Pharmacokinetic and pharmacodynamic profiles of a novel phospholipid-aspirin complex liquid formulation and low dose enteric-coated aspirin: results from a prospective,randomized, crossover study

Journal of Thrombosis and Thrombolysis - Low dose enteric-coated aspirin (EC-ASA) is routinely used for secondary cardiovascular event prevention. However, absorption of EC tablets is poor, which...     

Impaired Responsiveness to the Platelet P2Y12 Receptor Antagonist Clopidogrel in Patients With Type 2 Diabetes and Coronary Artery Disease

Background

Several studies have shown that patients with diabetes mellitus (DM) exhibit an impaired response to clopidogrel. This may contribute to their increased risk of recurrent atherothrombotic events, despite the use of dual-antiplatelet therapy. The mechanisms for impaired clopidogrel response in DM patients have not been fully elucidated.

Objectives

The aim of this study was to explore the mechanisms for impaired clopidogrel-mediated platelet inhibition in patients with DM using a comprehensive methodological approach embracing both pharmacokinetic (PK) and pharmacodynamic (PD) assessments as well as ex vivo and in vitro investigations.

Methods

Patients (DM, n = 30; non-DM, n = 30) with stable coronary artery disease taking aspirin 81 mg/day and P2Y₁₂ antagonist naive were enrolled. Blood was collected before and at various times (0.5, 1, 2, 4, 6, and 24 h) after a 600-mg loading dose of clopidogrel. PD assessments included vasodilator-stimulated phosphoprotein, light transmission aggregometry, and VerifyNow P2Y₁₂ ex vivo, before and after dosing and following in vitro incubation with escalating concentrations (1, 3, and 10 μM) of clopidogrel’s active metabolite (Clop-AM). Exposure to Clop-AM was also determined.

Results

PD assessments consistently showed that during the overall 24-h study time course, residual platelet reactivity was higher in DM patients compared with non-DM patients. In vitro incubation with Clop-AM revealed altered functional status of the P2Y₁₂ signaling pathway in DM platelets as measured by vasodilator-stimulated phosphoprotein, but not with other PD assays. Clop-AM exposure was ∼40% lower in DM patients than in non-DM patients.

Conclusions

The present study suggests that among DM patients, impaired P2Y₁₂ inhibition mediated by clopidogrel is largely attributable to attenuation of clopidogrel’s PK profile. This is characterized by lower plasma levels of Clop-AM over the sampling time course in DM patients compared with non-DM patients and only modestly attributed to altered functional status of the P2Y₁₂ signaling pathway.     

Cigarette Smoking and Antiplatelet Effects of Aspirin Monotherapy Versus Clopidogrel Monotherapy in Patients with Atherosclerotic Disease: Results of a Prospective Pharmacodynamic Study

Smokers have a greater relative benefit of clopidogrel therapy compared with nonsmokers, likely attributed to its enhanced pharmacodynamic (PD) effects. However, to date, all PD studies have been conducted in patients on dual antiplatelet therapy with aspirin and clopidogrel, and it is unknown whether clopidogrel monotherapy can offer more effective antithrombotic effects compared with aspirin alone among smoking patients. Sixty aspirin-treated (81 mg/day) patients with vascular disease, classified as nonsmokers, light smokers, and heavy smokers according to cotinine serum levels, were enrolled. Patients were switched to clopidogrel (75 mg/day) monotherapy for 7–10 days. PD assessments were performed before and after switch by multiple electrode aggregometry (MEA) and kaolin-activated thromboelastography (TEG). Complete PD data were obtained in 57 patients (nonsmokers, n?=?27; light smokers, n?=?13; heavy smokers, n?=?17). On treatment platelet reactivity following MEA, adenosine diphosphate (ADP) + prostaglandin E₁ (PGE1) and thrombin receptor-activating peptide (TRAP) stimuli were significantly lower among heavy smokers following switch to clopidogrel. A significant inverse effect was observed with MEA arachidonic acid (ASPI), while neutral findings were shown with MEA collagen (COLL) stimulus. Thrombin and fibrin activity assessed by clot generation parameters were all nonsignificantly different but showed trends towards enhanced antithrombotic activity with clopidogrel among heavy smokers. In heavy smokers with vascular disease manifestations, clopidogrel is associated with enhanced platelet inhibitory effects, affecting purinergic and non-purinergic pathways, compared with aspirin as measured by MEA. Moreover, among smokers, clopidogrel offers trends towards enhanced effects on parameters of clot generation measured by TEG.     

Impact of Cigarette Smoking on P2Y12 Receptor Binding Activity Before and After Clopidogrel Therapy in Patients with Coronary Artery Disease

Smoking enhances the P2Y₁₂ receptor inhibitory effects of clopidogrel. Nicotine increases P2Y₁₂ receptor expression in platelet lysates from healthy volunteers. However, the impact of cigarette smoking on platelet P2Y₁₂ receptor binding in clopidogrel-treated patients with coronary artery disease (CAD) is unknown. Clopidogrel-naïve patients with stable CAD (n?=?20) were enrolled and stratified according to smoking status. P2Y₁₂ receptor binding activity was determined by radioligand receptor binding prior and 24 h after a 600-mg loading dose of clopidogrel. Baseline P2Y₁₂ receptor binding was 1.8-fold higher in smokers compared with nonsmokers. After a 600-mg loading dose of clopidogrel, smokers showed a 6.4-fold reduction in P2Y₁₂ receptor binding indicative of marked clopidogrel-mediated blockade, while there were minimal changes among nonsmokers. Among patients with stable CAD, smokers have more P2Y₁₂ receptor binding than nonsmokers and have a higher degree of clopidogrel-mediated platelet inhibition.     

Atopaxar: a review of its mechanism of action and role in patients with coronary artery disease

Platelet activation and aggregation is a complex and key process in thrombus formation after the rupture of an atherosclerotic plaque, which can lead to an acute coronary syndrome. Aspirin, an irreversible inhibitor of thromboxane A(2) synthesis, in combination with an inhibitor of P2Y(12) ADP platelet receptors (clopidogrel, prasugrel or ticagrelor), represents the current standard of care of antiplatelet therapy for patients with acute coronary syndrome and in those patients undergoing percutaneous coronary intervention. Despite the benefit of these agents, the risk of thrombotic events and bleeding complications may still occur while on such antiplatelet treatment regimens, thus representing an important limitation. Thrombin is one of the most important platelet activators. The inhibition of thrombin-mediated platelet activation by means of protease-activated receptor-1 inhibitors represents an attractive therapeutic option for patients with atherothrombotic disease processes. This article provides an overview on atopaxar (E5555), an orally active protease-activated receptor-1 antagonist that has recently completed Phase II clinical investigation.