Interaction between proton-pump inhibitors, clopidogrel clinically unimportant

The interaction between proton-pump inhibitors and clopidogrel is clinically unimportant, researchers found.

Researchers conducted an observational cohort study and self-controlled case series among 24,471 patients receiving clopidogrel and aspirin, using the United Kingdom General Practice Research Database with linked data from the Myocardial Ischaemia National Audit Project (MINAP) and the Office for National Statistics. Results were published online by BMJ on July 10.

Of the 24,471 patients prescribed clopidogrel and aspirin, 12,439 (50%) were also prescribed a proton-pump inhibitor at some time during the study. Death or myocardial infarction occurred in 1,419 patients (11%) receiving a proton-pump inhibitor compared with 1,341 patients (8%) who were not.

Multivariate analysis showed the hazard ratio for the association between proton-pump inhibitor use and death or incident myocardial infarction was 1.37 (95% CI, 1.27 to 1.48). Comparable results were seen for secondary outcomes and with other cytochrome P450 2C19 (CYP2C19) inhibitors and with non-CYP2C19 inhibitors.

A self-controlled case series design to remove the effect of differences between patients showed no association between proton-pump inhibitor use and myocardial infarction, with a rate ratio of 0.75 (95% CI, 0.55 to 1.01). There was no association with myocardial infarction for other CYP2C19 inhibitors/non-inhibitors.

The association found in the cohort analysis is unlikely to be causal for several reasons, the authors wrote:

• The effect is not specific to vascular events, as shown by the hazard ratio for non-vascular mortality of 1.61 (95% CI, 1.42 to 1.82).
• 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.
• Cohort results could be explained by confounding. Results provided no evidence of an increased risk of incident myocardial infarction during periods when patients were exposed to any proton-pump inhibitors (incident rate ratio [IRR], 0.75; 95% CI, 0.55 to 1.01), ranitidine (IRR, 0.57; 95% CI, 0.31 to 1.06) or citalopram (IRR, 0.84; 95% CI, 0.49 to 1.45).

“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,” the authors wrote. “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.”

An editorial expanded on the use of a self-controlled study to resolve residual confounding and offered clinical advice.

“Because patients with cardiovascular disease are at an especially high risk for morbidity and mortality after an acute gastrointestinal haemorrhage, clinicians should strongly consider prescribing a PPI to all patients who use dual antiplatelet drugs, especially in the presence of additional risk factors for gastrointestinal complications, such as age over 60; concomitant use of non-steroidal anti-inflammatory drugs, other anticoagulants, or corticosteroids; and important medical comorbidities,” the editorial stated.