Another Study Finds No Interaction Between PPIs and Clopidogrel

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In patients with a recent myocardial infarction (MI), use of a proton pump inhibitor (PPI) in combination with clopidogrel does not increase the risk of cardiovascular events before hospital discharge or at 1 year, according to a French registry study published online January 24, 2011, ahead of print in Circulation. Moreover, there was no clinically relevant association between adverse cardiovascular events or mortality and PPI use in carriers of a CYP2C19 loss-of-function allele.

Researchers led by Tabassome Simon, MD, PhD, of St. Antoine Hospital (Paris, France), examined data on the management and outcomes of 2,744 patients enrolled in the FAST-MI (French Registry of Acute-ST-Elevation and Non-ST-Elevation Myocardial Infarction) registry.

Among the overall cohort, 2,353 patients were given clopidogrel within 48 hours of diagnosis; of that group 1,453 also received a PPI. Omeprezole was the most common PPI (n = 993), followed by esomeprazole (n = 311), pantoprazole (n = 99), and lanzoprazole (n = 46).

No Increase in Events Seen

Overall, PPI use was not associated with an increased risk for any of the main in-hospital events (death, reinfarction, stroke, major bleeding, and transfusion). Continued PPI treatment also was not an independent predictor of survival in clopidogrel-treated patients at 1 year (table 1).

Table 1. PPI Use and 1-Year Outcomes

Among hospital survivors, major bleeding did not differ in patients with continued PPI use compared with those not using PPIs (n = 10) and 6 patients with or without continued PPI use (adjusted HR 1.06; 95% CI 0.75-1.53; P = 0.71).

Additionally, 1-year event rates were similar for the different types of PPIs. However, a numerically higher percentage of events was observed with pantoprazole compared with other PPIs.

Importantly, among propensity-matched cohorts of PPI users vs. nonusers, there was no interaction between CYP2C19 genotype and PPI use regarding the incidence of in-hospital and 1-year ischemic events (table 2).

Table 2. Risk of Events by Genotype in PPI vs. No PPI Patients

The researchers caution that harm could not be formally excluded in patients with 2 loss-of-function alleles since the study was not powered to determine that association.

Registry Supports Prior Study Findings

These results are in line with several prior observational studies and also support the findings of the randomized PLATO trial, which found no clinically relevant effect of PPI use on clopidogrel efficacy in 18,624 ACS patients with or without STEMI. The new findings also are consistent with the recently published COGENT trial, which found that among ACS patients receiving dual antiplatelet therapy, the composite endpoint of cardiovascular death, nonfatal MI, CABG, PCI, or confirmed ischemic stroke was equivalent in patients receiving omeprazole (4.9%) and placebo (5.7%). However, the study authors point out that a handful of other retrospective analyses have shown an increase in cardiovascular events with coadministration of PPIs and clopidogrel.

Overall, Dr. Simon and colleagues say the findings provide “a strong suggestion” of the lack of a clinically relevant interaction between PPIs and dual antiplatelet therapy. “Therefore, at the current stage, our results do not support the avoidance of PPI use in patients receiving clopidogrel who are at increased risk of gastrointestinal bleeding, particularly patients without CYP2C19 loss of function,” they write. “Further randomized studies are needed, however, to confirm these results.”

Question About Impact of Carrying 2 Reduced-Function Alleles Persists

In an editorial accompanying the study, Michelle L. O’Donoghue, MD, MPH, of Brigham and Women’s Hospital (Boston, MA), says that while the French registry results provide supportive evidence that PPIs and clopidogrel can be safely coadministered, more research is needed to clarify the relationship between in vitro platelet reactivity and adverse clinical outcomes.

“It is plausible that the pharmacodynamic interaction between clopidogrel, PPIs, calcium channel blockers, or lipophilic statins is too weak to translate into cardiovascular harm,” Dr. O’Donoghue writes. On the other hand, “the shape of the relationship between platelet reactivity and clinical outcomes is not linear; rather, there might exist a threshold effect such that platelet reactivity must be raised above a certain threshold before a patient is placed at increased risk,” she observes.

Dr. O’Donoghue says the most intriguing question addressed in the new analysis is whether any pharmacodynamic interaction between PPIs and clopidogrel is clinically relevant only to those individuals who carry a loss-of-function CYP2C19 allele. The data support the findings from the TRITON-TIMI 38 study, which similarly demonstrated that PPI use was not associated with an increased risk of adverse outcomes in patients who carry either the wild-type or loss-of-function CYP2C19 alleles. And although the current study was not powered to examine whether a drug-drug interaction might exist in carriers of 2 loss-of-function CYP2C19 alleles, such an interaction is unlikely to be clinically meaningful, she writes.

“Until the relationship between platelet function assays and clinical outcomes is better delineated, the weight of the evidence suggests that clopidogrel can be administered safely in combination with a PPI for patients at risk of gastrointestinal complications,” Dr. O’Donoghue concludes.

1. Simon T, Steg PG, Gilard M, et al. Clinical events as a function of proton pump inhibitor use, clopidogrel use, and cytochrome P450 2C19 genotype in a large nationwide cohort of acute myocardial infarction: Results from the French Registry of Acute ST-Elevation and Non-ST-Elevation Myocardial Infarction (FAST-MI) registry. Circulation. 2011;Epub ahead of print.

2. O’Donoghue ML. CYP2C19 genotype and proton pump inhibitors in clopidogrel-treated patients. Does it take two to tango? Circulation. 2011;Epub ahead of print.

Related Stories:

• Consensus Statement Supports Judicious Use of PPIs Plus Antiplatelet Therapy
• FDA Repeats Warning on Concomitant Use of Clopidogrel, Omeprazole
• COGENT Published: No Adverse Interaction Between Omeprazole, Clopidogrel