More evidence published this week suggests that the concomitant use of
clopidogrel (Plavix, Bristol-Myers Squibb/Sanofi-Aventis) and proton-pump
inhibitors (PPIs) attenuates the benefits of antiplatelet therapy and increases
the risk of future events. Among discharged acute coronary syndrome (ACS)
patients prescribed the two drugs, there was an increased risk of adverse
clinical outcomes compared with clopidogrel alone, including higher rates of
death or rehospitalization for ACS [1].

"I don't think our study changes the guidelines or the recommendations for
clopidogrel use after ACS hospitalization," lead investigator Dr P Michael Ho
(Denver Veterans Affairs Medical Center, CO) told heartwire, "but it does
suggest, along with other studies, that proton-pump inhibitors shouldn't be
prescribed prophylactically just because the patient is on aspirin and
clopidogrel. Given the accumulating evidence, this study suggests that unless
there is a clear indication for the PPI medication, there might be other stomach
medications that patients can take."

The results of the study are published in the March 4, 2009 issue of the Journal
of the American Medical Association.

FDA Issued an Early Communication About Safety Review

Clopidogrel is a prodrug converted in the liver to its active form by cytochrome
P450 isoenzymes, with P450 2C19 playing a particularly important role. There is
evidence suggesting that various PPIs can inhibit P450 2C19, which would alter
the effectiveness of clopidogrel and potentially lead to an increased risk of
adverse cardiovascular outcomes. As noted by the investigators, many patients
treated with clopidogrel and aspirin following ACS are also treated with PPIs to
reduce the risk of gastrointestinal bleeding with dual antiplatelet therapy.

In January, the Food and Administration (FDA) announced it was continuing to
study the effectiveness of clopidogrel in patients taking other medications,
particularly PPIs, as well as in those with genetic variants linked with
clopidogrel resistance. Despite the early communication from the FDA, the
existing data were insufficient to make firm recommendations, leading
investigators to analyze the interaction in a large cohort of Veterans Affairs
patients.

In this retrospective cohort study, 8205 patients with ACS taking clopidogrel
after discharge from the hospital between 2003 and 2006 were identified. Of
these patients, 64% were prescribed a PPI at discharge or during follow-up,
while 36% were not prescribed a PPI. Those prescribed a PPI tended to be older
and have more comorbid disease, including higher rates of diabetes, prior MI,
previous CABG surgery, peripheral vascular disease, and lung and renal disease.

Concomitant use of clopidogrel and a PPI was associated with a 25% greater risk
of death or rehospitalization for ACS, the primary end point in this analysis.
Individual end points, including rehospitalization for ACS and revascularization
procedures, were also significantly increased with the combination, although
all-cause mortality was not significantly different between the two treatment
regimens.

Various sensitivity analyses examining time periods of use, as well as a nested
case-control analysis, confirmed the findings and suggested it was the
interaction of the medications responsible for the increased risk. The increased
risk of an adverse outcome associated with the use of clopidogrel and PPI
remained statistically significant after researchers excluded those with a
history of gastrointestinal bleeding prior to hospitalization for ACS, those who
had a bleeding event during hospitalization, and those prescribed an
H2-antagonist.

Speaking with heartwire, Ho noted that the risk appears primarily due to
recurrent hospitalization for ACS, which is consistent with mechanistic studies
suggesting an increased prothrombotic state due to the inhibition of platelet
activity with clopidogrel and PPIs. He noted that 8% of patients in this study
had a previous history of gastrointestinal bleeding, while 25% had an
in-hospital bleed or during follow-up, making them eligible for a PPI. Still,
with 64% prescribed a PPI in this study, "it suggests there are a large number
of patients prescribed the drug prophylactically," said Ho.

Regarding the lack of mortality risk associated with the interaction, Ho said
that researchers had access only to all-cause mortality data and that more
detailed causes of death might show a signal, particularly with cardiovascular
death.

The researchers also note that 60% of patients taking a PPI were prescribed
omeprazole, a drug available over the counter since 2003, and that there was a
strong association between its use with clopidogrel and adverse clinical
outcomes. Overall, said Ho, the findings highlight the importance of a drug
interaction not observed in large clinical trials and suggest that drug
surveillance is critical after drug approval to monitor unintended side effects
and interactions.

SCAI Issues a Statement

In light of the findings, the Society for Cardiovascular Angiography and
Interventions (SCAI) issued a statement that patients prescribed clopidogrel and
other antiplatelet medications after undergoing interventional cardiology
procedures should continue taking the drugs unless told to stop by their
physician.

An expert consensus document developed by the American College of Cardiology,
American Heart Association, and American College of Gastroenterology and
published in 2008 notes that PPIs should be the mainstay of treatment and
prevention of gastrointestinal ulcers and bleeding in patients on antiplatelet
therapy who are at increased risk for the gastrointestinal complications.
High-risk patients who might benefit from a PPI include patients with a history
of ulcer disease, gastrointestinal bleeding, a need for dual antiplatelet
therapy, or an indication for warfarin or other anticoagulants, according to the
report.

SCAI recommends physicians continue prescribing dual antiplatelet therapy after
stent implantation according to the guidelines and prescribe a PPI medication
when there is a clinical indication for it.


Ho PM, Maddox TM, Wang L, et al. Risk of adverse outcomes associated with
concomitant use of clopidogrel and proton pump inhibitors following acute
coronary syndrome. JAMA 2009; 301:937-944.