The Influence of Proton Pump Inhibitors on the Antiplatelet Potency of Clopidogrel Evaluated by 5 Different Platelet Function Tests

Abstract

Proton pump inhibitors (PPIs) are metabolized by the cytochrome P450 enzyme system to a variable degree and may therefore interact with the metabolism of clopidogrel to its active form. The conflicting data on this potential interaction may be due to the use of different PPIs and platelet function tests in recent studies. We therefore evaluated the influence of different PPIs on the antiplatelet effect of clopidogrel by 5 platelet function tests in the same population. Adenosine diphosphate (ADP)-inducible platelet reactivity was assessed in 230 patients on dual antiplatelet therapy after angioplasty and stenting for cardiovascular disease by the light transmission aggregometry, VerifyNow P2Y12 assay, vasodilator-stimulated phosphoprotein phosphorylation assay, multiple electrode aggregometry, and Impact-R. ADP-inducible platelet reactivity showed no significant differences between patients without (n = 95, 41.3%) and with PPI therapy (n = 135, 58.7%) in each test system (all P > 0.05). Furthermore, we observed no significant differences of ADP-inducible platelet reactivity between patients without PPIs and patients with pantoprazole (n = 95, 70.4%), esomeprazole (n = 22, 16.3%), omeprazole (n = 9, 6.65%), or lansoprazole (n = 9, 6.65%) (all P > 0.3). High on-treatment residual ADP-inducible platelet reactivity occurred to a similar extent in patients without and with PPI therapy in each assay (all P > 0.05). In conclusion, concomitant treatment with PPIs did not attenuate the antiplatelet effect of clopidogrel in patients on dual antiplatelet therapy irrespective of the type of PPI and the used test system.

Clinical relevance of clopidogrel-proton pump inhibitors interaction

“…Notably, PPIs differ in their ability to inhibit CYP2C19, omeprazole being a more potent inhibitor than the other members of the class [17,18] . Accordingly, some studies showed that omeprazole attenuates the antiplatelet effect of clopidogrel [13][14][15] but others did not confirm these findings [19,20] . In contrast, esomeprazole, lansoprazole, pantoprazole and rabeprazole did not affect platelet function in patients treated with clopidogrel [13,15,[19][20][21][22] .…”

“…Accordingly, some studies showed that omeprazole attenuates the antiplatelet effect of clopidogrel [13][14][15] but others did not confirm these findings [19,20] . In contrast, esomeprazole, lansoprazole, pantoprazole and rabeprazole did not affect platelet function in patients treated with clopidogrel [13,15,[19][20][21][22] . However, it is unclear whether these ex vivo findings have clinical importance, i.e., if the co-administration of clopidogrel with omeprazole or other PPIs will result in reduced protection against cardiovascular events.…”

Recent Safety Concerns With Proton Pump Inhibitors

“…22,33,35 Three studies performed head-to-head comparisons between different PPIs (Table 2); none found any significant differences. 35,37,46 Five studies 32,34,41,44,45 reported subgroup analyses for platelet outcomes with different PPIs. Generally, no effect was found for pantoprazole, an effect was demonstrated for omeprazole, and findings with esomeprazole were equivocal.…”

“…1,6,22, This has usually been assessed by the platelet reactivity index vasoactive-stimulated phosphoprotein or the adenosine diphosphate-induced platelet aggregometry. 35,45,[52][53][54][55][56] Nineteen studies have found that PPI use was associated with a statistically significant reduction of the antiplatelet activity of clopidogrel, 1,6,22,30,33,34,36,[40][41][42][43][44][45][46][47][48][49][50][51] whereas 4 35,[37][38][39] found no effect. Three studies found that dose separation between clopidogrel and the PPI did not prevent the pharmacokinetic interaction and did not alter the influence on antiplatelet effect.…”

Concomitant Use of Proton Pump Inhibitors and Thienopyridines in Acute Coronary Syndrome Patients Followed Up in the Intensive Cardiac Care Unit

“…Omeprazol ile gösterilen bu ilaç etkileşimi diğer bazı PPI'larda (pantoprazol ve esomeprazol) çok daha az belirgindir. Bunun nedeni bu PPI'ların CYP2CA9'u daha az oranda etkilemesidir (12,13) . Öbür yandan PRINCIPLE-TIMI 44 çalışmasının post-hoc analiz sonuçlarına göre klopidogrel kullanımı ile birlikte herhangi bir PPI kullanımı sonrası azalmış platelet inhibisyonu izlenmiştir (14) .…”