A study reveals an increase in
cardiovascular mortality with proton pump inhibitors. However, further studies
are required to validate the findings.
Proton pump inhibitors (PPIs) are medications that work by reducing the amount of stomach acid to
relieve symptoms of acid reflux or gastroesophageal reflux disease
(GERD) as well as for treatment of peptic and
stomach ulcers. It is estimated that as high as 113 million PPI prescriptions
are filled annually and as a group PPIs constitute more than $13 billion in sales worldwide.
Some studies have shown that PPIs
reduce the efficacy of the antiplatelet agent clopidogrel
in patients with a history of acute coronary syndrome (ACS), which is typically
prescribed for the risk reduction of subsequent ischemic events. One of the mechanisms in which PPIs cause
increase in major adverse cardiovascular events (MACE)
in patients with ACS is by inhibiting the clopidogrel-activating liver
isoenzyme, CYP2C19. Thus, PPIs interfere with the anti-clotting capacity of
clopidogrel, thereby potentially increasing the risk for coronary thrombosis
and myocardial infarction
Past research suggests the association of
cardiovascular risk with the use of PPIs including in patients who are not
taking antiplatelet agents as well as those without any vascular disease.
Hence, a systematic study was undertaken to explore the association of PPIs and
cardiovascular risk in general US population by using a novel and recently
validated data-mining approach for pharmacovigilance. The study authors
analyzed multiple electronic medical record datasets as well as examined a
prospectively followed clinical cohort.
Two sources were used for the data mining
analysis, out of which the primary source was from Stanford and a secondary
source from Practice Fusion, as well as one prospective source for data
analysis. The authors also examined the relation between PPI use at enrollment
and cardiovascular mortality in GenePAD (the Genetic Determinants of Peripheral
Arterial Disease) study.
Presence of GERD was used to define
baseline population who were divided into two study groups. The primary study
group consisted of patients taking PPIs, which included a subgroup of patients
on clopidogrel. The second group had patients who were on H2
blockers or H2
B (such as cimetidine, famotidine,
nizatidine, and ranitidine) for the treatment of GERD. Controls were selected
from the baseline population using propensity score matching.
The researchers studied over 16 million
clinical documents on 2.9 million individuals to examine whether PPI usage was
linked with cardiovascular risk in the general population.
At the end of the study period, the
authors found an association between PPI use and risk of MI in the population
of patients treated for GERD in the two independent data sets. These results
were independent of clopidogrel use as well as any age-related risks.
Patients using PPIs were found to have a
1.16 fold increased association (95% CI 1.09-1.24) with MI. Results of survival
analysis in the prospective cohort demonstrated a two-fold (HR = 2.00; 95% CI
1.07-3.78; P = 0.031) increase in cardiovascular mortality event. The study
also did not find any correlation between MI and patients treated with H2
blockers for GERD in the same
Thus the study reveals an increase in
cardiovascular mortality with PPIs, whereas no such associations were
identified with H2
use. The study authors stipulate that PPIs could possibly cause this risk via
an unknown mechanism that does not directly involve platelet aggregation.
One of the major limitations of the study
was that it wasn't able to take into account factors such as obesity and
insulin resistance. There was also a possibility that PPIs were prescribed for
angina, which was misdiagnosed as acid reflux.
The findings of the study along with the preclinical
results show a need for further investigation.