OMEPRAZOLE AND CLOPIDOGREL: CURRENT RECOMMENDATIONS

Dr. Antonio C. Comia

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

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

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

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.

Question 1

• Will you give antiplatelets:– ASA alone – Clopidogrel alone– Give combination ASA and Clopidogrel

• Will you give anti-coagulants?

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

Question 2

• Would you give anything to prevent drug-induced gastropathy and gastrointestinal bleeding?

• What will you give:– PPI – Rebamipide– H2 blockers– Antacids

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

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

Combined ASA and anticoagulantrecommendation

• 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

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)

HIGH RISK1. history of a previously

complicated ulcer2. multiple (>2) risk factors

MODERATE RISK (1-2 risk factors)1. age > 65 years2. high dose NSAID therapy3. previous history of uncomplicated ulcer4. concurrent use of aspirin (inc. low dose), corticosteroids or anticoagulants

Patients at increased risk for NSAID GI toxicity

LOW RISK1. no risk factors

H.pylori is an independentrisk factor and needs tobe addressed separately

Lanza, etal,Am J Gastroenterol 2009

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

Question #3

• Which PPI will you give?– Omeprazole– Esomeprazole– Lansoprazole– Dexlansoprazole– Rabeprazole– Pantoprazole

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

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)

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 2011Sinai Center for Thrombosis

Pharmacodynamic Studies VS. Clinical Studies

• Does PPI co-administration lead to increased rates of clinical adverse events?– Myocardial infarction– Stent occlusion– Stroke– Death

• 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 statementsAHA/ACG/ACCF

• 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 statementsAHA/ACG/ACCF

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

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.

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.

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.

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.

THANK YOU!