Prescribing Proton Pump Inhibitor and Clopidogrel Together

Current State of Recommendations

Neena S. Abraham

Disclosures

Curr Opin Gastroenterol. 2011;27(6):558-564. 

In This Article

Evidence Supporting a Clinically Relevant Clopidogrel–proton Pump Inhibitor Interaction

Two potential hypotheses were proposed to explain impaired antiplatelet activity among some patients co-prescribed PPI with clopidogrel. The first postulated a reduction in biological activity of clopidogrel secondary to competitive inhibition of the CYP2C19 enzyme by PPI. Clopidogrel is a pro-drug that requires activation in the hepatocyte via the cytochrome P-450 enzyme system. One of the key isoenzymes required for its conversion is the CYP2C19 enzyme, which is also required for the metabolism of all PPIs (Fig. 1).[30•] Competitive inhibition of this isoenzyme was thought to result in reduced production of clopidogrel's active thiol metabolite which binds to the P2Y12 receptor on the platelet to exert its antiplatelet activity. Initial studies using ex-vivo platelet aggregation[25,28] as a surrogate marker for clinically significant impairment of antiplatelet activity suggested that PPIs reduce the biological action of clopidogrel, possibly through competitive inhibition of CYP2C19. However, early observational studies using pharmacy-based and administrative datasets[20,22,31–34] failed to consistently demonstrate a deleterious effect of co-prescription. Among those studies that demonstrated impaired platelet activity with PPI co-prescription,[20,22,32] significant differences in comorbidity existed among patients who were and were not prescribed a PPI. In addition, significant prescription channeling was observed in these observational studies, whereby PPI agents tended to be prescribed to sicker patients – thus, introducing a significant confounder in the analysis.

Figure 1.

Potential mechanisms of drug–drug interaction between clopidogrel and omeprazole

Recent meta-analyses have revealed that the presence and magnitude of the relative hazard associated with PPI and clopidogrel co-prescription can be explained by the type of study and method of analysis.[3••,35–37] Indeed, the risk diminishes as the methodologic rigor of the study increases,[30•] such that among large observational studies with proper statistical adjustment for potential prescription channeling and post hoc analyses of large RCTs in which randomization has occurred, no evidence supports a clinically meaningful clopidogrel–PPI interaction.[3••,30•,35,36] These findings support the 2010 ACC–ACG–AHA expert panel assertion that the strength of association of cardiovascular risk attributable to PPI fails to meet the conventional thresholds of statistical significance and, more importantly, may not be clinically relevant, given a magnitude of association that falls below a threshold of hazard or an odds ratio of 2.[3••,30•,38]

What was needed to clarify whether a significant harmful relationship existed between antiplatelet agents and PPIs was an RCT to ensure that important confounding variables were well balanced between patients who had and had not been prescribed a PPI. The COGENT trial[39••] was designed to examine reduction in antiplatelet-related gastrointestinal bleeding associated with PPI prescription, randomizing 3627 patients to dual-antiplatelet therapy (i.e., clopidogrel plus ASA) with omeprazole versus dual-antiplatelet therapy with placebo. This landmark trial revealed a 66% reduction in all gastrointestinal bleeding events and an 87% reduction in overt gastrointestinal bleeding events with PPI co-prescription. Notably, there was no significant difference in the secondary endpoint of cardiovascular death, MI or revascularization between the two groups. It is important to note that the trial was not powered for this secondary safety outcome, and premature termination of the trial resulted in a truncated follow-up period. However, fewer cardiovascular events occurred than anticipated – 55 events in the PPI arm versus 54 events in the placebo arm over 180 days. Sufficient power was achieved to examine the primary outcome of reduction in gastrointestinal bleeding events. The scarcity of cardiovascular events observed during the abbreviated follow-up period resulted in wide confidence intervals (hazard ratio 0.99; 95% CI 0.68–1.44), suggesting a range that extends from no increased risk of cardiovascular events up to a 44% increased risk.

An alternative hypothesis for the observed impairment of antiplatelet activity in certain patients co-prescribed a PPI is genetic variation in the metabolism of both drugs. The hepatic cytochrome P450 system is critical for the metabolism of PPI and for the conversion of clopidogrel to its active thiol metabolite. Both PPIs (especially omeprazole) and clopidogrel are extensively metabolized by the CYP2C19 and CYP3A4 system (Fig. 1).[30•] The presence of a reduced-function CYP2C19 genetic polymorphism has been associated with less active clopidogrel metabolite. Carriers of this loss-of-function allele are at a two-fold to four-fold increased risk of cardiovascular event rates than noncarriers.[31,34,40–42] The prevalence of having one copy of the CYP2C19*2 loss-of-function allele is estimated to be 51% among Asians, 33% among African–Americans and less common among whites (24%) and Mexican-Americans (16%). The reduction in clopidogrel efficacy associated with this genetic polymorphism is 47% with one copy and 65% with two copies of this allele.[42–45] These emerging data present a new investigative area for both cardiologists and gastroenterologists – prescription strategies based on individual genetic capability to metabolize both an antiplatelet agent and a gastroprotective agent. Early studies examining this 'point-of-care' testing are now being published.[46–48]

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