Balancing Heart and Gut Risks of NSAIDs and Heart and Gut Risks of NSAIDs and Antiplatelets ......

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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

  • 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