José Luis Ferreiro

Diabetes and Antiplatelet Therapy in Acute Coronary Syndrome

Cardiovascular disease, particularly coronary artery disease resulting from accelerated atherosclerosis, is the leading cause of morbidity and mortality in patients with diabetes mellitus (DM).1 Of note, DM patients without a history of coronary artery disease have overall the same cardiac risk as non-DM patients with a history of myocardial infarction (MI).2 Furthermore, patients with DM also have a higher risk of cardiovascular complications and recurrent atherothrombotic events than non-DM patients.3 In fact, in the setting of acute coronary syndromes (ACS), the presence of DM is a strong independent predictor of short-term and long-term recurrent ischemic events, including mortality.4,5 The concomitant presence of cardiovascular risk factors and comorbidities that negatively affect the outcomes of ACS is higher in DM patients.6 The negative impact of DM on outcomes is maintained across the ACS spectrum, including unstable angina and non–ST-elevation MI (NSTEMI),7 ST-elevation MI (STEMI) treated medically,8 and ACS undergoing percutaneous coronary intervention (PCI).9,10 Platelets of DM patients are characterized by dysregulation of several signaling pathways, both receptor (eg, increased expression) and intracellular downstream signaling abnormalities, which leads to increased platelet reactivity.11,–,15 This may play a role not only in the higher risk of developing ACS and the worse outcomes observed in DM, but also in the larger proportion of DM patients with inadequate response to antiplatelet agents compared with non-DM subjects,13,16,–,18 which may also contribute to the impaired outcomes observed in DM patients despite compliance with recommended antiplatelet treatment regimens. The aim of this article is to provide an overview of the current status of knowledge on platelet abnormalities that characterize DM patients, to analyze the benefits and limitations of currently available antiplatelet agents used in ACS, focusing …

Impact of Chronic Kidney Disease on Platelet Function Profiles in Diabetes Mellitus Patients With Coronary Artery Disease Taking Dual Antiplatelet Therapy

OBJECTIVES We sought to assess the impact of renal function on platelet reactivity in patients with diabetes mellitus (DM) and coronary artery disease on aspirin and clopidogrel therapy. BACKGROUND Diabetes mellitus is a key risk factor for chronic kidney disease (CKD). In aspirin-treated DM patients the presence of moderate/severe CKD is associated with reduced clinical efficacy of adjunctive clopidogrel therapy. Whether these findings may be attributed to differences in clopidogrel-induced effects is unknown. METHODS This was a cross-sectional observational study in which DM patients taking maintenance aspirin and clopidogrel therapy were studied. Patients were categorized into 2 groups according to the presence or absence of moderate/severe CKD. Platelet aggregation after adenosine diphosphate (ADP) and collagen stimuli were assessed with light transmittance aggregometry and defined patients with high post-treatment platelet reactivity (HPPR). Markers of platelet activation, including glycoprotein IIb/IIIa activation and P-selectin expression, were also determined using flow cytometry. RESULTS A total of 306 DM patients were analyzed. Patients with moderate/severe CKD (n = 84) had significantly higher ADP-induced (60 +/- 13% vs. 52 +/- 15%, p = 0.001) and collagen-induced (49 +/- 20% vs. 41 +/- 20%, p = 0.004) platelet aggregation compared with those without (n = 222). After adjustment for potential confounders, patients with moderate/severe CKD were more likely to have HPPR after ADP (adjusted odds ratio: 3.8, 95% confidence interval: 1.7 to 8.5, p = 0.001) and collagen (adjusted odds ratio: 2.4; 95% confidence interval: 1.1 to 5.4; p = 0.029) stimuli. Markers of platelet activation were significantly increased in patients with HPPR. CONCLUSIONS In DM patients with coronary artery disease taking maintenance aspirin and clopidogrel therapy, impaired renal function is associated with reduced clopidogrel-induced antiplatelet effects and a greater prevalence of HPPR.

Pharmacodynamic Effects of Different Aspirin Dosing Regimens in Type 2 Diabetes Mellitus Patients With Coronary Artery Disease

Background— Patients with type 2 diabetes mellitus (T2DM) have reduced aspirin-induced pharmacodynamic effects. This may be attributed to increased platelet turnover rates resulting in an increased proportion of non–aspirin-inhibited platelets during the daily dosing interval. The hypothesis of this study was that an increase in the frequency of drug administration [twice daily (bid) versus once daily (od)] may provide more effective platelet inhibition in T2DM patients. Methods and Results— T2DM patients with stable coronary artery disease were prospectively recruited. Patients modified their aspirin regimen on a weekly basis according to the following scheme: 81 mg/od, 81 mg/bid, 162 mg/od, 162 mg/bid, and 325 mg/od. Pharmacodynamic assessments included light-transmittance aggregometry after arachidonic acid, collagen and adenosine diphosphate stimuli; VerifyNow-Aspirin assay; and serum thromboxane B2 (TXB2) levels. Twenty patients were analyzed. All patients were sensitive and compliant to aspirin irrespective of dose, as assessed by arachidonic acid–induced aggregation. When aspirin was administered once daily, there was no significant effect on platelet reactivity by increasing the once-daily dosing using aspirin-sensitive assays (collagen-induced aggregation and VerifyNow-Aspirin). An increase in aspirin dose by means of a second daily administration was associated with a significant reduction in platelet reactivity assessed by collagen-induced aggregation and VerifyNow-Aspirin between 81 mg/od and 81 mg/bid (P<0.05 for both assays) and between 81 mg/od and 162 mg/bid (P<0.05 for both assays). There was no impact of aspirin dosing regimens on adenosine diphosphate–induced aggregation. A dose-dependent effect of aspirin was observed on serum TXB2 levels (P=0.003). Conclusions— Aspirin dosing regimens are associated with different pharmacodynamic effects in platelets from T2DM patients and stable coronary artery disease, with a twice-daily, low-dose aspirin administration resulting in greater platelet inhibition than once-daily administration as assessed by aspirin-sensitive assays and a dose-dependent effect on serum TXB2 levels. The clinical implications of a modified aspirin regimen tailored to T2DM patients warrant further investigation. Clinical Trial Registration— URL: http://www.clinicaltrials.gov. Unique identifier: NCT01201785.

Clopidogrel response variability: Current status and future directions

Antiplatelet drugs represent the basis of treatment for cardiovascular atherothrombotic disease processes. Clopidogrel selectively inhibits the platelet adenosine diphosphate (ADP) P2Y12 receptor and is accepted as the antiplatelet drug of choice in addition to aspirin for patients with unstable angina and non-ST-segment elevation myocardial infarction (NSTEMI) (1, 2) as well as for patients undergoing percutaneous coronary intervention (PCI) (3–5). Clopidogrel has also shown to improve outcomes in patients with ST-segment elevation myocardial infarction (STEMI) (6, 7). In spite of the clear clinical benefit of clopidogrel therapy as shown in numerous large-scale trials, a considerable number of cardiovascular events continue to occur. Recurrent events despite adjunctive clopidogrel therapy have been, in part, attributed to variability in interindividual response profiles to this antiplatelet agent (8). The present manuscript provides an overview of the current status of knowledge on clopidogrel response variability as well as the possible future strategies to overcome the clinical implications associated with this phenomenon.

Platelet function testing and risk of bleeding complications

Antiplatelet therapy has a key role in preventing atherothrombotic events in patients with coronary artery disease, particularly in those undergoing revascularisation procedures. However, this may occur at the expense of an increase risk of bleeding. Therefore, the balance between thrombotic and bleeding events is critical in order to achieve optimal outcomes. Since there is a broad variability in individual response profiles to antiplatelet therapy, these outcomes (thrombosis vs. bleeding) may depend on the level of platelet inhibition achieved in a given subject. Platelet function assays have emerged as a useful tool for its potential to determine patients at a higher risk of ischaemic and bleeding complications. The present manuscript will review the available evidence associating platelet function testing with adverse clinical outcomes, in particular bleeding, and their potential applications in lieu of novel and more potent antithrombotic agents that will be introduced into clinical practice in the near future.

Review article: Platelet abnormalities in diabetes mellitus:

Patients with diabetes mellitus (DM) have accelerated atherosclerosis, which is the main underlying factor contributing to the high risk of atherothrombotic events in these patients. Atherothrombotic complications are the leading cause of morbidity and mortality in patients with DM. Among factors contributing to the prothrombotic condition which characterise patients with DM, platelet hyperreactivity plays a pivotal role. Platelets of DM patients are characterised by dysregulation of several signalling pathways leading to intensified adhesion, activation and aggregation. Multiple mechanisms are involved in platelet dysfunction of patients with DM, which can be categorised as follows: a) hyperglycaemia, b) insulin deficiency and resistance, c) associated metabolic conditions, and d) other cellular abnormalities.The present manuscript aims to provide an overview on the current status of knowledge on platelet abnormalities that characterise patients with DM.

Cangrelor: a review on its mechanism of action and clinical development

In patients with acute coronary syndromes and undergoing percutaneous coronary intervention, numerous large-scale clinical trials have shown that adjunctive treatment with the P2Y12 receptor antagonist clopidogrel in addition to aspirin reduces ischemic events. These studies underscore the importance of blockade of the P2Y12 signaling pathway in these settings. However, recent findings have shown that clopidogrel therapy may have some shortcomings. These include its broad range of interindividual-response profiles, where patients with low P2Y12 inhibitory effects have an increased risk of recurrent ischemic events, including stent thrombosis, and its irreversible mechanism of action. These observations underscore the need for novel antiplatelet agents overcoming these limitations. Cangrelor (AR-C69931MX) is an intravenous, direct-acting and reversible P2Y12 receptor antagonist. Cangrelor has a rapid onset and offset of action and achieves significantly greater degrees of platelet inhibition compared with clopidogrel. This article provides an overview of the current status of knowledge on cangrelor, focusing on its pharmacologic properties, clinical development and potential future applications.

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 clopidogrels 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 clopidogrels 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.

Platelet Adenosine Diphosphate P2Y12 Receptor Antagonism: Benefits and Limitations of Current Treatment Strategies and Future Directions

Platelet P2Y12 receptor antagonism with clopidogrel has represented a major advancement in the pharmacological management of patients with atherothrombotic disease, in particular those with acute coronary syndromes and undergoing percutaneous coronary interventions. Despite the benefit associated with clopidogrel therapy in these high risk settings, laboratory and clinical experience have led to identify some of its caveats, among which its wide range of platelet inhibitory response is the most relevant. Genetic, cellular and clinical factors are implied in variability in response to clopidogrel. Importantly, pharmacodynamic findings have shown to have important prognostic implications, underscoring the need for more optimal antiplatelet treatment strategies. The aim of this manuscript is to provide an overview on the current status and future directions in P2Y12 receptor antagonism, with particular emphasis on interindividual variability in response to clopidogrel and strategies, including novel antiplatelet agents, to improve platelet P2Y12 inhibition.

Inhibición del receptor plaquetario P2Y12 de adenosina difosfato plaquetario: efectos beneficiosos y limitaciones de las estrategias terapéuticas actuales y perspectivas futuras

La inhibicion del receptor plaquetario P2Y12 con el empleo de clopidogrel ha representado un importante avance en el tratamiento farmacologico de los pacientes con enfermedad aterotrombotica, especialmente en los sindromes coronarios agudos y en el intervencionismo coronario percutaneo. A pesar de los efectos beneficiosos asociados al tratamiento con clopidogrel en estos contextos de alto riesgo, las experiencias clinicas y de laboratorio ha permitido identificar algunas de sus limitaciones, la mas relevante de las cuales es la amplia variabilidad existente en la respuesta inhibitoria plaquetaria. En esta variabilidad de la respuesta al clopidogrel se han involucrado diferentes factores clinicos, geneticos y celulares. Es importante senalar que los hallazgos farmacodinamicos han demostrado tener repercusiones pronosticas, lo cual subraya la necesidad de mejores estrategias de tratamiento antiagregante plaquetario. El objetivo de este articulo es aportar una vision general del estado actual y las perspectivas futuras sobre el antagonismo del receptor P2Y12, con especial referencia a la variabilidad interindividual en la respuesta a clopidogrel y a las estrategias destinadas a mejorar la inhibicion del receptor P2Y12, incluidos los farmacos antiagregantes plaquetarios mas recientes.