PPIs Seem Safe to Use With Antiplatelet Drugs

A retrospective study involving 13,809 patients found no evidence that proton pump inhibitors interfere with the antiplatelet drugs clopidogrel and prasugrel in patients with acute cardiac syndrome. Existing guidelines, which endorse the content use of proton pump inhibitors with antiplatelet drugs in these patients, will therefore not need to be changed.

The results contrast with other recent studies suggesting that proton pump inhibitors (PPIs), especially omeprazole, might diminish the drugs' antiplatelet effects and clinical efficacy. The study, which was published online in the Lancet, was presented concurrently by Dr. Michelle L. O'Donoghue at the annual congress of the European Society of Cardiology in Barcelona.

Clopidogrel and prasugrel are in a class of drugs called thienopyridines. They are pro-drugs that are converted by the cytochrome P450 enzyme system into their active metabolites. It was thought that PPIs might interfere with this through their inhibition of a cytochrome P450 isozyme in the liver called 2C19. As a result of these concerns, and of earlier studies that seem to suggest problems, the Food and Drug Administration and the European Medicines Agency (EMEA) issued safety warnings discouraging the use of PPIs with clopidogrel unless absolutely necessary.

The new study involved a retrospective analysis of one large trial involving 13,608 patients and one small trial involving 201 patients. Both were randomized, controlled trials intended to compare clopidogrel with prasugrel in patients undergoing elective percutaneous coronary intervention. In both trials, the use of a PPI was at the discretion of the treating physician. At the time of randomization, 26% of patients in the smaller trial and 33% in the larger trial were taking PPIs.

The investigators, led by Dr. O'Donoghue of Brigham and Women's Hospital, Boston, adjusted their results for 28 potential confounders, including age; sex; ethnic origin; history of hypertension, hypercholesterolemia, heart failure, peptic ulcer disease, carotid or vertebral artery disease, or diabetes; previous MI; previous coronary artery bypass graft surgery (CABG); family history; and the use of a drug-eluting stent (Lancet 2009 [doi:10.1016/S0140-6736(09)61525-7

Although the investigators did find that PPIs were associated with a reduction in the antiplatelet effects of clopidogrel and prasugrel, this did not translate into any significant differences in clinical outcome. There were no significant differences in all cause death, cardiovascular death, MI, stent thrombosis, major or minor bleeding in thrombolysis-induced myocardial infarction, or net clinical outcome (a combination of death, MI, stroke, and major non-CABG bleeding).

In an accompanying editorial, the authors Dr. Dirk Sibbing and Dr. Adnan Kastrati of Technische Universität München (Munich) raised a number of questions. For example, they suggested that patient compliance with thienopyridines might be worse in real life than in the context of the clinical trials. Dr. Sibbing and Dr. Kastrati concluded that PPIs appear not to interact with clopidogrel or prasugrel in terms of clinical outcomes and that patients with a risk profile similar to that in the trials can be safely treated with a PPI (Lancet 2009 [doi:10.1016/S0140-6736(09)61562-2

“However,” they wrote, “caution is needed when prescribing PPIs for selected high-risk patients with an intrinsically reduced response to thienopyridines. … In all cases, careful monitoring of patients' compliance with a thienopyridine drugs is mandatory.”

The original trials received grant funding from Eli Lilly & Co. and from Daiichi Sankyo. The investigators conducting the retrospective analysis stated that they received no external sources of funding.

Dr. Sibbing acknowledged receiving lecture fees from Dynabyte and fees for advisory board activities from Eli Lilly. Dr. Kastrati acknowledged receiving lecture fees from Bristol-Myers Squibb, Daiichi Sankyo, and Eli Lilly.

Careful monitoring is necessary when patients with reduced response to thienopyridines take PPIs.

Source Dr. Kastrati

A retrospective study involving 13,809 patients found no evidence that proton pump inhibitors interfere with the antiplatelet drugs clopidogrel and prasugrel in patients with acute cardiac syndrome. Existing guidelines, which endorse the content use of proton pump inhibitors with antiplatelet drugs in these patients, will therefore not need to be changed.

The results contrast with other recent studies suggesting that proton pump inhibitors (PPIs), especially omeprazole, might diminish the drugs' antiplatelet effects and clinical efficacy. The study, which was published online in the Lancet, was presented concurrently by Dr. Michelle L. O'Donoghue at the annual congress of the European Society of Cardiology in Barcelona.

Clopidogrel and prasugrel are in a class of drugs called thienopyridines. They are pro-drugs that are converted by the cytochrome P450 enzyme system into their active metabolites. It was thought that PPIs might interfere with this through their inhibition of a cytochrome P450 isozyme in the liver called 2C19. As a result of these concerns, and of earlier studies that seem to suggest problems, the Food and Drug Administration and the European Medicines Agency (EMEA) issued safety warnings discouraging the use of PPIs with clopidogrel unless absolutely necessary.

The new study involved a retrospective analysis of one large trial involving 13,608 patients and one small trial involving 201 patients. Both were randomized, controlled trials intended to compare clopidogrel with prasugrel in patients undergoing elective percutaneous coronary intervention. In both trials, the use of a PPI was at the discretion of the treating physician. At the time of randomization, 26% of patients in the smaller trial and 33% in the larger trial were taking PPIs.

The investigators, led by Dr. O'Donoghue of Brigham and Women's Hospital, Boston, adjusted their results for 28 potential confounders, including age; sex; ethnic origin; history of hypertension, hypercholesterolemia, heart failure, peptic ulcer disease, carotid or vertebral artery disease, or diabetes; previous MI; previous coronary artery bypass graft surgery (CABG); family history; and the use of a drug-eluting stent (Lancet 2009 [doi:10.1016/S0140-6736(09)61525-7

Although the investigators did find that PPIs were associated with a reduction in the antiplatelet effects of clopidogrel and prasugrel, this did not translate into any significant differences in clinical outcome. There were no significant differences in all cause death, cardiovascular death, MI, stent thrombosis, major or minor bleeding in thrombolysis-induced myocardial infarction, or net clinical outcome (a combination of death, MI, stroke, and major non-CABG bleeding).

In an accompanying editorial, the authors Dr. Dirk Sibbing and Dr. Adnan Kastrati of Technische Universität München (Munich) raised a number of questions. For example, they suggested that patient compliance with thienopyridines might be worse in real life than in the context of the clinical trials. Dr. Sibbing and Dr. Kastrati concluded that PPIs appear not to interact with clopidogrel or prasugrel in terms of clinical outcomes and that patients with a risk profile similar to that in the trials can be safely treated with a PPI (Lancet 2009 [doi:10.1016/S0140-6736(09)61562-2

“However,” they wrote, “caution is needed when prescribing PPIs for selected high-risk patients with an intrinsically reduced response to thienopyridines. … In all cases, careful monitoring of patients' compliance with a thienopyridine drugs is mandatory.”

The original trials received grant funding from Eli Lilly & Co. and from Daiichi Sankyo. The investigators conducting the retrospective analysis stated that they received no external sources of funding.

Dr. Sibbing acknowledged receiving lecture fees from Dynabyte and fees for advisory board activities from Eli Lilly. Dr. Kastrati acknowledged receiving lecture fees from Bristol-Myers Squibb, Daiichi Sankyo, and Eli Lilly.

Careful monitoring is necessary when patients with reduced response to thienopyridines take PPIs.

Source Dr. Kastrati

A retrospective study involving 13,809 patients found no evidence that proton pump inhibitors interfere with the antiplatelet drugs clopidogrel and prasugrel in patients with acute cardiac syndrome. Existing guidelines, which endorse the content use of proton pump inhibitors with antiplatelet drugs in these patients, will therefore not need to be changed.

The results contrast with other recent studies suggesting that proton pump inhibitors (PPIs), especially omeprazole, might diminish the drugs' antiplatelet effects and clinical efficacy. The study, which was published online in the Lancet, was presented concurrently by Dr. Michelle L. O'Donoghue at the annual congress of the European Society of Cardiology in Barcelona.

Clopidogrel and prasugrel are in a class of drugs called thienopyridines. They are pro-drugs that are converted by the cytochrome P450 enzyme system into their active metabolites. It was thought that PPIs might interfere with this through their inhibition of a cytochrome P450 isozyme in the liver called 2C19. As a result of these concerns, and of earlier studies that seem to suggest problems, the Food and Drug Administration and the European Medicines Agency (EMEA) issued safety warnings discouraging the use of PPIs with clopidogrel unless absolutely necessary.

The new study involved a retrospective analysis of one large trial involving 13,608 patients and one small trial involving 201 patients. Both were randomized, controlled trials intended to compare clopidogrel with prasugrel in patients undergoing elective percutaneous coronary intervention. In both trials, the use of a PPI was at the discretion of the treating physician. At the time of randomization, 26% of patients in the smaller trial and 33% in the larger trial were taking PPIs.

The investigators, led by Dr. O'Donoghue of Brigham and Women's Hospital, Boston, adjusted their results for 28 potential confounders, including age; sex; ethnic origin; history of hypertension, hypercholesterolemia, heart failure, peptic ulcer disease, carotid or vertebral artery disease, or diabetes; previous MI; previous coronary artery bypass graft surgery (CABG); family history; and the use of a drug-eluting stent (Lancet 2009 [doi:10.1016/S0140-6736(09)61525-7

Although the investigators did find that PPIs were associated with a reduction in the antiplatelet effects of clopidogrel and prasugrel, this did not translate into any significant differences in clinical outcome. There were no significant differences in all cause death, cardiovascular death, MI, stent thrombosis, major or minor bleeding in thrombolysis-induced myocardial infarction, or net clinical outcome (a combination of death, MI, stroke, and major non-CABG bleeding).

In an accompanying editorial, the authors Dr. Dirk Sibbing and Dr. Adnan Kastrati of Technische Universität München (Munich) raised a number of questions. For example, they suggested that patient compliance with thienopyridines might be worse in real life than in the context of the clinical trials. Dr. Sibbing and Dr. Kastrati concluded that PPIs appear not to interact with clopidogrel or prasugrel in terms of clinical outcomes and that patients with a risk profile similar to that in the trials can be safely treated with a PPI (Lancet 2009 [doi:10.1016/S0140-6736(09)61562-2

“However,” they wrote, “caution is needed when prescribing PPIs for selected high-risk patients with an intrinsically reduced response to thienopyridines. … In all cases, careful monitoring of patients' compliance with a thienopyridine drugs is mandatory.”

The original trials received grant funding from Eli Lilly & Co. and from Daiichi Sankyo. The investigators conducting the retrospective analysis stated that they received no external sources of funding.

Dr. Sibbing acknowledged receiving lecture fees from Dynabyte and fees for advisory board activities from Eli Lilly. Dr. Kastrati acknowledged receiving lecture fees from Bristol-Myers Squibb, Daiichi Sankyo, and Eli Lilly.

Careful monitoring is necessary when patients with reduced response to thienopyridines take PPIs.

Source Dr. Kastrati