Recent trial and non-experimental studies have reported that an interaction between PPIs and clopidogrel increases the risk for a second MI by up to 40%, which if substantiated, would be of major clinical and public health importance. In the study presented here, we applied traditional and more advanced confounding control techniques to an analysis of 18,565 North American patients in three cohorts. The patients were adults 65 years and older who had recently undergone PCI or an ACS hospitalization. To our knowledge, ours is the largest study of this question to date. While the point estimates we observed in each of the three cohorts indicated a slightly increased risk of MI or death in older patients initiating both clopidogrel and a PPI, the possible increase in risk was modest, the confidence intervals were wide, and we did not observe consistent evidence of a substantial or statistically significant clopidogrel-PPI interaction. Progressively better control of confounding reduced the apparent risk from the initial crude estimates, suggesting that some or all of the final observed risk may be the result of residual unmeasured confounding. Our data suggest that if a true interaction does exist, its effect is unlikely to exceed a 20% risk increase.
In both of the recently published studies evaluating the interaction between clopidogrel and PPIs,18, 19
patients who received PPIs had more comorbidity than those prescribed clopidogrel alone, leading to a concern about confounding by indication.28
For example, physicians may be more likely to use gastroprotective drugs in frailer patients -- such as those started on a PPI during an intensive care unit stay – or in smokers, who have a higher incidence of upper gastrointestinal disease. Conventional adjustment as employed by Ho et al. and Juurlink et al. may inadequately account for confounding in this treatment group. In our study, we performed more extensive confounding adjustment25
and in a sensitivity analysis, verified that after adjustment, the PPI users were not more likely to be at increased risk for MI or death. Further complicating the interpretation of Ho et al.'s results is their inclusion of “immortal person time” in the study's primary analysis.22
This design results in bias due to the fact that exposure status was determined during follow-up; those who were sickest and had an MI early in follow-up would have had a lower chance of being exposed such that consequently, unexposed patients would have been oversampled. Our study design avoided such biases only starting follow-up after the 7-day run-in period during which exposure status was determined for all patients.
The possibility of a modest risk posed by a PPI-clopidogrel interaction would be consistent with the findings of the randomized study by Gilard et al.,12
in which omeprazole partially reduced the inhibitory effect of clopidogrel, as assessed by tests of platelet activity. The correlation between the results of the assay used by these investigators and subacute coronary stent thrombosis has been previously observed.29
Separately, two other recent studies reported that patients with substantial loss-of-function mutations in the metabolic pathway that activates clopidogrel (CYP2C19)16, 17
have a doubling of risk of coronary events. CYP2C19 is also the putative mechanism by which clopidogrel and PPIs interact.
If PPIs do indeed reduce the beneficial effect of clopidogrel, then 20% may well be the upper bound for any increase in the relative risk of MI or death. In post-PCI or ACS patients using clopidogrel, the baseline risk of the outcome is high. If absolute risk increases are constant, relative risks are smaller in patients with high baseline risk.30
Further, the Gilard et al. study indicated only a partial reduction in clopidogrel's anti-platelet action; that is, even with a drug-drug interaction, clopidogrel would still provide some benefit. Finally, the CYP2C19 polymorphism, which is likely equally prevalent in the PPI user and non-user groups, itself reduces the protective effect of clopidogrel in a certain fraction of the population. This attenuation would yield a decrease in relative risk as compared to a population in which nobody carried the allele.
To the extent possible in our non-randomized study, we drew upon the design principles of an RCT: we limited the patient population to those who were clopidogrel-naïve, instituted a 7-day run-in period, and only started follow-up from the time that patients' exposure status had been fully determined. To minimize the effects of unmeasured confounding, in particular confounding due to the “channeling” to one treatment or another in response to disease severity and patient prognosis,28
we adjusted by a high-dimensional propensity score. Adjusting for or matching on a propensity score that includes all pertinent confounders should serve a role analogous to randomization in an RCT;26
the hd-PS method allowed us to enrich the standard propensity score with more of those pertinent confounders than are possible to specify a priori
. The hd-PS we adjusted for included our investigator-identified covariates alongside 400 additional variables empirically identified from the claims codes in our databases, and therefore allowed for more confounding adjustment than did standard propensity score or multivariate analysis. One confounder that remained unmeasured was aspirin use, though in this population of patients who have all had cardiac events, aspirin would have been indicated for and likely used by almost all members of the cohort and would thus be a weak confounding factor.
In the United States, omeprazole has been available over-the-counter (OTC) since June 2003; as a result, our study may be open to some misclassification of exposure. In PA and NJ, however, the low-income patient population we studied would have little incentive to buy PPIs OTC, as their copayment for prescription PPIs was less than half of OTC prices.31
In Canada, PPIs are not available OTC -- though it is possible that BC residents purchased OTC PPIs in the United States -- yet the BC data reflected the same findings as those from NJ and PA. With respect to potential misclassification of the outcomes, the “hard” endpoint of MI or death was defined in a highly specific and non-differential way; such specificity should lead to a non-existent or negligible misclassification bias in the relative risk.32
Conversely, the discretion involved in choosing upon whom to perform a revascularization procedure likely explains at least some of the heterogeneity of the revascularization results: very sick patients are less likely to receive such treatment due to the overall risk-benefit assessment.33, 34
In conclusion, the results of this large study of community-dwelling patients 65 years and older followed up after PCI or ACS, failed to demonstrate a large or statistically significant increase in the relative risk of MI or death owing to concurrent use of clopidogrel and PPIs, as previously reported. Our data are however consistent with the possibility of an interaction with only modest clinical effect in routine care of older adults.