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.

Newly Formed Reticulated Platelets Undermine Pharmacokinetically Short-Lived Antiplatelet Therapies.

OBJECTIVE: Aspirin together with thienopyridine P2Y12 inhibitors, commonly clopidogrel, is a cornerstone of antiplatelet therapy. However, many patients receiving this therapy display high on-treatment platelet reactivity, which is a major therapeutic hurdle to the prevention of recurrent thrombotic events. The emergence of uninhibited platelets after thrombopoiesis has been proposed as a contributing factor to high on-treatment platelet reactivity. Here, we investigate the influences of platelet turnover on platelet aggregation in the face of different dual-antiplatelet therapy strategies. APPROACH AND RESULTS: Traditional light transmission aggregometry, cytometry, advanced flow cytometric imaging, and confocal microscopy were used to follow the interactions of populations of platelets from healthy volunteers and patients with stable cardiovascular disease. Newly formed, reticulated platelets overproportionately contributed to, and clustered at, the core of forming aggregates. This phenomenon was particularly observed in samples from patients treated with aspirin plus a thienopyridine, but was absent in samples taken from patients treated with aspirin plus ticagrelor. CONCLUSIONS: Reticulated platelets are more reactive than older platelets and act as seeds for the formation of platelet aggregates even in the presence of antiplatelet therapy. This is coherent with the emergence of an uninhibited subpopulation of reticulated platelets during treatment with aspirin plus thienopyridine, explained by the short pharmacokinetic half-lives of these drugs. This phenomenon is absent during treatment with ticagrelor, because of its longer half-life and ability to act as a circulating inhibitor. These data highlight the important influences of pharmacokinetics on antiplatelet drug efficacies, especially in diseases associated with increased platelet turnover.

Cancer Event Rate and Mortality with Thienopyridines: A Systematic Review and Meta-Analysis.

INTRODUCTION: Thienopyridines are a class of antiplatelet drugs widely used in cardiovascular disease prevention and treatment. A recent concern has come to light regarding the safety of thienopyridines because of the possible risk of malignancy. We therefore performed a systematic review and meta-analysis to evaluate the association between thienopyridine exposure and malignancy. METHODS: We searched the MEDLINE and EMBASE databases in March 2016 for studies that evaluated incident cancer and cancer mortality with and without exposure to thienopyridines. Relevant studies were identified, and data were extracted and analysed using random-effects meta-analysis. RESULTS: A total of nine studies (six randomised controlled trials and three cohort studies) that included 282,084 participants were included. The cancer event rate with clopidogrel and prasugrel was 3.25% and 1.58% respectively. When compared with standard aspirin or placebo, thienopyridines are not significantly associated with cancer mortality and event rate (odds ratio [OR] 1.12, 95% confidence interval [CI] 0.80-1.56, n = 3; and OR 0.92, 95% CI 0.52-1.64, n = 2, respectively. Further analyses examining clopidogrel showed no significant association with cancer event rate or malignancy-related death. When comparing prasugrel with clopidogrel, no significant association was noted for cancer event rate (OR 1.10, 95% CI 0.89-1.37, n = 2]. Subanalyses according to cancer location showed that thienopyridines are not significantly associated with malignancy mortality and/or incidence. CONCLUSIONS: Our results suggest that there is currently insufficient evidence to suggest that thienopyridine exposure is associated with an increased risk of cancer event rate or mortality.

The role of P2Y12 receptor and activated platelets during inflammation.

Platelets play an important role not only during thrombosis, but also in modulating immune responses through their interaction with immune cells and by releasing inflammatory mediators upon activation. The P2Y12 receptor is a Gi-coupled receptor that not only regulates ADP-induced aggregation but can also dramatically potentiate secretion, when platelets are activated by other stimuli. Considering the importance of P2Y12 receptor in platelet function, a class of antiplatelet drugs, thienopyridines, have been designed and successfully used to prevent thrombosis. This review will focus on the role of activated platelets in inflammation and the effects that P2Y12 antagonism exerts on the inflammatory process. A change in platelet functions was noted in patients treated with thienopyridines during inflammatory conditions, suggesting that platelets may modulate the inflammatory response. Further experiments in a variety of animal models of diseases, such as sepsis, rheumatoid arthritis, myocardial infarction, pancreatitis and pulmonary inflammation have also demonstrated that activated platelets influence the inflammatory state. Platelets can secrete inflammatory modulators in a P2Y12-dependent manner, and, as a result, directly alter the inflammatory response. P2Y12 receptor may also be expressed in other cells of the immune system, indicating that thienopyridines could directly influence the immune system rather than only through platelets. Overall the results obtained to date strongly support the notion that activated platelets significantly contribute to the inflammatory process and that antagonizing P2Y12 receptor can influence the immune response.

Thienopyridines resistance and recovery of platelet function after discontinuation of thienopyridines in cardiac surgery patients.

OBJECTIVES: Patients who undergo cardiac operations under the effects of thienopyridines have a greater risk of major postoperative bleeding, transfusions and surgical revision due to bleeding. Discontinuation of thienopyridine is suggested but an adequate recovery period following discontinuation is still under debate, with opinions ranging from 3 to 7 days. The aim of this study was to assess the rate of recovery of thienopyridine-resistant patients and the time taken for resumption of platelet function after discontinuation of thienopyridine, in the setting of patients scheduled for cardiac operations. METHODS: This was a retrospective study, based on 344 patients screened for platelet aggregation before cardiac operations. All the patients received thienopyridines within 7 days prior to the test. Multiple electrode aggregometry adenosine diphosphate test was used to assess platelet aggregation before the operation. RESULTS: Thienopyridine resistance rate was 28%. Patients receiving clopidogrel had a significantly higher rate (32%) of resistance, compared with those receiving ticlopidine (14%) and thienopyridine resistance was significantly associated with platelet count (P = 0.006). The time taken to recover platelet function after thienopyridine discontinuation was variable between individuals; the only factor associated with a faster recovery time was the serum bilirubin value (P = 0.002). Platelet aggregation values high enough to avoid major bleeding were reached 3 days after discontinuation (95% confidence interval: 2-4 days); however, a complete recovery of platelet function was reached only after 8 days (95% confidence interval: 7-9 days). CONCLUSIONS: Patient-specific factors determine the effectiveness of thienopyridine treatment and platelet function recovery rate. Among these, platelet count (for thienopyridine resistance) and serum bilirubin values (for platelet function recovery rate) should be considered.

[Oral antiplatelet agents can still be used along with proton pump inhibitors in spite of drug interactions]. / Orale trombocythæmmere kan fortsat anvendes med protonpupehæmmere trods farmakologiske interaktioner.

Acetylsalicylic acid and P2Y12-receptor antagonists are antiplatelet agents widely used in the treatment and secondary prevention of cardiovascular disease. Since upper gastrointestinal bleeding is common during antiplatelet treatment, many patients are also treated with a proton pump inhibitor. In recent years it has been heavily discussed if proton pump inhibitors may attenuate the cardiovascular protection achieved with oral antiplatelet agents. Pharmacodynamic studies have suggested important drug interactions, but clinical studies have failed to confirm any clinical impact.

Preparation of the thienopyridine derivatives loaded liposomes and study on the effect of compound-lipid interaction on release behavior.

The article describes characterization of two liposome formulations containing thienopyridine derivatives, namely TP-58 and TP-67. By preparing the liposomes, the concentration of the two compounds in ultrapure water was increased up to three orders of magnitude. After i.v. administration of the liposomes in rats, the initial compound plasma concentrations were enhanced more than fifty times relative to that after i.g. administration of the compound suspensions. It was found out that the release rate of TP-67 from the liposome both in vitro and in vivo was not significantly different from that of TP-58. TP-58 was more lipophilic than TP-67 according to partition coefficiency, and TP-67 had greater polarity than TP-58 based on polar surface area (PSA). With DSC, it was found out that the interaction magnitude between TP-67 and the lipid bilayer was not significantly different from that between TP-58 and the lipid bilayer, which accounted for the similarity of the two compounds in release rate both in vitro and in vivo. It indicated liposome can be used as a potential carrier for broading the application of TP-58 and TP-67. Interaction between the thienopyridine derivatives and the lipid bilayer is probably the decisive factor for compound release from the liposomes.

Bridging antiplatelet therapy with cangrelor in patients undergoing cardiac surgery: a randomized controlled trial.

CONTEXT: Thienopyridines are among the most widely prescribed medications, but their use can be complicated by the unanticipated need for surgery. Despite increased risk of thrombosis, guidelines recommend discontinuing thienopyridines 5 to 7 days prior to surgery to minimize bleeding. OBJECTIVE: To evaluate the use of cangrelor, an intravenous, reversible P2Y(12) platelet inhibitor for bridging thienopyridine-treated patients to coronary artery bypass grafting (CABG) surgery. DESIGN, SETTING, AND PATIENTS: Prospective, randomized, double-blind, placebo-controlled, multicenter trial, involving 210 patients with an acute coronary syndrome (ACS) or treated with a coronary stent and receiving a thienopyridine awaiting CABG surgery to receive either cangrelor or placebo after an initial open-label, dose-finding phase (n = 11) conducted between January 2009 and April 2011. Interventions Thienopyridines were stopped and patients were administered cangrelor or placebo for at least 48 hours, which was discontinued 1 to 6 hours before CABG surgery. MAIN OUTCOME MEASURES: The primary efficacy end point was platelet reactivity (measured in P2Y(12) reaction units [PRUs]), assessed daily. The main safety end point was excessive CABG surgery-related bleeding. RESULTS: The dose of cangrelor determined in 10 patients in the open-label stage was 0.75 µg/kg per minute. In the randomized phase, a greater proportion of patients treated with cangrelor had low levels of platelet reactivity throughout the entire treatment period compared with placebo (primary end point, PRU <240; 98.8% (83 of 84) vs 19.0% (16 of 84); relative risk [RR], 5.2 [95% CI, 3.3-8.1] P < .001). Excessive CABG surgery-related bleeding occurred in 11.8% (12 of 102) vs 10.4% (10 of 96) in the cangrelor and placebo groups, respectively (RR, 1.1 [95% CI, 0.5-2.5] P = .763). There were no significant differences in major bleeding prior to CABG surgery, although minor bleeding episodes were numerically higher with cangrelor. CONCLUSIONS: Among patients who discontinue thienopyridine therapy prior to cardiac surgery, the use of cangrelor compared with placebo resulted in a higher rate of maintenance of platelet inhibition. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00767507.

Clinical effects and outcomes with new P2Y12 inhibitors in ACS.

Thienopyridines have become the cornerstone of treatment for percutaneous coronary intervention although no survival benefit has ever been shown with clopidogrel despite increasing loading doses. Newly developed P2Y12 inhibitors are more potent, more predictable, and have a faster onset of action than clopidogrel, characteristics that make them particularly attractive for high-risk percutaneous coronary intervention (PCI). Four new P2Y12 inhibitors have been tested each of them having particular individual properties. Prasugrel is an oral pro-drug leading to irreversible blockade of the P2Y12 receptor and is approved worldwide for ACS PCI. Ticagrelor is a direct-acting and reversible inhibitor of the P2Y12 receptor with potentially more pleiotropic effects. Cangrelor is an intravenous direct and reversible inhibitor of the P2Y12 receptor providing the highest level of inhibition, and elinogrel is an intravenous and oral P2Y12 antagonist with a direct and reversible action. Both prasugrel and ticagrelor, opposed to clopidogrel, have shown that stronger P2Y12 inhibition led respectively to significant 19 and 16% relative risk reduction of a similar primary end point combining cardiovascular death, non-fatal myocardial infarction, or non-fatal stroke. Both drugs showed a significant 0.6% absolute excess of TIMI major bleeding not related to CABG surgery. Because in clinical trials, patients perceived to be at higher risk of bleeding usually are excluded, the risk of major and even fatal bleeding might even be higher in a 'real-world' setting, i.e. in the elderly patient with comorbidities. On the other hand, these newly developed P2Y12 inhibitors decrease mortality after PCI compared with clopidogrel. The risk/benefit ratio is particularly favorable in PCI for patients with STEMI.

Impact of concomitant use of proton-pump inhibitors and thienopyridine derivatives on the antiplatelet effects.

BACKGROUND: Although there has been an intense debate whether concomitant use of proton-pump inhibitors (PPIs) attenuates the antiplatelet effects of thienopyridine derivatives, the drug-drug interaction remains unclear in Japanese patients with coronary artery disease. METHODS AND RESULTS: Platelet function test was performed in 461 patients who were scheduled for or had undergone stent implantation, treated with 100mg/day of aspirin and a thienopyridine (200mg/day of ticlopidine or 75 mg/day of clopidogrel) for at least 14 days. Adenosine diphosphate-induced platelet aggregation was evaluated with screen filtration pressure method, and the upper quartile of high platelet reactivity was defined as high on-treatment platelet reactivity (HPR). PPI use was at physician's discretion. Patients taking a thienopyridine plus a PPI (n=166) were older and had a higher incidence of acute coronary syndromes on admission compared with patients taking a thienopyridine without a PPI (n=295). The rate of HPR was higher in patients taking a thienopyridine plus a PPI than in patients taking a thienopyridine without a PPI (31% vs 21%, p=0.01). On multivariate logistic regression analysis, independent predictors of HPR were concomitant PPI use [odds ratio (OR): 1.66, 95% confidence interval (CI): 1.03-2.68], diabetes mellitus (OR: 1.76, CI: 1.11-2.81), and calcium channel blockers use (OR: 1.93, CI: 1.18-3.18). However, there was no significant difference in the rate of extremely high platelet reactivity [58 patients (12.5%) with PATI<4.0 µM] between patients treated with a thienopyridine plus a PPI and those without a PPI (14% vs 11%, NS). CONCLUSION: HPR was frequently observed in Japanese patients treated with thienopyridines plus PPIs compared to those without PPIs. Further prospective studies are needed to estimate the risk of adverse cardiovascular events associated with concomitant use of PPIs and thienopyridines.

Oral antiplatelet agents in ACS: from pharmacology to clinical differences.

Antiplatelet agents play an essential role in the treatment of acute coronary syndrome (ACS). Numerous clinical trials have established the value of antiplatelet therapies for ACS. Aspirin (ASA), thienopyridines and GP IIb/IIIa antagonists comprise the major classes of antiplatelet therapies demonstrated to be of benefit in the treatment of ACS. Thienopyridines are a class of drugs that function via inhibition of the adenosine diphosphate (ADP) P2Y12 platelet receptors. Currently, clopidogrel, a second generation thienopyridine, is the main drug of choice and the combination of aspirin and clopidogrel is administered orally for the treatment of ACS. Recently, a third generation of thienopyridines has been introduced represented by prasugrel that has demonstrated promising results in ACS patients treated with percutaneous coronary intervention (PCI). A number of nonthienopyridine oral antiplatelet drugs are under development, and one of them, ticagrelor has already been tested in a major phase III clinical trial, PLATO, with the inclusion of a broad spectrum of patients with ACS. The present review aims to discuss the present knowledge about the safety and efficacy of oral antiplatelet treatment of patients with ACS.