Balancing Heart and Gut Risks of NSAIDs and Antiplatelets · Balancing Heart and Gut Risks of NSAIDs and Antiplatelets ... history of NSAID induced ulcer bleed. ... Relative risk

Balancing Heart and Gut Risks of NSAIDs and Antiplatelets

Dato’ Dr Tan Huck JooSenior Consultant Gastroenterologist and Hepatologist

Sunway Medical Centre, Petaling Jaya Selangor

Email: [email protected]

Contents

• NSAID and risk of PUD

– Prevention

• NSAID/COX2i and CV risks

– Choosing the right NSAIDs

• Antiplatelet and PUD

– Prevention strategy

• Antiplatelet and PPI

PPI is protective against NSAID induced GI toxicity

0

0.5

1

1.5

2

2.5

3

3.5

4

4.5

NSAID NSAID +PPI

Acute users

Chronic users

Pilotto A et al. Aliment Pharmacol Ther 2004

Odds ratio after adjusted for age, gender, H pylori

A 70 year old lady with rheumatoid arthritis and history of NSAID induced ulcer bleed. She also has dyspepsia. You would

1. Prescribe coxib

2. Add PPI to NSAID

3. Use non NSAID analgesia

4. Prescribe PPI and coxib

Coxibs vs diclofenac plus omeprazole

0

5

10

15

20

25

30

35

Bleeding ulcers Endoscopiculcers

All ulcers

4.9

18.7

24.1

6.4

25.6

32.3

Celecoxib

Diclofenac +Omeprazole

Chan FK et al. N Engl J Med 2002

Chan FK et al. Gastroenterology 2004

6-month cumulative incidence of ulcers

Celecoxib vs lansoprazole and naproxen

0

2

4

6

8

10

12

14

16

Recurrent ulcer Dyspepsia

Celecoxib

Naproxen +Lansoprazole

Lai KC et al. Am J Med 2005

Recurrent ulcer complications at 6 months

Coxib+PPI in Very High Risk

0

1

2

3

4

5

6

7

8

9

Coxib+PPI Coxib+placebo

Chan FK et al. Lancet 2007

13 month cumulative incidence of recurrent ulcer bleeding

P=0.0004

Helicobacter pylori eradication in patients starting NSAID

Chan FK et al. Lancet 2002

0

5

10

15

20

25

30

35

Peptic ulcer Complicated ulcers

HP erad

Placebo

6-month probability of ulcers and complicated ulcers

0

2

4

6

8

10

12

14

16

18

20

Aspirin NSAID

Erad group

PPIP=0.05

PPI vs HP Eradication in Preventing Recurrent Bleeding

P=NS

Chan FK. NEJM 2001

Probability of recurrent bleeding at 6 months

N=400

PPI prevent ulcer complications after HP eradication in pts on aspirin

0

2

4

6

8

10

12

14

16

Lansaprazole Placebo

n-=123

Ulcer recurrence at 12 months

Lai KC et al. NEJM 2002

NSAID AND CV RISKS

Is cardiovascular toxicity a class effect

• Rofecoxib (VIGOR, APPROVe trials)

• Celecoxib (APC trial)

• Paracoxib + Valdecoxib (post-coronary bypass)

• Lumiracoxib (TARGET trial)

YES

Is cardiovascular toxicity dose dependent? (APC trial)

• Adenoma Prevention with Celecoxib trial

• N= 2035 patients

• Celecoxib 200mg or 400md bid vs placebo

• Follow up 2.8 to 3.1 years

• End point – cardiovascular and non-cardiovascular events

Soloman SD et al. N Engl J Med 2005;352(11):1071-80

CV toxicity is dose dependent

Soloman SD et al. N Engl J Med 2005;352(11):1071-80

Cardiovascular toxicity is related to treatment duration

Bresalier et al. N Engl J Med 2005

IS CONVENTIONAL NSAID SAFER THAN COXIBS?

NSAID is no safer than coxib in cardiovascular toxicity

0

0.2

0.4

0.6

0.8

1

1.2

1.4

1.6

1.8

celecoxib rofecoxib NSAID

Adjusted rate ratio

Mamdani M et al. Lancet 2004;363:1751-6

• The risk of CCF was higher in patients prescribed rofecoxib or NSAID than celecoxib

• The risk of death and recurrent CCF were similar between patients prescribed NSAID and rofecoxib

Hudson M. BMJ 2005

• The incidence of serious cardiovascular events were similar between celecoxib and NSAID

White WB. Am J Cardiol 2002

A 70 year old gentleman with IHD presented with acute gout. You would prescribe

1. Ibuprofen

2. Naproxen

3. Coxib

Naproxen is protective?

Juni P et al. Arch Intern Med 2002

Juni et al. Lancet 2004

CAN CONCOMITANT ASPIRIN REDUCE CARDIOVASCULAR RISK OF COXIBS AND

NSAIDS?

Aspirin does not reverse CV risk of high dose rofecoxib

0

0.5

1

1.5

2

2.5

ASA+rofecoxib 25mg ASA+rofecoxib >25mg od

RR of MI

Levesque LE et al. Ann Intern Med 2005

Aspirin negates GI toxicity sparing effect of coxibs

0

2

4

6

8

10

12

14

16

18

Placebo

Aspirin

ASA+ rofecoxib

Ibuprofen

Cumulative incidence of ulcers

Laine L et al Gastroenterology 2004;127(2):395-402

Aspirin negates GI toxicity sparing effects of coxibs

0

0.5

1

1.5

2

2.5

3

ulcer complications Symptomatic ulcer

celecoxib

NSAID

Annual incidence %

Silverstein et al JAMA 2000

Patients not taking aspirin

0

1

2

3

4

5

6

Ulcer complications Symptomatic ulcer

Celecoxib

NSAID

Annual incidence %

Patients taking aspirin

Silverstein et al JAMA 2000

P=0.49

P=0.92

Aspirin Increases GI risk of NSAIDs

0

1

2

3

4

5

6

7

8

A75 A150 A300 NSAID Combined

Relative risk of UGIB

Weil et al. BMJ 1995

Ibuprofen negates CV protective effect of aspirin

MacDonald TM et al. Lancet 2003

Ibuprofen abrogates the benefits of aspirin for prevention of MI

0

0.2

0.4

0.6

0.8

1

1.2

1.4

1.6

1.8

ASA+ibuprofen ASA+naproxen

30 days >

60 days >

Hazard ratio for recurrent AMI

Hudson M et al. J Rheumatol 2005

Trend towards lower rate of AMI

NSAID & CV toxicity

• Coxibs increase cardiovascular risk (class effect)

• Different coxibs have different CV toxicities

• NSAID is no safer – naproxen is safer choice

• CV toxicity is dose dependent

• CV toxicity is related to treatment duration

• Aspirin does not reverse CV toxicity of NSAID/Coxib

• Aspirin plus NSAID increase risk of UGI bleed

• Ibuprofen negates CV protective effect of aspirin

Long term NSAID use: Risk vs Benefit

Low GI Risk High GI Risk

Low CV Risk NSAIDs COX2i + PPI

High CV Risk Naproxen GI risk concern: COX2i + PPI

CV risk concern: Naproxen + PPI

A 75 year old lady with IHD presented with aspirin induced gastric ulcer bleeding. You would

1. Switch aspirin to clopidogrel

2. Add PPI to aspirin long term

3. prescribe PPI + clopidogrel

4. Stop aspirin

ASPIRIN PLUS PPI VS CLOPIDOGREL

Aspirin plus esomeprazole vs clopidogrel in recurrent ulcer prevention

0

1

2

3

4

5

6

7

8

Clopidogrel ASA + esomeprazole

Clopidogrel

ASA + esomeprazole

Doggrell SA. Expert Opin Pharmacother 2005

Clopidogrel vs aspirin plus esomeprazole

0

1

2

3

4

5

6

7

8

9

Clopidogrel ASA + esomeprazole

Cumulative incidence of recurrent ulcer bleeding at 12 months

P=0.001

Chan FK et al. N Engl J Med 2005;352(3):238-44

PPI + ASPIRIN OR PPI + CLOPIDOGREL?

0

5

10

15

20

25

30

35

40

45

PPI + Plavix PPI + aspirin

All ulcers

GU

DU

GU+DU

Ng FH et al. Aliment Pharmacol Ther 2004

Clopidogrel vs PPI plus aspirin

• Among patients with previous history of aspirin induced ulcer bleeding

– Aspirin plus esomeprazole is superior to clopidogrel in the prevention of recurrent ulcer bleeding

– Early conversion of aspirin to clopidogrel or continuing with aspirin, both in the presence of PPI, are equally safe

– PPI plus clopidogrel may not be safer than PPI plus aspirin

Conclusions

• Balancing CV and GI risks is important

• PPI reduces risk of PUD in patients taking NSAID and aspirin

• Both coxib and NSAID increases CV risks except naproxen

• Aspirin does not reverse the CV risk of NSAID/coxib and negate GI toxicity sparing effect of coxib

THANK YOU