Rita Achermann: Effect of proton pump inhibitors on clopidogrel therapy

Adviser: Prof. Dr. Werner Stahel

March 2010

Abstract:

In the present study, the interaction between clopidogrel and proton pump inhibitors (PPI) is investigated. A PPI might reduce the anti platelet function of clopidogrel and increase the risk of a second myocardial infarction. Patients with both drugs prescribed have a higher risk for such an event, but whether this is due to individual risk factors or a reduced effect of clopidogrel is an open question. The present study aims to assess the effect due to an interaction between the two drugs using health insurance data. Methods to adjust for confounders in observational data were applied, and new graph theory developments in combination with probability theory were evaluated.

The study population consisted of 4 623 patients with prescribed clopidogrel, a hospital stay of at most 30 days before the first administration of clopidogrel, and health insurance coverage with Helsana. Hospitalization due to cardiac event and death were used as the clinical endpoints to assess, whether proton pump inhibitor prescription was associated with a higher risk of rehospitalization.

A graph was constructed based on knowledge to derive theoretically, whether the effect was identifiable. Causal inference rules applied to this knowledge based graph showed, that the effect is identifiable when observational data are used. Graphs estimated from data did not disprove these findings. The effect of PPI on clopidogrel was calculated from the interventional distribution defined  by the graph. Also standard statistical techniques, a Cox proportional hazard regression, was applied, once with covariates to adjust for confounding and once with a propensity score. An instrumental variable approach was not feasible, since no instrument was found.

Patients with concomitant use of clopidogrel and proton pump inhibitors had a higher risk for rehospitalization due to a cardiac event by a factor of 1.33 (CI 95%: 1.10, 1.61) compared to patients with no prescription for PPI. Important for the analysis was, that some patients had PPI administred together with clopidogrel but had no prescription before. Treatment guidelines recommend PPI to prevent stomach bleeding, a side effect caused by clopidogrel. It is assumed that this patients had no higher individual risk for a recurrent myocardial infarction compared to patients with no PPI prescription. Hence, the patients can be compared to patients with no PPI prescription before and during the study phase to estimate the effect. Comparison of the baseline characteristics for 23 drug groups, as well as age and gender revealed only minor differences. Results calculated based on the interventional distribution defined by the graph showed similar results compared to Cox regression. Finally, the propensity score used as a stratifier in a Cox proportional hazard regression yielded similar results  either. As alternative treatments for PPI are available, patients should not take these two drugs together.

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