Manejo perioperatorio de pacientes usuarios de antiagregantes plaquetarios / Perioperative management of patients using antiplatelet agents

Resumen El uso de fármacos antiagregantes plaquetarios para prevención primaria y secundaria de eventos cardiovasculares es una práctica común en clínica. La terapia antiagregante plaquetaria disminuye significativamente la incidencia de eventos cardiovasculares, incluyendo infarto agudo al miocardio y accidente cerebro-vascular. Cada vez es más frecuente enfrentarse a pacientes en terapia antiagregante plaquetaria que serán sometidos a algún procedimiento quirúrgico, por tanto es fundamental conocer el manejo perioperatorio de estos fármacos, para disminuir los riesgos y complicaciones asociados a la suspensión o mantención de estas drogas en el período perioperatorio. Los antiagregantes plaquetarios de mayor uso en Chile son la aspirina y las tienopiridinas, siendo el clopidogrel el fármaco más utilizado en este grupo. El enfrentamiento perioperatorio de estos fármacos está supeditado al riesgo trombótico individual de cada paciente y al riesgo hemorrágico de cada cirugía. En cirugías no cardiacas, se sugiere mantener la aspirina, excepto en pacientes con bajo-moderado riesgo trombótico que serán sometidos a cirugías con alto riesgo de sangrado, en los cuales se recomienda suspenderla 5-7 días previo a la intervención quirúrgica. El clopidogrel se sugiere suspenderlo 5 días antes de la cirugía, excepto en pacientes con alto riesgo trombótico que se someterán a procedimientos quirúrgicos con riesgo hemorrágico bajo-moderado. En cirugías de revascularización miocárdica, se recomienda mantener aspirina y suspender clopidogrel 5 días antes del procedimiento. En relación al reinicio postquirúrgico de estos fármacos, se sugiere reanudar aspirina 6 h posterior a la cirugía y clopidogrel durante las primeras 24 h postoperatorias, asegurando previamente una adecuada hemostasia quirúrgica.

The use of antiplatelet drugs for primary and secondary prevention of cardiovascular disease events is a common clinical practice. Antiplatelet therapy significantly decreases the incidence of cardiovascular disease events, including acute myocardial infarction and cerebrovascular accident. It is increasingly common to face patients on antiplatelet therapy who will undergo some surgical procedure, so it is essential to know the perioperative management of these drugs, to reduce the risks and complications associated with the suspension or maintenance of these therapies in the perioperative period. The most common antiplatelet agents used in Chile are acetylsalicylic acid and thienopyridines, of which clopidogrel is the most frequent one. The perioperative management of these drugs has to be based on the individual thrombotic risk of each patient and the risk of hemorrhage of each surgery. In noncardiac surgeries, it is suggested to maintain acetylsalicylic acid, except in patients with low to moderate thrombotic risk who will undergo surgeries with a high risk of bleeding, in which case it is recommended to suspend it 5 to 7 days before surgery. Clopidogrel is suggested to be discontinued 5 days before surgery, except in patients with high thrombotic risk who will undergo surgical procedures with low to moderate risk of hemorrhage. In myocardial revascularization surgeries, it is recommended to maintain acetylsalicylic acid and to suspend clopidogrel 5 days before the procedure. Once assuring adequate surgical hemostasis, it is suggested to reinitiate acetylsalicylic acid 6 hours after surgery and to reinitiate clopidogrel during the first 24 postoperative hours.

Interações medicamentaosas: definições e mecanismos / Drug interactions: definitions and mechanisms

Com mudanças na expectativa de vida, comorbidades edisponibilidade de novos fármacos, aumentou a ocorrênciade interações medicamentosas por mecanismos farmacocinéticose farmacodinâmicos. Para a biotransformação dosmedicamentos, os organismos desenvolveram sistemas enzimáticoscapazes de metabolizar e excretar esses produtos.Os polimorfismos genéticos dessas enzimas condicionamsua eficiência em metabolizar determinados medicamentos.A conjugação com moléculas solúveis em água, adicionadasao medicamento, facilitam sua excreção. Os transportadoresdesempenham importante papel no influxo, efluxo e na excreçãode medicamentos através dos sistemas biliar e urinário.O tratamento de doenças cardiovasculares frequentementeenvolve uso de múltiplos fármacos, principalmente nos pacientesidosos e portadores de comorbidades. Nesse sentido, éimportante o conhecimento dessas interações medicamentosas,frequentemente responsáveis pelos insucessos terapêuticos epela ocorrência de efeitos adversos...

With changes in life expectancy, co-morbidities and theavailability of new drugs, the occurrence of drug interactionsby pharmacokinetic and pharmacodynamic mechanisms hasincreased. For the bio-transformations of medications theorganisms have developed enzymatic systems able to metabolizeand excrete these products. The genetic polymorphisms ofthese enzymes affect their efficiency in metabolizing certaindrugs. The combination with water-soluble molecules addedto the medication facilitates the excretion. Transporters playan important role in the inflow, outflow and the excretion ofmedications through the biliary and urinary systems. Thetreatment of cardiovascular diseases often involves the useof multiple drugs especially in elderly patients and patientswith co-morbidities. In this sense, it is very important theknowledge about these drugs interactions which are oftenresponsible for the therapeutic failure and for the occurrenceof adverse effects...

Cytochrome P450 2C19 Polymorphism is Associated with Reduced Clopidogrel Response in Cerebrovascular Disease

PURPOSE: Clopidogrel is a prodrug that requires transformation into an active metabolite by cytochrome P450 (CYP) in the liver in order to irreversibly inhibit the P2Y12 adenosine diphosphate platelet receptor. CYP2C19 polymorphism has been reported to correlate with reduced antiplatelet activity of clopidogrel in coronary artery disease. We assessed the association between CYP2C19 polymorphism and clopidogrel resistance in patients with cerebrovascular disease. MATERIALS AND METHODS: We retrospectively gathered data from patients who experienced cerebrovascular disease, received clopidogrel, and were tested for clopidogrel resistance and CYP2C19 polymorphism. Clopidogrel resistance was tested by the VerifyNow P2Y12 system, and the CYP2C19 polymorphism was tested by the Seeplex CYP2C19 ACE Genotyping system. Clopidogrel resistance was expressed in P2Y12 reaction units (PRU) and percent inhibition. High PRU and low percent inhibition suggests clopidogrel resistance. CYP2C19 polymorphisms were expressed as extensive, intermediate, and poor metabolizers. Clopidogrel resistance was assessed according to the subgroup of CYP2C19 polymorphism. RESULTS: A total of 166 patients were evaluated. The PRU values of extensive CYP2C19 metabolizers (195.0+/-84.9) were significantly lower than those of intermediate and poor metabolizers (237.9+/-88.0, 302.2+/-58.9). The percent inhibition of extensive metabolizers (44.6+/-21.8) was significantly higher than that of intermediate and poor metabolizers (30.5+/-21.5, 14.0+/-13.4). CONCLUSION: Intermediate and poor metabolizing CYP2C19 polymorphism is associated with reduced clopidogrel antiplatelet activity in patients with cerebrovascular disease. The clinical implications of this finding require further investigation.

Antiplatelet activity of white and pink Nelumbo nucifera Gaertn flowers / Atividade antiplaquetária de flores Nelumbo nucifera Gaertn branco e rosa

Nelumbo nucifera Gaertn (Nelumbonaceae) a plant used in Ayurvedic medicine (common name: lotus), is a perennial, large and rhizomatous aquatic herb most prevalent in South India. Preliminary phytochemical screening of both white and pink Nelumbo nucifera flowers revealed the presence of phytochemical constituents (flavonoids, alkaloids, phenols etc,). Hence, an attempt has been made to screen the effect of Nelumbo nucifera flowers (both types) on platelet aggregation. The antiplatelet activity of hydroethanolic extract of both types of flowers was studied using platelet-rich plasma in different concentrations (100-500µg/ml). Both white and pink Nelumbo nucifera flower extracts showed dose-dependent effective antiplatelet activity with maximum activity at 500µg/ml concentration; prevention of platelet aggregation was 50 percent of that achieved with standard aspirin. Furthermore, the antiplatelet activity of white flowers was relatively high (p<0.05; ANOVA) compared to pink flowers. In conclusion, these observations suggest that both varieties of Nelumbo nucifera flower extracts exert different levels of inhibitory action on platelets in vitro (secretion and platelet aggregation suppression) due to differences in phytochemical content (alkaloids, flavonoids, phenols, tannins, phytosteroids, glycosides and saponins).

Nelumbo nucifera Gaertn (Nelumbonaceae, planta utilizada na medicina Ayurvédica, é erva aquática rizomatosa grande, predominante no sul da Índia. A triagem fitoquímica preliminar das flores brancas e cor-de-rosa de Nelumbo nucifera revelou a presença de constituintes fitoquímicos (flavonoides, alcaloides, fenóis etc). Assim, tentou-se a triagem do efeito das flores de Nelumbo nucifera de ambos os tipos na agregação plaquetária. A atividade antiplaquetária dos extratos hidroetanólico de ambos os tipos de flores foi estudada, utilizando-se plasma rico em plaquetas em duas diferentes concentrações (100 - 500 µg/mL). Tanto os extratos das flores brancas quanto daquelas de cor-de-rosa mostraram atividade antiplaquetária dose-dependente, com o máximo na concentração de 500 µg/mL. A prevenção da agregação plaquetária foi 50 por cento daquela alcançada com o padrão de ácido acetilsalicílico. Além disso, a atividade antiplaquetária das flores brancas foi, relativamente, alta (p<0,05; ANOVA), comparativamente às flores cor-de-rosa. Estas observações sugerem que ambas as variedades de extratos de flores de Nelumbo nucifera exercem diferentes níveis de ação inibitória nas plaquetas in vitro (supressão da secreção e da agregação plaquetária) devido a diferentes constituintes fitoquímicos (alcaloides, flavonoides, fenóis, taninos, fitoesteróides, glicosídeos e saponinas).

Safety, pharmacokinetic and pharmacodynamic studies of batifiban injection following single- and multiple-dose administration to healthy Chinese subjects / 华中科技大学学报（医学）（英德文版）

Batifiban, a synthetic cyclic peptide, is a potent platelet glycoprotein GPIIb/IIIa antagonist which may be useful in the treatment and prevention of acute coronary syndromes. The pharmacokinetics and pharmacodymanic (inhibition of platelet aggregation) effects, and tolerability of batifiban were investigated in healthy subjects following single bolus injection with doses of 55, 110, or 220 microg/kg, or multiple doses of an bolus followed intravenous infusion for 24 h (180 microg/kg plus 2.0 microg/min.kg, and 220 microg/kg plus 2.5 microg/min.kg) in this phase I clinical trial. Plasma levels of batifiban and areas under the curve were found to be proportional to doses. Batifiban was rapidly eliminated with a half-life of approximately 2.5 h. Significant differences were noted for plasma levels of batifiban and areas under the curve between males and females. No significant differences in the terminal half-life were found between males and females. Batifiban reversibly inhibited ex vivo platelet aggregation in a dose- and concentration-dependent manner, consistent with its mechanism as a GPIIb/IIIa antagonist. Single and multiple intravenous doses of batifiban were found to be safe and well tolerated in healthy subjects. These results support a bolus injection plus intravenous infusion regimen of batifiban for the treatment and prevention of acute coronary syndromes.

The Long-term Clinical Results of a Platelet Glycoprotein IIb/IIIa Receptor Blocker (Abciximab: ReoPro (R) ) Coated Stent in Patients with Coronary Artery Disease

BACKGROUND: Previously, the inhibition of coronary restenosis with Abciximab (ReoPro (R) ) -coated stent in a porcine model was reported. ReoPro (R) inhibits platelet aggregation, the proliferation of vascular smooth muscle cells and the inflammatory reaction. METHODS: A prospective randomized trial was performed to compare two types of stent for revascularization in the native coronary artery. The primary effective end points were major adverse coronary events (MACE) : cardiac death, acute myocardial infarction, target vessel revascularization (TVR) and restenosis at the 6-month clinical and angiographic follow-ups. RESULTS: One hundred and fifty-five patients were enrolled between August 2001 and June 2003. The mean ages (56.0 +/- 10.0 vs. 56.9 +/- 10.8 years), baseline diameter of stenosis and minimal luminal diameter were no different between the two groups. There was one myocardial infarction and revascularization during the hospital stay in control stent group. During the clinical follow-up there were two myocardial infarctions in control group. Follow-up coronary angiograms were performed in 62.3% (48/77) and 65.4% (51/78) of the coated and control groups, respectively. The diameter of stenosis and late loss were significantly less in the ReoPro (R) -coated stent group compared with the controls (16.4 +/- 5.8% vs. 34.3 +/- 6.1%, p=0.009; and 0.33 +/- 0.28 mm vs. 0.88 +/- 0.41 mm; p=0.002). The restenosis and TVR rates of the ReoPro (R) -coated stent were relatively lower compared with the control stent [14.6% (7/48) vs. 29.4% (15/51), p=0.062; and 9.2% (7/76) vs. 14.7% (11/75) ; p=0.327]. CONCLUSION: A ReoPro (R) -coated stent is safe, and may be effective in the prevention of coronary restenosis.

Bloqueadores de las glicoproteínas IIb/IIIa: una nueva clase de antiagregantes plaquetarios de uso en cardiología / Glycoproteins IIB/IIIA blockers: a new class of platelets aggregates used in cardiology

La agregación plaquetaria es el mecanismo fisiopatológico más importante en la génesis de los síndromes coronarios agudos. Recientemente se ha incorporado una nueva clase de antiagregantes plaquetarios para el manejo de estos síndromes: los bloqueadores de las glicoproteínas IIb/IIIa (GP IIb/IIIa). En este trabajo se presenta una somera revisión de los mecanismos de agregación plaquetaria y de sus posibles vías de inhibición, con especial énfasis en el bloqueo de los receptores GP IIb/IIIa, vía final de la agregación plaquetaria. Se revisa la literatura concerniente al uso e indicaciones de los diferentes bloqueadores GP IIb/IIIa (intravenosos y orales) y los principales estudios randomizados de angioplastia transluminal percutánea coronaria (PTCA), angina inestable e infarto sin onda Q. En general, se observa una disminución de un 35 por ciento de la mortalidad y del infarto en relación a intervenciones coronarias y un porcentaje variable en la reducción de eventos coronarios a largo plazo. Estudios futuros deberán establecer la efectividad del uso de estas drogas en combinación con trombolíticos para el manejo del infarto del miocardio con onda Q