options

■ Modification of risk factors

■ Gastroprotective agent + aspirin

■ H. pylori eradication

■ Clopidogrel

■ Clopidogrel + gastroprotective agent

Prevention of UGI complications from antiplatelet use of aspirin

Ask for risk factors

Evaluate the indication for aspirin use

Use smaller dose (80 mg daily)

Avoid co-administration with NSAIDs, corticosteroids,

anticoagulants

Inform patient for potential complications

Modification of risk factors for upper GI complications


There are data only for ΡΡΙ:

Aspirin + placebo: rebleeding 15 % within one year

Aspirin + ΡΡΙ 1x1: » 1,6 % » Ρ=0.008

Lai et al. NEJM 2002

Protective agent + aspirin


equally effective to PPI for the prevention of rebleeding

Chan NEJM 2001

H. Pylori eradication


Chan NEJM 2001

0%

20%

40%

60%

80%

100%

0,9 %1,9 %

Aspirin + H. pylori eradication

Aspirin + PPIAspirin + PPI

Rebleeding within 6 months

Patients with recent upper GI

bleeding from aspirin

(n =250)

P=ΝS


H. Pylori eradication

Aspirin + PPI

For patients with average risk for upper GI complications

◘ Clopidogel safer than aspirin

CARPIE steering committee. Lancet 1996

◘ Clopidogrel or Aspirin: safer than Clopidogerl + Aspirin

Peters et al. Circulation 2003

Denier et al. Lancet 2004

Clopidogrel


In patients with history of upper GI Bleeding

Not safe enough: rebleeding 9 - 22 % within 1 year

Ng et al. Aliment Pharm Ther 2003Chan et al. NEJM 2005

Lai et al. Clin Gastroenterol Hepatol 2006

Less safe than aspirin+ ΡΡΙ: (rebleeding 0 - 0,7 % within 1 year)

Lai et al. Clin Gastroenterol Hepatol 2006

Chan et al. NEJM 2005

Clopidogerl


?Not enough information

Clopidogrel + ΡΡΙ


Clopidogrel + Aspirin + Enoxaparin + ΡΡΙ

2.7% GI bleeding O.R. 0.068 (0.010-0.272) P<0.001

Ng FH et al. Am J Gastro 2008

AspirinClopidogrel

Aspirin + H. pylori eradication

Up

per

Gas

tro

inte

stin

al S

afet

y

Aspirin + PPI =


Final algorithm of protection1. General Measures for all patients under NSAIDs or aspirin

Seek and Modify risk factors

► Look for risk factors for upper GI complications

► Re-evaluate the indication for NSAID administration

► Evaluate – modify risk factors for cardiovascular disease

AGA Consensus. Clin Gastroenterol Hepatol 2006

Go MF. Gastrointest Endosc Clin N Am 2006

► Select the less toxic NSAID

► Reduce dose and duration of treatment

► Avoid coadministration of a second NSAID, corticosteroids, anticoagulants

► Eradicate known H. pylori infection

► Be alert for cardiovascular complications

► Inform patients for potential complications

Risk factors for cardiovascular disease Personal history of cardiovascular disease Family history of cardiovascular disease Age Male gender Dyslipoproteinemias Diabetes mellitus Arterial hypertension Atrial fibrillation Obesity Smoking Alcohol abuse Diet rich in saturated fat, cholesterol , trans fatty acids Reduced physical activity

Pearson et al. Circulation 2002

2. Specific algorithm of protection depending on the

individual patient risk

Final algorithm of protection

Risk of upper GI complications

Risk of cardiovascular disease

Low

Highασπιρίνη)

No need for NSAID Need for NSAID

Low

(no risk factors)

Non-selective NSAID

+ Eradication of known H. pylori

If symptoms: ΡΡΙ

Aspirin 80 mg

+ Eradication of known H. pylori

If symptoms: ΡΡΙ

Aspirin 80 mg

+ ΡΡΙ

+ Look for H. pylori →

eradication

+ naproxen

Moderate

(1 or 2 risk factors except the following)

+ Eradicate known H. pylori

Aspirin 80 mg

+ ΡΡΙ

+ Look for H. pylori →eradication

High

(Hx of complicated ulcer or

coadministration of steroids or

anticoagulants or ≥ 3 risk factors)

COX-2 inhibitor

+ ΡΡΙ

+ Look for H. pylori→ eradication

Aspirin 80 mg

+ ΡΡΙ

+ + Look for Hp→ eradication

+ alternative analgesia

(NOT NSAID)

COX-2

inhibitor

Non-selective NSAID

+

ΡΡΙ (or misoprostol)

or

Conclusions

■ The complications from NSAIDs and aspirin in the upper GI tract can be

significantly prevented with the recognition and modification of risk

factors

■ In high-risk groups for upper GI complications,

after evaluating also the risk factors of cardiovascular disease, the upper GI

risk can be diminished with the appropriate treatment strategies:

● coadministration of a PPI

● eradication of H. pylori

● substitution of non-selective NSAID with a COX-2 inhibitor

• A sixty year old man with recent history of

myocardial infarction and no history

gastrointestinal disease will receive aspirin.

What should we do?

1. Administer PPI

2. Eradicate H. pylori

3. Administer PPI and eradicate H. pylori

4. Administer misoprostol

5. Nothing

• A sixty year old man with recent history of

myocardial infarction and no history

gastrointestinal disease will receive aspirin.

What should we do?

1. Administer PPI

2. Eradicate H. pylori

3. Administer PPI and eradicate H. pylori

4. Administer misoprostol

5. Nothing

• A seventy-year woman is on corticosteroids and has

severe arthritic pain. She does not suffer from

cardiovascular disease and she takes aspirin from time

to time. What is the treatment of choice?

1. Non selective NSAID + PPI

2. Non selective NSAID + H. pylori eradication

3. Non selective NSAID + PPI + H. pylori eradication

4. COX-2 inhibitor + PPI

5. COX-2 inhibitor + PPI + H. pylori eradication

• A seventy-year woman is on corticosteroids and has

severe arthritic pain. She does not suffer from

cardiovascular disease and she takes aspirin from time

to time. What is the treatment of choice?

1. Non selective NSAID + PPI

2. Non selective NSAID + H. pylori eradication

3. Non selective NSAID + PPI + H. pylori eradication

4. COX-2 inhibitor + PPI

5. COX-2 inhibitor + PPI + H. pylori eradication

Documents

PUD and complications from NSAIDs and antiplatelet agents ......NSAID related dyspepsia→improved compliance Rostom et al. Cochrane Database Syst Rev 2002 clinical compications of