Using a traditional cohort analysis we observed an increased risk of myocardial infarction or all cause mortality among clopidogrel and aspirin users exposed to a proton pump inhibitor, with a hazard ratio of 1.37 (1.27 to 1.48). We also saw a similar increased risk for the individual outcomes of all cause mortality, incident myocardial infarction, and vascular mortality. Comparable results were seen when we looked at non-vascular mortality and drug exposures other than proton pump inhibitors, including drugs that would not be expected to interact with clopidogrel (such as ranitidine and citalopram). These observed associations with exposures and outcomes that would not be expected from the theoretical drug interaction suggest these results could be driven by important differences between proton pump inhibitor users and non-users rather than showing a causal association. When we used a within person study design to remove the influence of differences between people we found no association between proton pump inhibitor exposure and myocardial infarction, with a rate ratio of 0.75 (0.55 to 1.01) in a self controlled case series.
We believe the association found in the cohort analysis is unlikely to be causal for several reasons. Firstly, the mechanism behind a possible causal association involves a pharmacokinetic drug interaction between clopidogrel and proton pump inhibitors at the CYP450 2C19 enzyme. This interaction would reduce the effectiveness of clopidogrel’s antiplatelet activity and would be expected to lead specifically to an increased risk of vascular events in proton pump inhibitor users compared with non-users. While our results show such an increase in risk, the effect is not specific to vascular events, as shown by the hazard ratio for non-vascular mortality of 1.61 (1.42 to 1.82). One explanation for this strong and unpredicted finding could be unmeasured confounding, whereby people receiving proton pump inhibitors are at an increased risk for harmful outcomes, independent of proton pump inhibitor use. The baseline characteristics of users and non-users suggest that users are older and have more comorbidities than non-users, which would support this hypothesis. Although we adjusted for several confounding factors, it is likely that unadjusted confounding remains, whether from illnesses we have not been able to measure, through systematic differences in the severity of underlying diseases, which we were unable to determine or incomplete ascertainment of the known confounders.
Secondly, the results of secondary analyses examining the effects of other long term drug use are revealing. The results for other strong CYP450 2C19 inhibitors such as paroxetine/fluoxetine mirror those seen for proton pump inhibitors, which is consistent with an interaction at the 2C19 enzyme. The similar results seen for ranitidine and citalopram, however, would not be predicted from the pharmacokinetics of these drugs. An alternative and plausible explanation is that people who are prescribed long term drug treatment in addition to clopidogrel are inherently at higher risk of harmful outcomes but not through a causal association with the treatments they receive. Intuitively, this makes sense as “illness” is itself a risk factor for adverse outcomes and is clearly also associated with an increased chance of receiving drugs. Such confounding can be difficult to overcome in non-randomised studies of drug use.
The results of the self controlled case series analysis also suggest that the cohort results could be explained by confounding between people. The self controlled case series design removes all fixed confounding between individuals as the comparisons are made within an individual, relying on patients who have both exposed and unexposed periods for the main comparison of interest. These results provide no evidence of an increased risk of incident myocardial infarction during periods when patients are exposed to proton pump inhibitors (incident rate ratio 0.75 (0.55 to 1.01) for proton pump inhibitor, 0.57 (0.31 to 1.06) for ranitidine, or 0.84 (0.49 to 1.45) for citalopram). The near protective effect seen with proton pump inhibitors and ranitidine is difficult to explain; it could represent higher adherence to aspirin and clopidogrel during periods of co-prescribing with these drugs, though this is not testable in the present study. Although the incident rate ratio for paroxetine/fluoxetine was raised (1.65), this estimate was based on a relatively small number of events and the 95% confidence interval of 0.87 to 3.15 suggests it could well be a chance finding.
Taken together, a plausible explanation for our results is that the increased risk of both vascular and non-vascular harmful outcomes seen in patients receiving proton pump inhibitors and other long term drugs could be caused by confounding between people. Although accounting for such confounding can be difficult, the use of approaches such as the self controlled case series, which is less prone to differences between people, can solve this problem. The lack of association seen between proton pump inhibitor use and myocardial infarction with this approach argues against a clinically relevant interaction between clopidogrel and proton pump inhibitors.
Strengths and limitations of study
The main advantages of this study are the large sample size taken from a well validated population based data source and the use of newly established data linkages allowing accurate ascertainment of incident myocardial infarction cases and recorded causes of death.
Some limitations could arise from the possibility of imperfect recording of exposures and outcomes. The Myocardial Ischaemia National Audit Project does not record data for patients who die before they reach hospital, and so these cases are systematically missing in our ascertainment of incident myocardial infarction. It is unlikely that underascertainment would happen differently for proton pump inhibitor users and non-users and would therefore be expected to bias any result towards the null. It is also unlikely that this would have any impact on the primary outcome, as all cause mortality includes patients who die before arriving at hospital.
Exposure status was probably incorrectly assigned to some extent as it was determined from prescribing records and we cannot know whether patients obtained all drugs from the pharmacist or took them as directed. For our analysis we had to make an assumption about likely exposure status for all drugs during apparent gaps in prescribing records. We chose to consider gaps of less than 180 days to indicate continued treatment, allowing for possible stockpiling or obtaining drugs from alternative sources. We also repeated analyses when the continuous treatment period was assumed to be shorter (60 or 90 days), and these alternative assumptions had no substantial effect on the results presented here.
Comparison with other studies
These results need to be viewed in the context of other studies examining this drug interaction. Our overall findings are consistent with several studies that also failed to find an association between proton pump inhibitors and less favourable outcomes in clopidogrel users.2
Of note, the case control study by Valkhoff et al12
did find a harmful association but when comparisons were restricted to former or current users of proton pump inhibitors the association was not found, again suggesting a biased result driven by confounding between people. The only randomised trial designed to specifically answer this question was unfortunately stopped early and so is underpowered and unable to rule out a clinically relevant effect.11
The available results, however, did not point towards any harmful association.
Of note, the 2C19 enzyme is subject to genotypic variation, with some people having naturally poor 2C19 metabolic activity. It might be expected that poor metabolisers would experience reduced benefit from taking clopidogrel if the 2C19 pathway is critical for the metabolism of clopidogrel to its active form. A recent meta-analysis, however, found that 2C19 genotype does not influence clopidogrel effectiveness.24
This finding questions the critical role of the 2C19 pathway for clopidogrel effectiveness; it is possible that other pathways compensate in patients with compromised 2C19 activity.
The findings from our cohort analysis are also consistent with several studies showing an association between proton pump inhibitor use and vascular harm,1
but we believe we have shown why this association is unlikely to be causal. In extreme cases the magnitude of harm observed by others was greater than the maximum likely protective effect of clopidogrel,4
again suggesting an alternative explanation is needed for the results. Nonetheless, some studies have preferentially identified a harmful effect of strong CYP450 2C19 inhibitors but not weak inhibitors, a finding that is not readily explained.1
Because of prescribing patterns in the UK, more than 90% of proton pump inhibitor use is accounted for by lansoprazole, omeprazole, and esomeprazole, all of which are strong inhibitors. When we restricted our exposure to only these proton pump inhibitors, the results were similar.
Conclusions and policy implications
In conclusion, these results suggest that the drug interaction between proton pump inhibitors and clopidogrel does not result in clinical harm. The observed associations between proton pump inhibitor use and several harmful outcomes are likely to be non-causal and could be explained by differences between people. An analysis within individuals, which removes the effect of differences between people, found no association between proton pump inhibitor use and myocardial infarction. Current guidelines from the American College of Cardiology Foundation/American Heart Association recognise the conflicting nature of previous studies of this question and recommend re-evaluation of the need for proton pump inhibitor use in this setting.25
The use of a proton pump inhibitor with clopidogrel and aspirin is well proved to prevent harm through gastrointestinal bleeding, and we should continue to consider proton pump inhibitors as important prophylactic drugs in patients at high risk.
What is already known on this topic
- Over recent years there has been a debate over whether the pharmacokinetic drug interaction between clopidogrel and proton pump inhibitors reduces the antiplatelet effects of clopidogrel and leads to an increased risk of vascular events
- Studies aiming to answer this question have had conflicting findings
What this study adds
- The combination of a proton pump inhibitor with clopidogrel is associated with an increased risk of both vascular and non-vascular adverse outcomes, but that this association is unlikely to be causal
- The association is probably because of important differences between proton pump inhibitor users and non-users as a comparison within individuals, which removes the effect of differences between people, found no association between the use of a proton pump inhibitor and the risk of myocardial infarction