2. INTRODUCTON
• PROTON PUMP INHIBITORS
– Has been available since the 1980’s
– Inhibits the parietal cell’s proton pump
– Most potent suppressor of gastric acid secretion
• CLOPIDOGREL
– Antiplatelet agent, thienopyridine class
– Indicated for: recent stroke, MI, ACS, PAD, AF,
post-PTA, peripheral artery bypass surgery
3. CLOPIDOGREL AND ASPIRIN
• Individually, are used in reducing the
combined risk of CV events, ischemic stroke,
MI, and vascular death
• In combination, significantly reduces risk of
stroke, MI and death in patients with Acute
Coronary Syndrome
• BUT: increases risk of severe gastrointestinal
bleeding
4. Case
• 58 year old male came in for loss of appetite
and generalized debility which started a few
days prior to consult.
• He is a known hypertensive and diabetic for
ten years now on metformin, sitagliptin,
atorvastatin, aspirin and telmisartan.
• On consult noted to be hypotensive,
tachycardic with irregular rhythm, in mild
respiratory distress and afebrile
5. Case
• He was then admitted to the ICU and
subsequently managed as Sepsis secondary to
Community acquired pneumonia, DM2.
• During his ICU stay he developed AMI and
immediately underwent angioplasty
• Subsequent hospital stay was uneventful and
patient was disharged.
6. Question 1
• Will you give antiplatelets:
– ASA alone
– Clopidogrel alone
– Give combination ASA and Clopidogrel
• Will you give anti-coagulants?
7. Recommendation
• Dual antiplatelet therapy with aspirin and
clopidogrel is recommended treatment for
percutaneous coronary intervention (PCI) and
acute coronary syndromes (ACS)
Smith SC Jr. et al. ACC/AHA/SCAI 2005 guideline, J Am Coll Cardiol 2006
Anderson JL, Adams CD, Antman EM, et al., J Am Coll Cardiol 2007
Antman EM, Anbe DT, Armstrong PW, et al, J Am Coll Cardiol 2004
8. Question 2
• Would you give anything to prevent drug-
induced gastropathy and gastrointestinal
bleeding?
• What will you give:
– PPI
– Rebamipide
– H2 blockers
– Antacids
9. ASA and Bleeding
• Topical injury to the mucosa and systemic
effects induced by prostaglandin depletion
• Low-dose prophylaxis is associated with 2-4
fold increase in UGI events
• Recommendation – a gastroprotective therapy
should be prescribed for at-risk patients.
• PPIs are the preferred agents for the therapy
and prophylaxis ASA associated GI injury
ACC/ACG/AHA consensus document 2008
10. Clopidogrel and bleeding
• Main mechanism of action is impaired
angiogenesis
• Anti-angiogenic effects may impair healing of
gastric erosions or small ulcerations that
develop because of other meds or H. pylori
leading to bleeding
ACC/ACG/AHA consensus document 2008
11. Combined ASA and anticoagulant
recommendation
• Combination is associated with significantly
increased risk of major extracranial bleeding, a
large proportion in the GIT
• Should be used only in established vascular,
arrhythmic or valvular indication
• Patients should receive concomitant PPIs as
well
ACC/ACG/AHA consensus document 2008
12. GI BLEEDING
• GI bleeding increased mortality rate from 8%
and up to 16% of patients with AMI (Nikolsky
et al, 2009)
• Omeprazole reduced upper GI bleeding
induced by aspirin-clopidogrel combination by
87% compared with placebo (Bhatt, et al,
2010)
13. HIGH RISK
1. history of a previously
complicated ulcer
2. multiple (>2) risk factors
MODERATE RISK (1-2 risk
factors)
1. age > 65 years
2. high dose NSAID therapy
3. previous history of
uncomplicated ulcer
4. concurrent use of aspirin
(inc. low dose), corticosteroids
or anticoagulants
Patients at increased risk for NSAID GI toxicity
LOW RISK
1. no risk factors
H.pylori is an independent
risk factor and needs to
be addressed separately
Lanza, etal,Am J Gastroenterol 2009
14. H. Pylori Treatment Regimen
• Primary Treatment of H. pylori Infection:
– a PPI, clarithromycin, and amoxicillin, or
metronidazole (clarithromycin-based triple
therapy) for 14 days
– a PPI or H2RA, bismuth, metronidazole, and
tetracycline (bismuth quadruple therapy) for 10–14
days.
ACG guidelines on H. pylori therapy 2007
15. Question #3
• Which PPI will you give?
– Omeprazole
– Esomeprazole
– Lansoprazole
– Dexlansoprazole
– Rabeprazole
– Pantoprazole
16. The U.S. Food and Drug Administration (FDA)
has new data showing that omeprazole
(Prilosec/Prilosec OTC)—a medicine used to
reduce stomach acid—reduces the anti-blood
clotting effect of clopidogrel (Plavix) by almost
half when these two medicines are taken by
the same patient. Patients at risk for heart
attacks or strokes who use clopidogrel to
prevent blood clots will not get the full effect
of this medicine if they are also taking
omeprazole. This effect is called a drug
interaction and it occurs because omeprazole
blocks the conversion of clopidogrel into its
active form.
FDA Advisory November 17, 2009
17. Rationale for Potential Interaction
• Clopidogrel is metabolized by Cytochrome
P450 to its active metabolite
• PPIs competitively inhibits Cytochrome P540
• All PPI have demonstrated ability to decrease
peak plasma concentrations of clopidogrel
active metabolite and subsequent platelet
aggregation (Frelinger et al,2012)
18.
19. Clopidogrel and PPI
• A diminished pharmacodynamic effect of
clopidogrel has been demonstrated in
patients treated with PPIs but whether its
clinical efficacy is reduced remains highly
controversial
Gurbel, et al, Nat Rev Cardiol 2011
Sinai Center for Thrombosis
20. Pharmacodynamic Studies VS. Clinical
Studies
• Does PPI co-administration lead to increased
rates of clinical adverse events?
– Myocardial infarction
– Stent occlusion
– Stroke
– Death
21. • Advanced age; concomitant use of warfarin,
steroids, or NSAIDs; or H. pylori infection all raise
the risk of GI bleeding with antiplatelet therapy.
• Patients with ACS and prior upper GI bleeding are
at substantial CV risk, so dual antiplatelet therapy
with concomitant use of a PPI may provide the
optimal balance of risk and benefit
2010 Consensus statements
AHA/ACG/ACCF
22. • In the absence of large-scale, randomized,
experimental studies that directly compare
PPIs with different pharmacokinetic
properties, the evidence remains weak for
diminished antiplatelet activity associated
with PPIs and thienopyridine co-prescription.
2010 Consensus statements
AHA/ACG/ACCF
23. Recent Meta-analyses
• Kwok, et al (2010)
– 23 studies (93,278 patients)
– They did not find an associated risk of PPI usage
with cardiovascular events.
• Kwok, et al(2012)
– Updated meta-analysis of studies from 2009-2011
(23 studies with 222,311 patients)
– Compares the risk of CV events of different PPIs
24. Recent Meta-analyses
• Kwok, et al (2012)
– There WAS an increase in CV events when PPI was
given with clopidogrel.
– The risk was also elevated when PPI was used
alone (without clopidogrel).
– There are no significant difference in risk when
comparing individual PPIs.
25. Recent Meta-analyses
• Kwok et al (2012)
• Conclusions:
– Results did not support clinically important
interaction between Clopidogrel and PPIs.
– The presence of confounding factors was
responsible for the reason that PPI therapy
without Clopidogrel was also associated with
increased cardiovascular events.
26. SUMMARY OR RECENT EVIDENCE
• The interaction between PPIs and clopidogrel
does not appear to be clinically significant for
the majority of patients.
• PPI users on clopidogrel are generally older
with greater co-morbidity indices, which in
itself has ha higher risk of cardiovascular
events.
• There are no significant differences in risks
between different PPIs.
27. RECOMMENDATIONS
• Clinicians can comfortably prescribe PPI +
clopidogrel to patients at high risk for
gastrointestinal bleeding in whom
combination therapy is warranted.
• As the absolute risk of bleeding with a single
antiplatelet agent is low, gastroprotection is
not usually recommended in the absence of
other risk factors.
