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

Contrary to previously reported data, PPIs did not increase the risk for cardiovascular events, including death, MI or stroke.

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 clopidogrel or prasugrel who were undergoing percutaneous coronary intervention for acute coronary syndrome. Results of the analysis were published in The Lancet.

Though proton-pump inhibitors (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).

No association observed

PRINCIPLE-TIMI 44 included 201 patients undergoing elective percutaneous coronary intervention. 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 acute coronary syndrome. Patients were randomly assigned prasugrel (n=6,813) or clopidogrel (n=6,795); the primary endpoint was cardiovascular death, MI or stroke. PPIs were used in both trials.

Data from PRINCIPLE-TIMI 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 on a PPI at randomization. Data demonstrated there was no association between PPI use and the risk for cardiovascular death, myocardial infarction 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, German Heart Center, 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.”

Sibbing and Kastrati did, however, recommend 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. – by Stacey L. Adams

Prior observational studies had concluded that 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 proton pump inhibitors (PPIs). Of course, only a randomized clinical trial can definitively answer the question.

– Deepak L. Bhatt, MD, MPH, FACC, FAHA, FSCAI

Chief of Cardiology, VA Boston Healthcare System Director,
Integrated Interventional Cardiovascular Program, Brigham and Women's Hospital
VA Boston Healthcare System Senior Investigator,
TIMI Study Group Harvard Medical School

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