Review of TIMI trials shows PPI use did not compromise thienopyridine efficacy

Issue: October 2009

According to data from an analysis of the PRINCIPLE-TIMI 44 and TRITON-TIMI 38 trials, proton-pump inhibitor use was not independently associated with an increased risk for adverse events in patients treated with the thienopyridines clopidogrel or prasugrel and who were undergoing percutaneous coronary intervention for acute coronary syndrome.

Although PPIs are recommended for use in patients receiving thienopyridines to reduce the risk for gastrointestinal bleeding, recent studies suggest that the use of PPIs — including omeprazole and pantoprazole — may decrease the antiplatelet effects of such drugs. Based on these studies, the FDA and European Medicines Agency added warnings to clopidogrel and discouraged concomitant use of thienopyridines and PPIs unless absolutely necessary.

To assess the association between PPIs and thienopyridines, researchers used data from the PRINCIPLE-TIMI 44 and TRITON-TIMI 38 trials. The analysis included data for several PPIs, including omeprazole and pantoprazole. The researchers aimed to determine whether concomitant use of PPIs decreased the efficacy or pharmacodynamic effects of clopidogrel or the recently approved thienopyridine, prasugrel (Effient, Eli Lilly).

PRINCIPLE-TIMI 44 included 201 patients undergoing elective PCI. Patients were randomly assigned a 60-mg loading dose of prasugrel (n=102) or 600-mg loading dose of clopidogrel (n=99); the primary outcome was platelet aggregation inhibition at six hours.

The TRITON-TIMI 38 trial included 13,608 patients with ACS. Patients were randomly assigned prasugrel (n=6,813) or clopidogrel (n=6,795); the primary endpoint was CV death, MI or stroke. PPIs were used in both trials.

Data from PRINCIPLE-TIMI 44 demonstrated that patients assigned to a PPI had significantly lower mean inhibition of platelet aggregation compared with those not assigned to a PPI at six hours after a 600-mg loading dose of clopidogrel (23.2% vs. 35.2%; P=.02). After a 60-mg loading dose of prasugrel, however, patients assigned to PPI and those not assigned to PPI had only modest differences in mean platelet aggregation inhibition (69.6% vs. 76.7%; P=.054).

Thirty-three percent of patients from the TRITON-TIMI 38 trial were receiving a PPI at randomization. Data demonstrated no association between PPI use and the risk for CV death, MI or stroke among patients assigned to clopidogrel (HR=0.94; 95% CI, 0.80-1.11) or prasugrel (HR=1.00; 95% CI, 0.84-1.20).

According to Dirk Sibbing, MD, and Adnan Kastrati, MD, from the German Heart Center and authors of an accompanying editorial, questions arise as a result of the varying data, including whether the interaction of PPIs with thienopyridines is fact or fiction.

“The interaction is a fact in terms of pharmacodynamics,” they wrote. “For clinical outcomes, this interaction seems to be a fiction for most patients with a risk profile similar to that of patients enrolled in the TRITON-TIMI 38 trial. Such patients can safely be treated with a PPI on top of their thienopyridine.”

However, Sibbing and Kastrati recommended that clinicians use caution when prescribing PPIs to high-risk patients with reduced response to thienopyridines.

“If absolutely needed, specific PPIs that are less likely to interfere with the platelet response to thienopyridines could be given to these patients. In all cases, careful monitoring of patients’ compliance with thienopyridine drugs is mandatory,” they wrote.

O’Donoghue ML. Lancet. 2009;doi:10.1016/S0140-6736(09)61525-7.

Prior observational studies had concluded there was a significant interaction between clopidogrel and PPIs. This current analysis is a well-done study that suggests that there is no clinically relevant interaction between clopidogrel (or prasugrel) and PPIs. Of course, only a randomized clinical trial can definitively answer the question.

– Deepak L. Bhatt, MD, MPH

Cardiology Today Editorial Board member