Monday, December 20, 2010

Clopidogrel- with or without PPI ??

Recently, concerns have been raised about the potential for PPIs to blunt the efficacy of clopidogrel.
Mechanism -  the interaction between the two is most likely due to competitive inhibition of the CYP2C19 isoenzyme trough which clopidogrel is metabolised to its active form.

A 2008 publication in JACC involving 124 pts. showed that omeprazole significantly reduced Clopidogrel's inhibitory effect on platelet P2Y12 measured by a method called Vasodilator stimulated vasoprotein(VASP) phosphorylation testing. A retrospective observational study(JAMA 2009) on 8000 patients on clopidogrel showed that concomitant use of clopidogrel and PPI after hospital discharge for ACS was associated with an increased risk of adverse outcomes than use of clopidogrel without PPI (adjusted odds ratio [AOR], 1.25; 95%confidence interval [CI],1.11-1.41)

This issue was addressed in the recent prospective randomized trial - COGENT ...published in NEJM . around 3700 patients taking clopidogrel and aspirin for cardiovascular reasons were randomly assigned to receive either omeprazole or placebo. The group on PPI showed a significant reduction in the number of GI bleed in 6 months ((1.1% with omeprazole and 2.9% with placebo (hazard ratio with omeprazole, 0.34, 95% confidence interval [CI], 0.18 to 0.63; P<0.001)). Both the groups had similar rates of adverse cardiovascular events. Also....subgroup analysis of trials like CREDO, TRITON  did not show any increase in cardiovascular event with PPI and clopidogrel. 
In spite of these data...FDA put a black box warning on the Clopidogrel-PPI interaction in Nov 2009.

The AHA/ ACC and American College of Cardiology jointly published a consensus statement 2 weeks ago based on the COGENT trial ---
 1.In patients with histories of upper GI bleeding and those at high risk for this complication (e.g., advanced age; concomitant use of warfarin, steroids, or nonsteroidal anti-inflammatory drugs; Helicobacter pylori infection), the benefits of PPI therapy probably outweigh the very small risk that PPI therapy will interfere with clopidogrel's efficacy. 
2.Patients at low risk for GI bleeding who require clopidogrel therapy should not receive concomitant PPIs.

There is some evidence that this interaction(if at all clinically significant) may not be a class effect. The authors of this study in Annals of Pharmacotherapy 2009 suggest that Omeprazole seems to interact more with clopidogrel's action in vitro..than Pantoprazole. May be ..until we get a solid answer from further trials......if PPI need to be used....lets use pantoprazole with clopidogrel (provided the insurance covers!!!!)


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