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
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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: hucktan@hotmail.com
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
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
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
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 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 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
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
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