Editorial comment
Platelet inhibition in acute coronary syndromes: A complex intervention that needs optimization
Inibição plaquetária nas síndromes coronárias agudas: uma intervenção complexa que deve ser otimizada
Carlos Aguiar
Serviço de Cardiologia, Hospital Santa Cruz, CHLO, Lisboa, Portugal
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Ferreira, Mário Freitas, Graça Ribeiro, Luís A. Providência" "autores" => array:13 [ 0 => array:2 [ "nombre" => "Rogério" "apellidos" => "Teixeira" ] 1 => array:2 [ "nombre" => "Pedro" "apellidos" => "Monteiro" ] 2 => array:2 [ "nombre" => "Gilberto" "apellidos" => "Marques" ] 3 => array:2 [ "nombre" => "João" "apellidos" => "Pego" ] 4 => array:2 [ "nombre" => "Margarida" "apellidos" => "Lourenço" ] 5 => array:2 [ "nombre" => "Carlos" "apellidos" => "Tavares" ] 6 => array:2 [ "nombre" => "Alda" "apellidos" => "Reboredo" ] 7 => array:2 [ "nombre" => "Sílvia" "apellidos" => "Monteiro" ] 8 => array:2 [ "nombre" => "Francisco" "apellidos" => "Gonçalves" ] 9 => array:2 [ "nombre" => "Maria J." "apellidos" => "Ferreira" ] 10 => array:2 [ "nombre" => "Mário" "apellidos" => "Freitas" ] 11 => array:2 [ "nombre" => "Graça" "apellidos" => "Ribeiro" ] 12 => array:2 [ "nombre" => "Luís A." "apellidos" => "Providência" ] ] ] ] ] "idiomaDefecto" => "en" "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S2174204912000542?idApp=UINPBA00004E" "url" => "/21742049/0000003100000004/v1_201305151725/S2174204912000542/v1_201305151725/en/main.assets" ] "en" => array:15 [ "idiomaDefecto" => true "cabecera" => "<span class="elsevierStyleTextfn">Editorial comment</span>" "titulo" => "Platelet inhibition in acute coronary syndromes: A complex intervention that needs optimization" "tieneTextoCompleto" => true "paginas" => array:1 [ 0 => array:2 [ "paginaInicial" => "275" "paginaFinal" => "277" ] ] "autores" => array:1 [ 0 => array:3 [ "autoresLista" => "Carlos Aguiar" "autores" => array:1 [ 0 => array:3 [ "nombre" => "Carlos" "apellidos" => "Aguiar" "email" => array:1 [ 0 => "ctaguiar@sapo.pt" ] ] ] "afiliaciones" => array:1 [ 0 => array:1 [ "entidad" => "Serviço de Cardiologia, Hospital Santa Cruz, CHLO, Lisboa, Portugal" ] ] ] ] "titulosAlternativos" => array:1 [ "pt" => array:1 [ "titulo" => "Inibição plaquetária nas síndromes coronárias agudas: uma intervenção complexa que deve ser otimizada" ] ] "resumenGrafico" => array:2 [ "original" => 0 "multimedia" => array:7 [ "identificador" => "fig0005" "etiqueta" => "Figure 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr1.jpeg" "Alto" => 1014 "Ancho" => 2062 "Tamanyo" => 146200 ] ] "descripcion" => array:1 [ "en" => "<p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">Sequence of events that determine response to a drug.</p>" ] ] ] "textoCompleto" => "<span class="elsevierStyleSections"><p id="par0005" class="elsevierStylePara elsevierViewall">Cardiovascular mortality has fallen in Portugal over the last decade, but mortality from stroke has declined much more sharply than from ischemic heart disease. Data from the European Commission show that from 1998–2000 to 2007–2009 mortality from stroke fell from 145.2 to 78.5 per 100<span class="elsevierStyleHsp" style=""></span>000 population, while death from ischemic heart disease only decreased from 65.7 to 44.6 per 100<span class="elsevierStyleHsp" style=""></span>000 population (age-adjusted rates).</p><p id="par0010" class="elsevierStylePara elsevierViewall">According to the Portuguese National Coordinating Body for Cardiovascular Disease, of the 18<span class="elsevierStyleHsp" style=""></span>075 patients admitted to cardiac care units during 2010, 5320 were admitted for non-ST elevation myocardial infarction (MI) and 4308 for ST-elevation MI, an increase of 7.8% and 8.6%, respectively, compared to 2009. Primary percutaneous coronary intervention (PCI) was the method of reperfusion in 2838 patients, 10.9% more than in the previous year. In 2009, there were 12<span class="elsevierStyleHsp" style=""></span>318 PCI procedures – 6.6% more than in 2009 – in which 15<span class="elsevierStyleHsp" style=""></span>122 stents were implanted, 10<span class="elsevierStyleHsp" style=""></span>590 of them drug-eluting.</p><p id="par0015" class="elsevierStylePara elsevierViewall">Acute coronary syndromes (ACS) require intensive treatment in the acute phase to alleviate myocardial ischemia and to prevent adverse events such as death, (re)infarction and potentially fatal arrhythmias. After clinical stabilization and hospital discharge, these patients still have relatively high rates of thrombotic complications, and thus intensive therapy needs to be maintained in the chronic phase. Recurrence of ACS, which can be fatal, in the weeks or months following discharge can have at least two causes. Firstly, intracoronary ultrasound studies show that most patients with ACS have at least two simultaneous plaque ruptures, and some have ruptured plaques in all three coronary arteries.<a class="elsevierStyleCrossRef" href="#bib0005"><span class="elsevierStyleSup">1</span></a> Consequently, a focal therapeutic approach aimed at treating the culprit lesion, which can often be achieved by PCI, does not remove the risk of short-term recurrence of instability due to other highly vulnerable plaques. Secondly, ACS are characterized by inflammation and oxidative stress.<a class="elsevierStyleCrossRef" href="#bib0010"><span class="elsevierStyleSup">2</span></a> In inflammatory states, circulating monocytes produce thromboxane A2 from arachidonic acid via the cyclooxygenase-2 pathway, an extra-platelet source of thromboxane A2 that is not inhibited by low doses of aspirin. In an oxidative environment, prostanoids are produced by non-enzymatic peroxidation from arachidonic acid in the cell membrane and circulating low-density lipoproteins. These increase platelet reactivity, leading to activation even in the presence of subthreshold concentrations of agonists.</p><p id="par0020" class="elsevierStylePara elsevierViewall">Platelets play a crucial role in the pathogenesis of ACS and their complications, and a combination of antiplatelet agents with different therapeutic targets strengthens platelet inhibition.<a class="elsevierStyleCrossRef" href="#bib0015"><span class="elsevierStyleSup">3</span></a> An important step in platelet activation is the release of granules containing adenosine phosphate (ADP), which binds to both the P2Y<span class="elsevierStyleInf">1</span> and P2Y<span class="elsevierStyleInf">12</span> receptors. Unlike the P2Y<span class="elsevierStyleInf">1</span> receptor, the P2Y<span class="elsevierStyleInf">12</span> receptor is found in few tissues and is thus a more promising therapeutic target. It is the binding of ADP to the P2Y<span class="elsevierStyleInf">12</span> receptor that increases platelet activation; inhibiting these receptors makes the thienopyridines more potent antiplatelet agents than aspirin, since ADP enables platelet aggregation even with low concentrations of any platelet agonists.</p><p id="par0025" class="elsevierStylePara elsevierViewall">In the light of these mechanisms, studies have demonstrated the superiority of dual platelet inhibition with aspirin and clopidogrel in non-ST elevation ACS as well as in ST-elevation MI.<a class="elsevierStyleCrossRefs" href="#bib0020"><span class="elsevierStyleSup">4,5</span></a> The benefit of dual antiplatelet therapy is apparent after only 24<span class="elsevierStyleHsp" style=""></span>hours of treatment and is independent of baseline clinical characteristics and therapeutic approach (with or without PCI). The European Society of Cardiology accordingly recommends dual antiplatelet therapy with aspirin and a P2Y<span class="elsevierStyleInf">12</span> receptor antagonist for all ACS patients, to be initiated as soon as possible and to be maintained for a year if bleeding risk permits.</p><p id="par0030" class="elsevierStylePara elsevierViewall">Despite the considerable improvements due to dual antiplatelet therapy with aspirin and clopidogrel, significant thrombotic risk remains in both the short and long term. The existence of marked interindividual variability in response to clopidogrel indicates that this residual risk is modifiable to some extent.<a class="elsevierStyleCrossRef" href="#bib0030"><span class="elsevierStyleSup">6</span></a> A weak response to clopidogrel is clinically relevant, since it is associated with increased risk of cardiovascular death, spontaneous MI, type 4a MI, stent thrombosis, stroke and target lesion revascularization,<a class="elsevierStyleCrossRef" href="#bib0035"><span class="elsevierStyleSup">7</span></a> and it is common (around a third of patients), because the ratio between the recommended clopidogrel dose and the minimum dose required to obtain its maximum pharmacodynamic effect is around one, which means that the usual dose only partially inhibits P2Y<span class="elsevierStyleInf">12</span> receptors.<a class="elsevierStyleCrossRef" href="#bib0040"><span class="elsevierStyleSup">8</span></a></p><p id="par0035" class="elsevierStylePara elsevierViewall"><a class="elsevierStyleCrossRef" href="#fig0005">Figure 1</a> shows the sequence of events required to achieve the desired therapeutic effect of any drug.</p><elsevierMultimedia ident="fig0005"></elsevierMultimedia><p id="par0040" class="elsevierStylePara elsevierViewall">Many factors affect the response to clopidogrel, some of which have been the subject of considerable research, particularly polymorphisms in the <span class="elsevierStyleItalic">ABCB1</span> gene, which codes for P-glycoprotein (an efflux pump in the intestinal epithelium that returns absorbed drugs to the intestinal lumen, thereby reducing their bioavailability), and in the gene that codes for the 2C19 isoenzyme of cytochrome P450 (CYP2C19), which is important for the activation of clopidogrel.<a class="elsevierStyleCrossRef" href="#bib0045"><span class="elsevierStyleSup">9</span></a> Clopidogrel is a prodrug, and its activation is complex (<a class="elsevierStyleCrossRef" href="#fig0010">Figure 2</a>).<a class="elsevierStyleCrossRef" href="#bib0035"><span class="elsevierStyleSup">7</span></a> Some 85% of the dose administered is hydrolyzed in the liver, where it is converted into an inactive metabolite (SR 26334); the remainder is metabolized by CYP2C19 and to a lesser degree by CYP1A2 and CYP2B6 to 2-oxo-clopidogrel. Around half of this metabolite, which is also inactive, is hydrolyzed and converted into an inactive thiolactone, while the other half is metabolized by the 3A4, 3A5, 2B6, 2C9 and 2C19 isoenzymes, finally producing the active metabolite (R-130964). The fact that a significant proportion of the absorbed drug is wasted (converted to inactive metabolites), the complex activation of the prodrug requiring two oxidation steps, and its heavy dependence on the function of the CYP2C19 isoenzyme (which is involved in the metabolization of numerous drugs and whose reduced-function genetic variants have a prevalence of around 25%), are the main pharmacokinetic factors affecting the variability of response to clopidogrel.</p><elsevierMultimedia ident="fig0010"></elsevierMultimedia><p id="par0045" class="elsevierStylePara elsevierViewall">The article by Teixeira et al. published in this issue of the <span class="elsevierStyleItalic">Journal</span> confirms the prognostic impact of reduced-function CYP2C19 variants in a Portuguese population.<a class="elsevierStyleCrossRef" href="#bib0050"><span class="elsevierStyleSup">10</span></a> The authors found these variants in 27% of a sample of 95 patients who survived ACS and were medicated with clopidogrel. Despite the study's limitations (particularly the small sample size), its main findings are in agreement with those of several other analyses. Recent studies suggest that reduced-function CYP2C19 variants are clinically relevant only in patients undergoing PCI with stenting, in whom they are associated with greater risk for MI and stent thrombosis.<a class="elsevierStyleCrossRef" href="#bib0055"><span class="elsevierStyleSup">11</span></a></p><p id="par0050" class="elsevierStylePara elsevierViewall">The question thus arises as to how to optimize platelet inhibition in ACS. Should platelet response to clopidogrel be tested? Should genetic variants that affect clopidogrel response be screened for? What should be done in the presence of weak platelet inhibition or a reduced-function genetic variant? Would it be better to use one of the new P2Y<span class="elsevierStyleInf">12</span> receptor antagonists, which provide faster, stronger and more consistent platelet inhibition? To put it another way, do we need personalized antiplatelet therapy or better antiplatelet agents?</p><p id="par0055" class="elsevierStylePara elsevierViewall">The concept of personalized medicine has significant limitations. It requires laboratory tests, but the ideal tests have not been identified, and existing tests lack standardization and clinical validation. Furthermore, a personalized approach to platelet therapy is a lengthy and costly process, and will never be 100% effective, firstly because some patients, when tested for response to clopidogrel, still present high platelet reactivity even after a 2400-mg loading dose and 300-mg maintenance dose,<a class="elsevierStyleCrossRefs" href="#bib0060"><span class="elsevierStyleSup">12,13</span></a> and secondly, because genetic variants in CYP2C19 explain only 12% of the variability of response to clopidogrel.<a class="elsevierStyleCrossRef" href="#bib0070"><span class="elsevierStyleSup">14</span></a> In the study by Teixeira et al., this may have contributed to the lack of impact of genotype on the results of platelet function tests.</p><p id="par0060" class="elsevierStylePara elsevierViewall">The future undoubtedly lies with the new P2Y<span class="elsevierStyleInf">12</span> receptor antagonists, particularly prasugrel and ticagrelor. These drugs are more effective than clopidogrel, even when administered in doses above those recommended.<a class="elsevierStyleCrossRef" href="#bib0075"><span class="elsevierStyleSup">15</span></a> In the TRITON-TIMI 38 trial, in individuals with ACS with scheduled PCI, prasugrel reduced major vascular events by 19%, but increased the risk of major bleeding; the risk/benefit ratio was better than for clopidogrel except in patients with a history of stroke or transient ischemic attack.<a class="elsevierStyleCrossRef" href="#bib0080"><span class="elsevierStyleSup">16</span></a> In the PLATO trial, ticagrelor reduced the incidence of major vascular events in patients with scheduled primary PCI or non-ST elevation ACS by 16%; it increased major bleeding risk compared to clopidogrel but did not increase risk for CABG-related bleeding.<a class="elsevierStyleCrossRef" href="#bib0085"><span class="elsevierStyleSup">17</span></a> It is hoped that these new drugs will reduce the high thrombotic risk associated with ACS and contribute significantly to further decreases in mortality from ischemic heart disease.</p><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">Conflicts of interest</span><p id="par0065" class="elsevierStylePara elsevierViewall">The author has no conflicts of interest to declare.</p></span></span>" "textoCompletoSecciones" => array:1 [ "secciones" => array:2 [ 0 => array:2 [ "identificador" => "sec0005" "titulo" => "Conflicts of interest" ] 1 => array:1 [ "titulo" => "References" ] ] ] "pdfFichero" => "main.pdf" "tienePdf" => true "NotaPie" => array:1 [ 0 => array:2 [ "etiqueta" => "☆" "nota" => "<p class="elsevierStyleNotepara">Please cite this article as: Inibição Plaquetária nas Síndromes Coronárias Agudas: Uma Intervenção Complexa que Deve Ser Optimizada. Rev Port Cardiol 2012. <span class="elsevierStyleInterRef" href="doi:10.1016/j.repc.2012.02.011">doi:10.1016/j.repc.2012.02.011</span>.</p>" ] ] "multimedia" => array:2 [ 0 => array:7 [ "identificador" => "fig0005" "etiqueta" => "Figure 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr1.jpeg" "Alto" => 1014 "Ancho" => 2062 "Tamanyo" => 146200 ] ] "descripcion" => array:1 [ "en" => "<p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">Sequence of events that determine response to a drug.</p>" ] ] 1 => array:7 [ "identificador" => "fig0010" "etiqueta" => "Figure 2" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr2.jpeg" "Alto" => 1500 "Ancho" => 1674 "Tamanyo" => 202303 ] ] "descripcion" => array:1 [ "en" => "<p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">Activation of clopidogrel.</p>" ] ] ] "bibliografia" => array:2 [ "titulo" => "References" "seccion" => array:1 [ 0 => array:2 [ "identificador" => "bibs0005" "bibliografiaReferencia" => array:17 [ 0 => array:3 [ "identificador" => "bib0005" "etiqueta" => "1" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Multiple atherosclerotic plaque rupture in acute coronary syndrome. 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| Year/Month | Html | Total | |
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| 2024 November | 8 | 5 | 13 |
| 2024 October | 39 | 32 | 71 |
| 2024 September | 40 | 24 | 64 |
| 2024 August | 47 | 19 | 66 |
| 2024 July | 40 | 26 | 66 |
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| 2024 May | 40 | 24 | 64 |
| 2024 April | 63 | 37 | 100 |
| 2024 March | 37 | 21 | 58 |
| 2024 February | 21 | 25 | 46 |
| 2024 January | 20 | 23 | 43 |
| 2023 December | 30 | 27 | 57 |
| 2023 November | 23 | 29 | 52 |
| 2023 October | 16 | 18 | 34 |
| 2023 September | 20 | 22 | 42 |
| 2023 August | 14 | 14 | 28 |
| 2023 July | 20 | 10 | 30 |
| 2023 June | 18 | 14 | 32 |
| 2023 May | 32 | 29 | 61 |
| 2023 April | 24 | 9 | 33 |
| 2023 March | 40 | 21 | 61 |
| 2023 February | 29 | 26 | 55 |
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| 2022 December | 44 | 24 | 68 |
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| 2022 September | 31 | 46 | 77 |
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| 2022 May | 32 | 31 | 63 |
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| 2022 March | 26 | 34 | 60 |
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| 2022 January | 16 | 26 | 42 |
| 2021 December | 21 | 31 | 52 |
| 2021 November | 41 | 33 | 74 |
| 2021 October | 25 | 34 | 59 |
| 2021 September | 16 | 26 | 42 |
| 2021 August | 29 | 26 | 55 |
| 2021 July | 19 | 18 | 37 |
| 2021 June | 14 | 24 | 38 |
| 2021 May | 22 | 39 | 61 |
| 2021 April | 24 | 33 | 57 |
| 2021 March | 56 | 13 | 69 |
| 2021 February | 49 | 18 | 67 |
| 2021 January | 24 | 18 | 42 |
| 2020 December | 21 | 9 | 30 |
| 2020 November | 27 | 16 | 43 |
| 2020 October | 23 | 20 | 43 |
| 2020 September | 35 | 8 | 43 |
| 2020 August | 24 | 10 | 34 |
| 2020 July | 39 | 7 | 46 |
| 2020 June | 18 | 7 | 25 |
| 2020 May | 30 | 5 | 35 |
| 2020 April | 41 | 8 | 49 |
| 2020 March | 27 | 11 | 38 |
| 2020 February | 41 | 9 | 50 |
| 2020 January | 28 | 8 | 36 |
| 2019 December | 19 | 3 | 22 |
| 2019 November | 31 | 3 | 34 |
| 2019 October | 33 | 6 | 39 |
| 2019 September | 19 | 8 | 27 |
| 2019 August | 31 | 10 | 41 |
| 2019 July | 30 | 11 | 41 |
| 2019 June | 12 | 7 | 19 |
| 2019 May | 28 | 28 | 56 |
| 2019 April | 29 | 21 | 50 |
| 2019 March | 27 | 16 | 43 |
| 2019 February | 41 | 15 | 56 |
| 2019 January | 14 | 8 | 22 |
| 2018 December | 41 | 10 | 51 |
| 2018 November | 68 | 8 | 76 |
| 2018 October | 204 | 29 | 233 |
| 2018 September | 80 | 11 | 91 |
| 2018 August | 49 | 6 | 55 |
| 2018 July | 39 | 5 | 44 |
| 2018 June | 62 | 9 | 71 |
| 2018 May | 61 | 4 | 65 |
| 2018 April | 71 | 7 | 78 |
| 2018 March | 47 | 10 | 57 |
| 2018 February | 29 | 4 | 33 |
| 2018 January | 25 | 7 | 32 |
| 2017 December | 45 | 7 | 52 |
| 2017 November | 41 | 15 | 56 |
| 2017 October | 38 | 10 | 48 |
| 2017 September | 39 | 6 | 45 |
| 2017 August | 41 | 14 | 55 |
| 2017 July | 27 | 10 | 37 |
| 2017 June | 27 | 3 | 30 |
| 2017 May | 29 | 5 | 34 |
| 2017 April | 32 | 3 | 35 |
| 2017 March | 28 | 10 | 38 |
| 2017 February | 23 | 3 | 26 |
| 2017 January | 19 | 2 | 21 |
| 2016 December | 28 | 13 | 41 |
| 2016 November | 20 | 12 | 32 |
| 2016 October | 27 | 9 | 36 |
| 2016 September | 20 | 8 | 28 |
| 2016 August | 2 | 0 | 2 |
| 2016 July | 14 | 7 | 21 |
| 2016 June | 6 | 10 | 16 |
| 2016 May | 5 | 6 | 11 |
| 2016 April | 34 | 1 | 35 |
| 2016 March | 57 | 15 | 72 |
| 2016 February | 58 | 24 | 82 |
| 2016 January | 46 | 14 | 60 |
| 2015 December | 45 | 14 | 59 |
| 2015 November | 46 | 15 | 61 |
| 2015 October | 53 | 23 | 76 |
| 2015 September | 43 | 11 | 54 |
| 2015 August | 47 | 14 | 61 |
| 2015 July | 52 | 6 | 58 |
| 2015 June | 29 | 4 | 33 |
| 2015 May | 33 | 7 | 40 |
| 2015 April | 43 | 15 | 58 |
| 2015 March | 29 | 18 | 47 |
| 2015 February | 46 | 14 | 60 |
| 2015 January | 44 | 8 | 52 |
| 2014 December | 57 | 23 | 80 |
| 2014 November | 62 | 10 | 72 |
| 2014 October | 59 | 12 | 71 |
| 2014 September | 58 | 10 | 68 |
| 2014 August | 24 | 10 | 34 |
| 2014 July | 42 | 10 | 52 |
| 2014 June | 33 | 8 | 41 |
| 2014 May | 30 | 11 | 41 |
| 2014 April | 40 | 11 | 51 |
| 2014 March | 51 | 21 | 72 |
| 2014 February | 48 | 19 | 67 |
| 2014 January | 45 | 17 | 62 |
| 2013 December | 36 | 10 | 46 |
| 2013 November | 56 | 18 | 74 |
| 2013 October | 50 | 14 | 64 |
| 2013 September | 51 | 12 | 63 |
| 2013 August | 60 | 26 | 86 |
| 2013 July | 66 | 26 | 92 |
| 2013 June | 50 | 14 | 64 |
| 2013 May | 56 | 14 | 70 |
| 2013 April | 64 | 26 | 90 |
| 2013 March | 51 | 19 | 70 |
| 2013 February | 56 | 21 | 77 |
| 2013 January | 64 | 25 | 89 |
| 2012 December | 67 | 13 | 80 |
| 2012 November | 50 | 15 | 65 |
| 2012 October | 46 | 17 | 63 |
| 2012 September | 31 | 6 | 37 |
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