Download Proton Pump Inhibitors Blamed for Clopidogrel Resistance

Proton Pump Inhibitors Blamed for
Clopidogrel Resistance
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By Michael Smith, North American Correspondent, MedPage Today
Published: January 29, 2009
Reviewed by Dori F. Zaleznik, MD; Associate Clinical Professor of Medicine, Harvard Medical
School, Boston.
TORONTO, Jan. 29 -- Some proton pump inhibitors reduce or eliminate the antiplatelet
benefits of clopidogrel (Plavix) and increase the risk of a second heart attack,
researchers here found.
Action Points

Explain to interested patients that clopidogrel (Plavix) is prescribed after a heart
attack for secondary prevention.

Note that this study found that taking the drug along with some proton pump
inhibitors increases the risk of recurrence.
The finding comes as the FDA begins a review of the so-called clopidogrel resistance
phenomenon, in which between 5% and 15% of patients have no response to the drug.
The agency will investigate whether genetic factors or drug interactions are responsible
for the effect. (See: FDA to Study Safety of Clopidogrel)
http://www.medpagetoday.com/ProductAlert/Prescriptions/12607
But the Canadian researchers are pointing at proton pump inhibitors, according to David
Juurlink, M.D., Ph.D., of Sunnybrook Health Sciences Center, and colleagues.
In a six-year population-based study of heart attack patients, current use of three proton
pump inhibitors was associated with a 27% increase in the risk of another MI, they said
online in the Canadian Medical Association Journal.
The findings "highlight a widely unappreciated, extremely common and completely
avoidable drug interaction in a population of patients at very high risk of re-infarction,"
the researchers concluded.
Page Two
Clopidogrel requires activation by cytochrome P450 enzymes in the liver, with
cytochrome P450 2C19 playing a major role. And there's emerging evidence that some
proton pump inhibitors block cytochrome P450 2C19, which would affect the
pharmacokinetics of clopidogrel, the researchers said.
To test that idea, Dr. Juurlink and colleagues conducted a nested case-control study
among patients 66 or older who started clopidogrel between April 1, 2002, and Dec. 31,
2007, after treatment of acute MI.
Cases in the study were those readmitted within 90 days with another MI; matching
controls were chosen from the cohort as a whole.
About one in every five patients (19.7%) were prescribed a proton pump inhibitor within
30 days of discharge and 31% within 90 days, the researchers found.
Among the 13,636 patients in the cohort, 782 were readmitted because of an acute MI
within 90 days after discharge and 734 were matched to at least one control.
Among those 734 cases, 194 were taking a proton pump inhibitor, compared with 424 of
2,057 controls, leading to an odds ratio for MI of 1.27, with a 95% confidence interval
from 1.03 to 1.57.
The risk was confined to patients currently taking the drugs, not those with past use.
Limitations of the study included no information on known cardiac risk factors, possible
miscoding of proton pump inhibitor exposure, and lack of data on over-the-counter
medications such as aspirin.
The researchers found that 46 of the cases had been prescribed pantoprazole (Protonix
and others), which does not inhibit cytochrome P450 2C19, and for those patients there
was no increase in risk.
But that was not the case for patients taking omeprazole (Losec, Prilosec), lansoprazole
(Prevacid), or rabeprazole (Aciphex) - which do inhibit cytochrome P450 2C19.
For those patients, the combined odds ratio for MI was 1.4, with a 95% confidence
interval from 1.10 to 1.77.
"These observations support the hypothesis that some proton pump inhibitors
significantly reduce or even abolish the cardioprotective effects of clopidogrel," the
researchers said.
Page Three
The study was supported by the Ontario Ministry of Health and Long-Term Care and the
Canadian Institutes of Health Research. Dr. Juurlink reported no conflicts.
Primary source: Canadian Medical Association Journal
Source reference:
Juurlink DN, et al "A population-based study of the drug interaction between proton pump
inhibitors and clopidogrel" CMAJ 2009; 180(7): DOI: 10.1503/cmaj.082001.
Related Article(s):

FDA to Study Safety of Clopidogrel
http://www.medpagetoday.com/Cardiology/MyocardialInfarction/tb/12607
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Filename: 2008-02-15-IBCMT-ProtonPumpInhibitorsBlamedForClopidogrelResistance.doc