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Proton Pump Inhibitor Usage and the Risk of Myocardial Infarction in the General Population.

Shah NH, LePendu P, Bauer-Mehren A, Ghebremariam YT, Iyer SV, Marcus J, Nead KT, Cooke JP, Leeper NJ - PLoS ONE (2015)

Bottom Line: We found that this association exists regardless of clopidogrel use.We also found that H2 blockers, an alternate treatment for GERD, were not associated with increased cardiovascular risk; had they been in place, such pharmacovigilance algorithms could have flagged this risk as early as the year 2000.These data provide an example of how a combination of experimental studies and data-mining approaches can be applied to prioritize drug safety signals for further investigation.

View Article: PubMed Central - PubMed

Affiliation: Stanford Center for Biomedical Informatics Research, Stanford University, Stanford, CA, United States of America.

ABSTRACT

Background and aims: Proton pump inhibitors (PPIs) have been associated with adverse clinical outcomes amongst clopidogrel users after an acute coronary syndrome. Recent pre-clinical results suggest that this risk might extend to subjects without any prior history of cardiovascular disease. We explore this potential risk in the general population via data-mining approaches.

Methods: Using a novel approach for mining clinical data for pharmacovigilance, we queried over 16 million clinical documents on 2.9 million individuals to examine whether PPI usage was associated with cardiovascular risk in the general population.

Results: In multiple data sources, we found gastroesophageal reflux disease (GERD) patients exposed to PPIs to have a 1.16 fold increased association (95% CI 1.09-1.24) with myocardial infarction (MI). Survival analysis in a prospective cohort found a two-fold (HR = 2.00; 95% CI 1.07-3.78; P = 0.031) increase in association with cardiovascular mortality. We found that this association exists regardless of clopidogrel use. We also found that H2 blockers, an alternate treatment for GERD, were not associated with increased cardiovascular risk; had they been in place, such pharmacovigilance algorithms could have flagged this risk as early as the year 2000.

Conclusions: Consistent with our pre-clinical findings that PPIs may adversely impact vascular function, our data-mining study supports the association of PPI exposure with risk for MI in the general population. These data provide an example of how a combination of experimental studies and data-mining approaches can be applied to prioritize drug safety signals for further investigation.

No MeSH data available.


Related in: MedlinePlus

PPI use is associated with an increased risk for MI, regardless of age or clopidogrel use.No association is identified for H2 Blocker use: In the fig, the dotted red line represents the reference point indicating no elevated risk for myocardial infarction (MI). The odds ratio and 95% confidence interval for each exposure are indicated by a blue dot and blue line, respectively, which are also represented numerically to the right of each fig. The size of the dot is proportional to the exposure size of each group (see Table 1). Fig A, derived from STRIDE (N = 70,477), shows that PPIs have a class-level effect for MI in the general population of patients with GERD. By comparison, H2 blockers, an alternate treatment, have no association. Fig B breaks down the associations for each PPI individually. Figs C and D use stratification to show that the signals are corroborated in two independent datasets (STRIDE and Practice Fusion) and are robust in important subgroups. Fig C shows that, for the STRIDE dataset, when patients on clopidogrel are excluded, the associations are unchanged. Also, in lower-risk age groups for MI, the associations are still present. Similar trends are seen in these subgroups in the Practice Fusion (PF) dataset (N = 227,438) shown in Fig D.
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pone.0124653.g001: PPI use is associated with an increased risk for MI, regardless of age or clopidogrel use.No association is identified for H2 Blocker use: In the fig, the dotted red line represents the reference point indicating no elevated risk for myocardial infarction (MI). The odds ratio and 95% confidence interval for each exposure are indicated by a blue dot and blue line, respectively, which are also represented numerically to the right of each fig. The size of the dot is proportional to the exposure size of each group (see Table 1). Fig A, derived from STRIDE (N = 70,477), shows that PPIs have a class-level effect for MI in the general population of patients with GERD. By comparison, H2 blockers, an alternate treatment, have no association. Fig B breaks down the associations for each PPI individually. Figs C and D use stratification to show that the signals are corroborated in two independent datasets (STRIDE and Practice Fusion) and are robust in important subgroups. Fig C shows that, for the STRIDE dataset, when patients on clopidogrel are excluded, the associations are unchanged. Also, in lower-risk age groups for MI, the associations are still present. Similar trends are seen in these subgroups in the Practice Fusion (PF) dataset (N = 227,438) shown in Fig D.

Mentions: For our data-mining method, a threshold of 1.0 on the lower bound of the 95% confidence interval of the adjusted odds ratios provides 39% sensitivity and 97.5% specificity in signaling an association—translating to a 3.5% false positive rate and a 61% false negative rate (making it a conservative test) [26]. Fig 1A shows that PPIs as a class (N = 32,363) are associated with MI with an adjusted odds ratio (AOR) of 1.16 (95% CI 1.09–1.24). Fig 1B shows the associations for each PPI individually. The strength of association varies slightly for each PPI, ranging from AOR 1.08 to 1.34.


Proton Pump Inhibitor Usage and the Risk of Myocardial Infarction in the General Population.

Shah NH, LePendu P, Bauer-Mehren A, Ghebremariam YT, Iyer SV, Marcus J, Nead KT, Cooke JP, Leeper NJ - PLoS ONE (2015)

PPI use is associated with an increased risk for MI, regardless of age or clopidogrel use.No association is identified for H2 Blocker use: In the fig, the dotted red line represents the reference point indicating no elevated risk for myocardial infarction (MI). The odds ratio and 95% confidence interval for each exposure are indicated by a blue dot and blue line, respectively, which are also represented numerically to the right of each fig. The size of the dot is proportional to the exposure size of each group (see Table 1). Fig A, derived from STRIDE (N = 70,477), shows that PPIs have a class-level effect for MI in the general population of patients with GERD. By comparison, H2 blockers, an alternate treatment, have no association. Fig B breaks down the associations for each PPI individually. Figs C and D use stratification to show that the signals are corroborated in two independent datasets (STRIDE and Practice Fusion) and are robust in important subgroups. Fig C shows that, for the STRIDE dataset, when patients on clopidogrel are excluded, the associations are unchanged. Also, in lower-risk age groups for MI, the associations are still present. Similar trends are seen in these subgroups in the Practice Fusion (PF) dataset (N = 227,438) shown in Fig D.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4462578&req=5

pone.0124653.g001: PPI use is associated with an increased risk for MI, regardless of age or clopidogrel use.No association is identified for H2 Blocker use: In the fig, the dotted red line represents the reference point indicating no elevated risk for myocardial infarction (MI). The odds ratio and 95% confidence interval for each exposure are indicated by a blue dot and blue line, respectively, which are also represented numerically to the right of each fig. The size of the dot is proportional to the exposure size of each group (see Table 1). Fig A, derived from STRIDE (N = 70,477), shows that PPIs have a class-level effect for MI in the general population of patients with GERD. By comparison, H2 blockers, an alternate treatment, have no association. Fig B breaks down the associations for each PPI individually. Figs C and D use stratification to show that the signals are corroborated in two independent datasets (STRIDE and Practice Fusion) and are robust in important subgroups. Fig C shows that, for the STRIDE dataset, when patients on clopidogrel are excluded, the associations are unchanged. Also, in lower-risk age groups for MI, the associations are still present. Similar trends are seen in these subgroups in the Practice Fusion (PF) dataset (N = 227,438) shown in Fig D.
Mentions: For our data-mining method, a threshold of 1.0 on the lower bound of the 95% confidence interval of the adjusted odds ratios provides 39% sensitivity and 97.5% specificity in signaling an association—translating to a 3.5% false positive rate and a 61% false negative rate (making it a conservative test) [26]. Fig 1A shows that PPIs as a class (N = 32,363) are associated with MI with an adjusted odds ratio (AOR) of 1.16 (95% CI 1.09–1.24). Fig 1B shows the associations for each PPI individually. The strength of association varies slightly for each PPI, ranging from AOR 1.08 to 1.34.

Bottom Line: We found that this association exists regardless of clopidogrel use.We also found that H2 blockers, an alternate treatment for GERD, were not associated with increased cardiovascular risk; had they been in place, such pharmacovigilance algorithms could have flagged this risk as early as the year 2000.These data provide an example of how a combination of experimental studies and data-mining approaches can be applied to prioritize drug safety signals for further investigation.

View Article: PubMed Central - PubMed

Affiliation: Stanford Center for Biomedical Informatics Research, Stanford University, Stanford, CA, United States of America.

ABSTRACT

Background and aims: Proton pump inhibitors (PPIs) have been associated with adverse clinical outcomes amongst clopidogrel users after an acute coronary syndrome. Recent pre-clinical results suggest that this risk might extend to subjects without any prior history of cardiovascular disease. We explore this potential risk in the general population via data-mining approaches.

Methods: Using a novel approach for mining clinical data for pharmacovigilance, we queried over 16 million clinical documents on 2.9 million individuals to examine whether PPI usage was associated with cardiovascular risk in the general population.

Results: In multiple data sources, we found gastroesophageal reflux disease (GERD) patients exposed to PPIs to have a 1.16 fold increased association (95% CI 1.09-1.24) with myocardial infarction (MI). Survival analysis in a prospective cohort found a two-fold (HR = 2.00; 95% CI 1.07-3.78; P = 0.031) increase in association with cardiovascular mortality. We found that this association exists regardless of clopidogrel use. We also found that H2 blockers, an alternate treatment for GERD, were not associated with increased cardiovascular risk; had they been in place, such pharmacovigilance algorithms could have flagged this risk as early as the year 2000.

Conclusions: Consistent with our pre-clinical findings that PPIs may adversely impact vascular function, our data-mining study supports the association of PPI exposure with risk for MI in the general population. These data provide an example of how a combination of experimental studies and data-mining approaches can be applied to prioritize drug safety signals for further investigation.

No MeSH data available.


Related in: MedlinePlus