Lipid-lowering treatment in secondary prevention of ischaemic cerebrovascular disease | Clínica e Investigación en Arteriosclerosis (English Edition)

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(B) Presence of LV thrombus (red arrow)." ] ] ] "autores" => array:1 [ 0 => array:2 [ "autoresLista" => "Rafael Ruiz-Gaviria, Timothy Vettiyanickal Joseph, Kalla Abhishek" "autores" => array:3 [ 0 => array:2 [ "nombre" => "Rafael" "apellidos" => "Ruiz-Gaviria" ] 1 => array:2 [ "nombre" => "Timothy" "apellidos" => "Vettiyanickal Joseph" ] 2 => array:2 [ "nombre" => "Kalla" "apellidos" => "Abhishek" ] ] ] ] ] "idiomaDefecto" => "en" "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S252991232030053X?idApp=UINPBA00004N" "url" => "/25299123/0000003200000004/v1_202007250816/S252991232030053X/v1_202007250816/en/main.assets" ] "en" => array:20 [ "idiomaDefecto" => true "cabecera" => "Review article" "titulo" => "Lipid-lowering treatment in secondary prevention of ischaemic cerebrovascular disease" "tieneTextoCompleto" => true "paginas" => array:1 [ 0 => array:2 [ "paginaInicial" => "175" "paginaFinal" => "182" ] ] "autores" => array:1 [ 0 => array:4 [ "autoresLista" => "Elisenda Climent, David Benaiges, Juan Pedro-Botet" "autores" => array:3 [ 0 => array:3 [ "nombre" => "Elisenda" "apellidos" => "Climent" "referencia" => array:2 [ 0 => array:2 [ "etiqueta" => "a" "identificador" => "aff0005" ] 1 => array:2 [ "etiqueta" => "b" "identificador" => "aff0010" ] ] ] 1 => array:3 [ "nombre" => "David" "apellidos" => "Benaiges" "referencia" => array:3 [ 0 => array:2 [ "etiqueta" => "a" "identificador" => "aff0005" ] 1 => array:2 [ "etiqueta" => "b" "identificador" => "aff0010" ] 2 => array:2 [ "etiqueta" => "c" "identificador" => "aff0015" ] ] ] 2 => array:4 [ "nombre" => "Juan" "apellidos" => "Pedro-Botet" "email" => array:1 [ 0 => "86620@parcdesalutmar.cat" ] "referencia" => array:4 [ 0 => array:2 [ "etiqueta" => "a" "identificador" => "aff0005" ] 1 => array:2 [ "etiqueta" => "b" "identificador" => "aff0010" ] 2 => array:2 [ "etiqueta" => "c" "identificador" => "aff0015" ] 3 => array:2 [ "etiqueta" => "*" "identificador" => "cor0005" ] ] ] ] "afiliaciones" => array:3 [ 0 => array:3 [ "entidad" => "Servicio Endocrinología y Nutrición, Hospital del Mar, Barcelona, Spain" "etiqueta" => "a" "identificador" => "aff0005" ] 1 => array:3 [ "entidad" => "Departament de Medicina, Universitat Autònoma de Barcelona, Campus Universitari Mar, Barcelona, Spain" "etiqueta" => "b" "identificador" => "aff0010" ] 2 => array:3 [ "entidad" => "Institut Hospital del Mar d’Investigacions Mèdiques (IMIM), Barcelona, Spain" "etiqueta" => "c" "identificador" => "aff0015" ] ] "correspondencia" => array:1 [ 0 => array:3 [ "identificador" => "cor0005" "etiqueta" => "⁎" "correspondencia" => "Corresponding author." ] ] ] ] "titulosAlternativos" => array:1 [ "es" => array:1 [ "titulo" => "Tratamiento hipolipemiante en la prevención secundaria de la enfermedad cerebrovascular isquémica" ] ] "resumenGrafico" => array:2 [ "original" => 0 "multimedia" => array:8 [ "identificador" => "fig0005" "etiqueta" => "Figure 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr1.jpeg" "Alto" => 1360 "Ancho" => 1417 "Tamanyo" => 112773 ] ] "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at0005" "detalle" => "Figure " "rol" => "short" ] ] "descripcion" => array:1 [ "en" => "Classic risk factors for vascular disease. AHT: arterial hypertension; LDL: low density lipoproteins." ] ] ] "textoCompleto" => "IntroductionData from the World Health Organisation 2016<a class="elsevierStyleCrossRefs" href="#bib0005">1,2</a> confirm that stroke is the second cause of death after myocardial infarction. It is worth noting that, according to the National Institute of Statistics (INE) 2017, it is already the leading of cause of death in women in Spain.<a class="elsevierStyleCrossRef" href="#bib0015">3</a> The Global Burden of Disease Study 2016<a class="elsevierStyleCrossRef" href="#bib0020">4</a> estimated the incidence of stroke and risk of death from all causes excluding stroke to calculate the lifetime risk of a first ischaemic or haemorrhagic stroke in adults aged 25 or more. The risk of ischaemic stroke was 18.3 percent and the risk of haemorrhagic stroke was 8.2 percent, with significant geographical variation.Patients with ischaemic stroke have a high risk of subsequent vascular events, including recurrent stroke, myocardial infarction and death from vascular causes.<a class="elsevierStyleCrossRef" href="#bib0025">5</a> In this regard, patients with a history of transient ischaemic attack or minor stroke were described to present a sustained risk of cardiovascular events during a 5-year follow-up period, half of which occurred between the second and the fifth year.<a class="elsevierStyleCrossRef" href="#bib0030">6</a> In fact, the risk for the primary objective comprising stroke, acute coronary syndrome or cardiovascular death was 12.9% and for isolated stroke it was 9.5%, both at 5 years, approximately double the rates per year of 6.2% and 5.1%, respectively.Although the vascular risk factors are the same for any site of atherosclerotic disease, the impact of each is different according to the arterial territory affected. Traditionally, and unlike coronary heart disease, the relationship between plasma cholesterol and stroke has been weak or non-existent, with high blood pressure being the main risk factor for stroke<a class="elsevierStyleCrossRef" href="#bib0035">7</a> (<a class="elsevierStyleCrossRef" href="#fig0005">Fig. 1</a>). However, more recent clinical evidence has shown an increased risk of cerebrovascular disease with high levels of cholesterol linked to low density lipoproteins (LDL), as well as a decrease in this risk with lipid lowering treatment.<a class="elsevierStyleCrossRefs" href="#bib0040">8,9</a> Along these lines, the meta-analysis by Amarenco and Labreuche<a class="elsevierStyleCrossRef" href="#bib0050">10</a> described that each mmol/L decrease in LDL cholesterol was accompanied by a reduction in the relative risk (RRR) of stroke of 21.1% (95% confidence interval [CI]: 6.3–33.5; P = .009).<elsevierMultimedia ident="fig0005"></elsevierMultimedia>Together with mortality data, we should not forget that cerebrovascular disease is the leading cause of acquired disability,<a class="elsevierStyleCrossRef" href="#bib0055">11</a> and therefore has substantial socioeconomic and health repercussions. However, it is important to note that up to at least 80% of recurrent cerebrovascular events could be prevented with appropriate therapeutic measures. For this reason, we considered it appropriate to conduct a narrative review of the impact of lipid-lowering therapy on secondary prevention of ischaemic stroke.Hypercholesterolaemia, cerebrovascular disease and mortalityOne of the first epidemiological studies to analyse the relationship between cholesterolaemia and cardiovascular mortality was published in 1989 by Iso et al.<a class="elsevierStyleCrossRef" href="#bib0060">12</a> in the context of the Multiple Risk Factor Intervention Trial (MRFIT) involving 350,977 men aged 35–57 years, with no previous history of coronary heart disease. The risk of death at 6 years of follow-up due to intracranial haemorrhage was 3 times higher in men with total cholesterol levels <160 mg/dL than in those with higher levels (P = .05). The inverse relationship between cholesterol levels and risk of death from haemorrhagic stroke was confined to patients with diastolic blood pressure ≥90 mmHg. As for non-haemorrhagic stroke, a positive and significant association was observed between cholesterol levels and risk of death from stroke.Along the same lines, the findings of the Prospective Studies Collaboration (PSC) of 1995<a class="elsevierStyleCrossRef" href="#bib0065">13</a> are worth noting, which included 45 prospective cohorts comprising 450,000 individuals with 13,387 recorded strokes and 16 years of follow-up. After adjusting for education level, age, sex, diastolic blood pressure, presence of coronary heart disease and ethnicity, no association between cholesterolaemia and stroke risk was documented. However, it should be noted that in this study the results were not categorised according to different types of stroke (ischaemic or haemorrhagic), unlike the MRFIT study.<a class="elsevierStyleCrossRef" href="#bib0060">12</a>Lipid-lowering treatment and reduction of risk of cerebrovascular diseaseIn contrast to the findings of epidemiological studies, the clinical evidence for the favourable effect of LDL cholesterol reduction in ischaemic cerebrovascular disease is more conclusive. The role of lipid lowering therapy in the secondary prevention of ischaemic stroke before and after the statin era will be described below.Initial studies of the “pre-statin” eraIn 1993 Atkins et al.<a class="elsevierStyleCrossRef" href="#bib0070">14</a> conducted one of the first meta-analyses to evaluate the effect of lipid lowering treatment prior to the introduction of statins, including dietary hygiene measures, cholestyramine, niacin or clofibrate, among others, on the risk of cerebrovascular disease (<a class="elsevierStyleCrossRef" href="#fig0010">Fig. 2</a>). With reference to fatal stroke, the overall odds ratio (OR) associated with therapeutic strategies to reduce plasma cholesterol levels was 1.32 (95% CI .94–1.86), and the odds ratio (OR) for the 10 single intervention trials was 1.34 (CI .91–1.96). Among the eight studies that included non-fatal episodes, the likelihood rate of non-fatal stroke for participants in the active treatment arm compared to controls was 0.88 (CI .70–1.11), and the likelihood rate of total stroke was 0.98 (CI .80–1.19). In the three clofibrate trials, this fibrate significantly increased the risk of fatal stroke (OR 2.64, CI 1.42–4.92) but not non-fatal stroke (OR 0.87, CI .61–1.26). Finally, logistic regression analysis did not reveal a significant association between the magnitude of cholesterol reduction and the risk of fatal stroke. Therefore, the main conclusion of this meta-analysis was that lowering cholesterol levels with hygiene-dietary measures or with lipid lowering drug treatment other than statins did not decrease cerebrovascular disease-related morbidity and mortality in middle-aged males.<elsevierMultimedia ident="fig0010"></elsevierMultimedia>Intervention studies with statinsSince the introduction of lovastatin in 1987 as the first 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase inhibitor approved for use in humans,<a class="elsevierStyleCrossRef" href="#bib0075">15</a> statins have become the most widely used lipid-lowering drugs, with proven efficacy in cardiovascular prevention in all age groups,<a class="elsevierStyleCrossRefs" href="#bib0080">16–19</a> mainly by reducing LDL cholesterol levels. In the following years, different studies have assessed the role of statins, and their consequent lowering of cholesterol, with the risk of a cerebrovascular event, showing much more promising results than those obtained in the "pre-statin" era. In fact, statin therapy has been considered one of the most important advances in stroke prevention since the advent of aspirin or antihypertensive treatment.<a class="elsevierStyleCrossRef" href="#bib0100">20</a><a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a> shows the main studies that have assessed the possible relationship between LDL cholesterol reduction with statins and the risk of stroke or transient ischaemic attack. In most secondary prevention of cardiovascular disease studies, such as the Simvastatin Survival Study Group (4S),<a class="elsevierStyleCrossRef" href="#bib0105">21</a> Cholesterol and Recurrent Event (CARE),<a class="elsevierStyleCrossRef" href="#bib0110">22</a> and Long Term Intervention with Pravastatin in Ischemic Disease (LIPID),<a class="elsevierStyleCrossRef" href="#bib0115">23</a> a significant reduction in stroke risk in patients with ischaemic heart disease was found, which reached 50% in the Myocardial Ischemia Reduction with Aggressive Cholesterol Lowering (MIRACL) Study<a class="elsevierStyleCrossRef" href="#bib0120">24</a> in patients with recent acute coronary syndrome. In contrast, in the West of Scotland Coronary Prevention Study (WOSCOPS),<a class="elsevierStyleCrossRef" href="#bib0125">25</a> a primary prevention study of cardiovascular disease, showed a non-significant 11% decrease in the risk of stroke during the 5 years of follow-up.<elsevierMultimedia ident="tbl0005"></elsevierMultimedia>Focussing on secondary prevention of cerebrovascular disease with statins, the Heart Protection Study (HPS)<a class="elsevierStyleCrossRef" href="#bib0130">26</a> was the first study to assess the effect of simvastatin treatment on secondary prevention of stroke in patients with previous cerebrovascular disease. A total of 20,536 patients at high risk of vascular events were included with a 5-year follow-up. Treatment with simvastatin significantly reduced the risk of vascular events (RRR of 24%, P < .00001) and stroke (RRR of 27%, P < .00001). This same study included 3280 randomly selected stroke patients (none with transient ischaemic attack) and 1822 stroke patients without established coronary heart disease. The RRR of serious cardiovascular events was 19% in all the stroke patients, which rose to 23% in the stroke patients without coronary heart disease. However, this study did not show a reduction in the risk of stroke among the patients with recurrent stroke (10.4% of patients in the statin group had recurrent stroke compared to 10.5% of the patients in the placebo group). Therefore, in the patients with a previous stroke, statins probably reduced the incidence of coronary events, but there was no evidence that statins also reduced the incidence of recurrent stroke.Stroke prevention by aggressive reduction of cholesterol levels (SPARCL)As a result of the findings of the MIRACL study,<a class="elsevierStyleCrossRef" href="#bib0120">24</a> the Stroke Prevention by Aggressive Reduction in Cholesterol Levels (SPARCL)<a class="elsevierStyleCrossRef" href="#bib0135">27</a> study was conducted, the first clinical trial designed to confirm the benefits of statin therapy in the secondary prevention of stroke. We included 4731 patients >18 with a history of established or transient ischaemic stroke in the previous 1–6 months and who did not have hypercholesterolaemia or coronary heart disease. Most were ischaemic strokes, and some were haemorrhagic. The patients received either atorvastatin 80 mg/day (n = 2365) or placebo (n = 2366) and were followed for almost 5 years. The primary objective of the study was to assess the incidence of fatal and non-fatal stroke. A 16% RRR was observed in recurrent stroke, a 35% RRR in severe coronary events and a 20% RRR in severe cardiovascular events. The superiority of atorvastatin over placebo was mainly in the patients with fatal stroke, who experienced a 43% reduction (P = .03). It would be unfair not to mention here the 66% increase in the relative risk of haemorrhagic stroke in the patients who were randomised to atorvastatin.On careful analysis of the results of the SPARCL study, there are certain aspects worth noting. Twenty-five percent of the patients who were assigned to the placebo arm ended up receiving statin treatment at some point in the study. Therefore, it could be argued that the results obtained underestimate the true clinical impact of high-dose statin therapy, given that atorvastatin was compared to a control group where one in four patients also received the same treatment. Therefore, one might ask whether the SPARCL findings underestimate the real effect of intensive statin therapy, or whether they underestimate the increased risk of intracerebral haemorrhage with statin therapy.In order to answer these questions, and address the issue of the actual benefits and risks of statin therapy in stroke patients, Amarenco et al.<a class="elsevierStyleCrossRef" href="#bib0140">28</a> re-analysed the data, but this time reclassified the patients not according to the assigned treatment arm, but according to the level of LDL cholesterol reduction. This was possible because the methodological aspects of the study included 4 serial tests per patient and year. The patients were classified into 3 categories: no change in their LDL cholesterol, a <50% decrease or a ≥50% decrease in LDL cholesterol, hypothesising that the latter group would indicate the true biological effect of intense LDL cholesterol reduction in recent stroke patients. As expected, most patients with a dramatic decrease in LDL cholesterol (≥50%) were in the atorvastatin group, although not all participants in the atorvastatin group had such a marked therapeutic response. Approximately one-third of them had a <50% decrease in LDL cholesterol, and the study confirms that there were some people in the placebo group who took statins when an intense reduction in LDL cholesterol was noted. Comparing the patients with a reduction in LDL cholesterol levels ≥50%, it was found that instead of an RRR of 16% for recurrent stroke, an RRR of 31% was achieved (for any subtype). There were also reductions in the risk of serious coronary events (RRR of 37%), and an RRR of 48% in the need for any revascularisation procedure. The main results of the SPARCL<a class="elsevierStyleCrossRef" href="#bib0135">27</a> study as well as the subsequent subanalysis<a class="elsevierStyleCrossRef" href="#bib0140">28</a> stratified by reduced LDL cholesterol levels are detailed in <a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a>.<elsevierMultimedia ident="tbl0010"></elsevierMultimedia>Risk of intracerebral haemorrhage associated with statin treatmentThe second question in analysing the results of the SPARCL<a class="elsevierStyleCrossRef" href="#bib0135">27</a> study was whether the final results underestimated the increased risk of intracerebral haemorrhage from statins. In this regard, it should be noted that in the SPARCL<a class="elsevierStyleCrossRef" href="#bib0140">28</a> sub-analysis described in the above section, no increase in haemorrhagic stroke was observed in the group with reduced cholesterol levels LDL > 50%, despite the fact that the atorvastatin group in the original analysis<a class="elsevierStyleCrossRef" href="#bib0135">27</a> presented an increased risk of haemorrhagic stroke.These results are consistent with those subsequently described by Goldstein et al.<a class="elsevierStyleCrossRef" href="#bib0145">29</a> in 2008, where risk factors for intracerebral haemorrhage were analysed in the SPARCL study. In this case, male sex (hazard ratio [HR]: 2.21, 95% CI: 1.20–4.09; P = .01), age (HR: 1.40, 95% CI: 1.08–1.81; P = .01) and intracerebral haemorrhage as the form of presentation (HR: 8.38, 95% CI: 3.78–18.56; P < .001), in addition to poor blood pressure control, were the factors associated with the risk of a haemorrhagic event. Notably, no quartile of LDL cholesterol was associated with an increased risk of intracerebral haemorrhage. More recently, Gaist et al.<a class="elsevierStyleCrossRef" href="#bib0150">30</a> confirmed that statin use was not associated with an increased risk of intracranial haemorrhage in patients with a history of established or transient ischaemic stroke.In a recent Mendelian randomisation study,<a class="elsevierStyleCrossRef" href="#bib0155">31</a> each mmol/L of genetically engineered LDL cholesterol was associated with RRRs of 0.75 (95% CI .60–.95) for ischaemic stroke and 1.13 (95% CI .91–1.40) for intracranial haemorrhage. In the same study, analysis of pharmacological reduction in LDL cholesterol confirmed that each mmol/L decrease was accompanied by an RRR of 0.80 (95% CI: 0.76−0.84) for ischaemic stroke and 1.17 (95% CI: 1.03–1.32) for intracerebral haemorrhage.In short, the available evidence has not been able to demonstrate a real increased risk of intracranial haemorrhage secondary to statin therapy.Combined treatmentThe current joint guideline 2019 of the European Society of Cardiology (ESC) and the European Atherosclerosis Society (EAS)<a class="elsevierStyleCrossRef" href="#bib0160">32</a> for the management of dyslipidaemia recommends with a degree of evidence A intensive lipid lowering therapy to reduce LDL cholesterol levels in established or transient ischaemic stroke patients. Although the therapeutic goals for LDL cholesterol can be achieved with statins in monotherapy in a substantial number of cases, a significant proportion of patients at high/very high risk or with elevated LDL cholesterol levels require additional drug therapy. In this clinical situation, where despite statin therapy at the maximum tolerated dose the therapeutic goal is not achieved, the combination with ezetimibe is recommended, and if still not achieved, the addition of a PCSK9 inhibitor is recommended.With regard to combination treatment with statins and ezetimibe, the Improved Reduction of Outcomes: Vytorin Efficacy International Trial (IMPROVE-IT)<a class="elsevierStyleCrossRef" href="#bib0165">33</a> provided clear evidence that reinforces the importance of reducing LDL cholesterol in cardiovascular prevention. In this regard, it should be stressed that the additional reduction in LDL cholesterol achieved with ezetimibe is of the same quality in terms of cardiovascular risk reduction, as that obtained with statins in monotherapy. Each mmol/L (38.7 mg/dL) reduction in LDL cholesterol obtained with statins in monotherapy or with the statin plus ezetimibe combination is associated with an approximate reduction in the RR of cardiovascular disease of 20%, findings which are in fully in line with those of the Cholesterol Treatment Trialist Collaboration.<a class="elsevierStyleCrossRef" href="#bib0085">17</a> In a complementary analysis of IMPROVE-IT, Bohula et al.<a class="elsevierStyleCrossRef" href="#bib0170">34</a> showed that simvastatin and ezetimibe combination therapy in patients stabilised after an acute coronary syndrome reduced the frequency of ischaemic stroke, especially in patients with previous stroke.Finally, there is recent evidence regarding the beneficial effects of treatment with PCSK9 inhibitors in cardiovascular prevention. The publication of the results of Further Cardiovascular Outcomes Research With PCSK9 Inhibition in Subjects With Elevated Risk (FOURIER)<a class="elsevierStyleCrossRef" href="#bib0175">35</a> with evolocumab and ODYSSEY Outcomes: Evaluation of Cardiovascular Outcomes After an Acute Coronary Syndrome During Treatment with Alirocumab<a class="elsevierStyleCrossRef" href="#bib0180">36</a> support the theory that the lower the LDL cholesterol the better in patients at high/very high cardiovascular risk, and together with IMPROVE-IT<a class="elsevierStyleCrossRef" href="#bib0165">33</a> point to the use of high-intensity lipid-lowering therapies.<a class="elsevierStyleCrossRef" href="#bib0185">37</a> These two studies were included in a recent systematic review and meta-analysis by Guedeney et al.<a class="elsevierStyleCrossRef" href="#bib0190">38</a> which documented an RRR of ischaemic stroke of 22% with treatment with PCSK9 inhibitors.The challengesDespite the availability of effective and potent therapeutic tools, real-life clinical practice studies show that patients at high/very high cardiovascular risk are under-treated and under-controlled. For example, the EUROASPIRE V registry<a class="elsevierStyleCrossRef" href="#bib0195">39</a> conducted in 27 countries with patients in secondary prevention found that 71% had LDL cholesterol ≥1.8 mmol/L (70 mg/dL) despite the fact that just over 80% of the patients were treated with statins. This highlights that undertreatment is one of the main barriers to overcome towards improving therapeutic performance. Almost contemporaneously, similar results were described in the PALM registry.<a class="elsevierStyleCrossRef" href="#bib0200">40</a> Less use and intensity of statins was observed in subgroup analyses by age and LDL cholesterol levels, although differences were not statistically significant in older patients and those with LDL ≥ 100 mg/dL. On the other hand, no statistically significant differences in statin use and intensity of statin therapy were observed among patients with coronary artery disease and stroke versus coronary artery disease alone. In this same study, the median (p25–p75) LDL cholesterol levels were 90 mg/dL (73–114), 88 mg/dL (69–111) and 83 mg/dL (66–107) for patients with cerebrovascular disease alone, coronary artery disease and cerebrovascular disease, or coronary artery disease alone, respectively (P < .001). It should be noted that only 59.2% of patients with cerebrovascular disease presented LDL cholesterol levels <100 mg/dL, and therefore, most of the patients did not achieve the therapeutic goals.Advances in analytical magnetic resonance imaging and mass spectrometry platforms have made substantial contributions to the field of metabolomics and lipidomics in general.<a class="elsevierStyleCrossRef" href="#bib0205">41</a> These emerging technologies have become increasingly sophisticated through the development of new statistical methods, bioinformatic tools and database resources. More recently, systems biology approaches have been applied to decipher biological and clinical complexities with the emergence of computational and mathematical models. Thus, the inclusion of metabolomics and lipidomics, along with other "omics", is possible.<a class="elsevierStyleCrossRef" href="#bib0210">42</a> Furthermore, fluxomics is a relatively new and ever-expanding field that characterises the dynamic metabolic profile of the cell phenotype and involves a more comprehensive assessment of complex metabolic networks related to disease. Fluxoma, the set of metabolic flows in a metabolic system, is a direct manifestation of the metabolic phenotype, and therefore is key to understanding any disease with a strong metabolic component. However, more research is needed to unravel the causal mechanisms of ischaemic stroke and pave the way for new drug treatments to help us achieve the therapeutic goals set for our patients.ConclusionsCerebrovascular disease is one of the main causes of mortality in our population, with hypercholesterolaemia being one of the modifiable risk factors described. Previous studies have shown that lipid-lowering treatment, both with statins and in combination with ezetimibe or PCSK9 inhibitors, are effective in secondary prevention of ischaemic stroke, by lowering LDL cholesterol levels. However, the main barrier in clinical practice remains the failure to achieve therapeutic goals in LDL cholesterol, the result of undertreatment. It has been documented that prior therapeutic planning<a class="elsevierStyleCrossRef" href="#bib0215">43</a> using updated Masana and Plana tables<a class="elsevierStyleCrossRef" href="#bib0220">44</a> and the use of computerised tools included in the clinical history<a class="elsevierStyleCrossRef" href="#bib0225">45</a> significantly improve the rate that therapeutic goals are met and thus achieve effective vascular prevention.FundingThis research study received no specific subsidies from public sector agencies, the commercial sector or non-profit organisations.Conflict of interestsThe authors have no conflict of interests to declare." "textoCompletoSecciones" => array:1 [ "secciones" => array:12 [ 0 => array:3 [ "identificador" => "xres1366600" "titulo" => "Abstract" "secciones" => array:1 [ 0 => array:1 [ "identificador" => "abst0005" ] ] ] 1 => array:2 [ "identificador" => "xpalclavsec1256247" "titulo" => "Keywords" ] 2 => array:3 [ "identificador" => "xres1366601" "titulo" => "Resumen" "secciones" => array:1 [ 0 => array:1 [ "identificador" => "abst0010" ] ] ] 3 => array:2 [ "identificador" => "xpalclavsec1256248" "titulo" => "Palabras clave" ] 4 => array:2 [ "identificador" => "sec0005" "titulo" => "Introduction" ] 5 => array:2 [ "identificador" => "sec0010" "titulo" => "Hypercholesterolaemia, cerebrovascular disease and mortality" ] 6 => array:3 [ "identificador" => "sec0015" "titulo" => "Lipid-lowering treatment and reduction of risk of cerebrovascular disease" "secciones" => array:5 [ 0 => array:2 [ "identificador" => "sec0020" "titulo" => "Initial studies of the “pre-statin” era" ] 1 => array:2 [ "identificador" => "sec0025" "titulo" => "Intervention studies with statins" ] 2 => array:2 [ "identificador" => "sec0030" "titulo" => "Stroke prevention by aggressive reduction of cholesterol levels (SPARCL)" ] 3 => array:2 [ "identificador" => "sec0035" "titulo" => "Risk of intracerebral haemorrhage associated with statin treatment" ] 4 => array:2 [ "identificador" => "sec0040" "titulo" => "Combined treatment" ] ] ] 7 => array:2 [ "identificador" => "sec0045" "titulo" => "The challenges" ] 8 => array:2 [ "identificador" => "sec0050" "titulo" => "Conclusions" ] 9 => array:2 [ "identificador" => "sec0055" "titulo" => "Funding" ] 10 => array:2 [ "identificador" => "sec0060" "titulo" => "Conflict of interests" ] 11 => array:1 [ "titulo" => "References" ] ] ] "pdfFichero" => "main.pdf" "tienePdf" => true "fechaRecibido" => "2019-11-17" "fechaAceptado" => "2019-12-17" "PalabrasClave" => array:2 [ "en" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Keywords" "identificador" => "xpalclavsec1256247" "palabras" => array:5 [ 0 => "Cholesterol" 1 => "Statins" 2 => "Ezetimibe" 3 => "Ischemic stroke" 4 => "PCSK9 inhibitors" ] ] ] "es" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Palabras clave" "identificador" => "xpalclavsec1256248" "palabras" => array:5 [ 0 => "Colesterol" 1 => "Estatinas" 2 => "Ezetimiba" 3 => "Ictus isquémico" 4 => "Inhibidores PCSK9" ] ] ] ] "tieneResumen" => true "resumen" => array:2 [ "en" => array:2 [ "titulo" => "Abstract" "resumen" => "Stroke is the second cause of death after myocardial infarction, and the main cause of acquired disability. Patients with ischaemic stroke have a higher risk of future vascular events, including recurrent stroke, myocardial infarction, and death by vascular cause. The initial epidemiological studies demonstrated a weak or non-existent relationship between cholesterolaemia and stroke. Subsequently, statin intervention trials showed a reduction in the risk of recurrence of cerebrovascular events. The Stroke Prevention by Aggressive Reduction in Cholesterol Levels (SPARCL), the first clinical trial designed to assess effects of statin therapy in secondary stroke prevention, highlighted the reduction of stroke recurrence with atorvastatin 80 mg/daily in patients with a recent ischaemic established or transient stroke, with a modest increase in the rate of haemorrhagic stroke. Successive studies have also reported the benefits of statin therapy combined with ezetimibe or PCSK9 inhibitors in primary and secondary ischaemic stroke prevention. Since 80% of recurrent cerebrovascular events could be prevented, it is considered of interest to carry out a narrative review of the benefits of lipid-lowering therapy in the secondary prevention of ischaemic cerebrovascular disease." ] "es" => array:2 [ "titulo" => "Resumen" "resumen" => "El accidente cerebrovascular es la segunda causa de mortalidad después del infarto de miocardio y la principal causa de discapacidad adquirida. Los pacientes con ictus isquémico tienen un elevado riesgo de posteriores episodios vasculares, incluyendo ictus recurrente, infarto de miocardio y muerte de causa vascular. Los primeros estudios epidemiológicos mostraron una relación débil o inexistente entre la colesterolemia y el ictus. Posteriormente, los estudios de intervención con estatinas revelaron una reducción del riesgo de recurrencia de episodios cerebrovasculares. El Stroke Prevention by Aggressive Reduction in Cholesterol Levels (SPARCL), primer ensayo clínico diseñado para analizar los efectos de la terapia con estatinas en la prevención secundaria del ictus, demostró que el tratamiento con atorvastatina 80 mg/día reducía la recurrencia de ictus en pacientes con un accidente cerebrovascular isquémico reciente establecido o transitorio, con un modesto aumento en la tasa de ictus hemorrágico. Estudios posteriores han recabado los beneficios de la terapia de estatinas, con ezetimiba o inhibidores de PCSK9 tanto en la prevención primaria como secundaria del accidente cerebrovascular isquémico. Dado que el 80% de los episodios cerebrovasculares recurrentes pueden prevenirse hemos considerado de interés realizar una revisión narrativa de los beneficios de la terapia hipolipemiante en la prevención secundaria de la enfermedad cerebrovascular isquémica." ] ] "NotaPie" => array:1 [ 0 => array:2 [ "etiqueta" => "☆" "nota" => "Please cite this article as: Climent E, Benaiges D, Pedro-Botet J. Tratamiento hipolipemiante en la prevención secundaria de la enfermedad cerebrovascular isquémica. Clin Investig Arterioscler. 2020;32:175–182." ] ] "multimedia" => array:4 [ 0 => array:8 [ "identificador" => "fig0005" "etiqueta" => "Figure 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr1.jpeg" "Alto" => 1360 "Ancho" => 1417 "Tamanyo" => 112773 ] ] "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at0005" "detalle" => "Figure " "rol" => "short" ] ] "descripcion" => array:1 [ "en" => "Classic risk factors for vascular disease. AHT: arterial hypertension; LDL: low density lipoproteins." ] ] 1 => array:8 [ "identificador" => "fig0010" "etiqueta" => "Figure 2" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr2.jpeg" "Alto" => 1071 "Ancho" => 2014 "Tamanyo" => 162148 ] ] "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at0010" "detalle" => "Figure " "rol" => "short" ] ] "descripcion" => array:1 [ "en" => "Cholesterolaemia reduction and risk of stroke in the pre-statin era." ] ] 2 => array:8 [ "identificador" => "tbl0005" "etiqueta" => "Table 1" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at0015" "detalle" => "Table " "rol" => "short" ] ] "tabla" => array:2 [ "leyenda" => "LDL: low density lipoproteins; NS: not significant." "tablatextoimagen" => array:1 [ 0 => array:2 [ "tabla" => array:1 [ 0 => """ <table border="0" frame="\n \t\t\t\t\tvoid\n \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Study \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Baseline LDL cholesterol (mg/dL) \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">LDL cholesterol reduction (%) \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Established or transient ischaemic stroke reduction (%) \t\t\t\t\t\t\n \t\t\t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">4S<a class="elsevierStyleCrossRef" href="#bib0105">21</a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">188 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">35 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">28 (P < .01) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">CARE<a class="elsevierStyleCrossRef" href="#bib0110">22</a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">139 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">28 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">32 (P < .05) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">LIPID<a class="elsevierStyleCrossRef" href="#bib0115">23</a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">150 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">25 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">19 (P < .05) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">WOSCOPS<a class="elsevierStyleCrossRef" href="#bib0125">25</a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">192 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">26 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">11 (P = NS) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">MIRACL<a class="elsevierStyleCrossRef" href="#bib0120">24</a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">124 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">40 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">50 (P < .05) \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab2347307.png" ] ] ] ] "descripcion" => array:1 [ "en" => "Established or transient ischaemic stroke reduction in the main statin intervention studies." ] ] 3 => array:8 [ "identificador" => "tbl0010" "etiqueta" => "Table 2" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at0020" "detalle" => "Table " "rol" => "short" ] ] "tabla" => array:2 [ "leyenda" => "LDL: low density lipoproteins; RRR: relative risk reduction." "tablatextoimagen" => array:1 [ 0 => array:2 [ "tabla" => array:1 [ 0 => """ <table border="0" frame="\n \t\t\t\t\tvoid\n \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black"> \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">SPARCL<a class="elsevierStyleCrossRef" href="#bib0135">27</a> \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Sub-analysis<a class="elsevierStyleCrossRef" href="#bib0140">28</a> (LDL cholesterol reduction ≥50%) \t\t\t\t\t\t\n \t\t\t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">RRR of recurrent stroke \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">16% \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">31% \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">(30% non-fatal stroke and 33% ischaemic stroke) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">RRR of severe coronary events \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">35% \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">37% \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">RRR severe cardiovascular events \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">20% \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">48% \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Increase in haemorrhagic stroke \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">66% \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">No increase \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab2347308.png" ] ] ] ] "descripcion" => array:1 [ "en" => "SPARCL study results and subsequent sub-analysis." ] ] ] "bibliografia" => array:2 [ "titulo" => "References" "seccion" => array:1 [ 0 => array:2 [ "identificador" => "bibs0005" "bibliografiaReferencia" => array:45 [ 0 => array:3 [ "identificador" => "bib0005" "etiqueta" => "1" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Anthology of stroke epidemiology in the 20th and 21st centuries: assessing the past, the present, and envisioning the future" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:1 [ 0 => "V.L. Feigin" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1177/1747493019832996" "Revista" => array:6 [ "tituloSerie" => "Int J Stroke." "fecha" => "2019" "volumen" => "14" "paginaInicial" => "223" "paginaFinal" => "237" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/30794102" "web" => "Medline" ] ] ] ] ] ] ] ] 1 => array:3 [ "identificador" => "bib0010" "etiqueta" => "2" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Heart disease and stroke statistics—2017 update: a report from the American Heart Association" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "E.J. Benjamin" 1 => "M.J. Blaha" 2 => "S.E. Chiuve" 3 => "M. Cushman" 4 => "S.R. Das" 5 => "R. Deo" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1161/CIR.0000000000000485" "Revista" => array:6 [ "tituloSerie" => "Circulation." "fecha" => "2017" "volumen" => "135" "paginaInicial" => "e146" "paginaFinal" => "e603" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/28122885" "web" => "Medline" ] ] ] ] ] ] ] ] 2 => array:3 [ "identificador" => "bib0015" "etiqueta" => "3" "referencia" => array:1 [ 0 => array:1 [ "referenciaCompleta" => "Instituto Nacional de Estadística 2017. Defunciones según causa de muerte [accessed 9 Nov 2019]. Available from: <a target="_blank" href="https://www.ine.es/prodyser/espa_cifras/2019/files/assets/common/downloads/page0021.pdf">https://www.ine.es/prodyser/espa_cifras/2019/files/assets/common/downloads/page0021.pdf</a>." ] ] ] 3 => array:3 [ "identificador" => "bib0020" "etiqueta" => "4" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "GBD 2016 Lifetime Risk of Stroke Collaborators. Global, regional, and country-specific lifetime risks of stroke, 1990 and 2016" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "V.L. Feigin" 1 => "G. Nguyen" 2 => "K. Cercy" 3 => "C.O. Johnson" 4 => "T. Alam" 5 => "P.G. Parmar" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1056/NEJMoa1804492" "Revista" => array:6 [ "tituloSerie" => "N Engl J Med." "fecha" => "2018" "volumen" => "379" "paginaInicial" => "2429" "paginaFinal" => "2437" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/30575491" "web" => "Medline" ] ] ] ] ] ] ] ] 4 => array:3 [ "identificador" => "bib0025" "etiqueta" => "5" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Global variation in the relative burden of stroke and ischemic heart disease/clinical perspective" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:2 [ 0 => "A.S. Kim" 1 => "S.C. Johnston" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1161/CIRCULATIONAHA.111.018820" "Revista" => array:6 [ "tituloSerie" => "Circulation." "fecha" => "2011" "volumen" => "124" "paginaInicial" => "314" "paginaFinal" => "323" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/21730306" "web" => "Medline" ] ] ] ] ] ] ] ] 5 => array:3 [ "identificador" => "bib0030" "etiqueta" => "6" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Five year risk of stroke after tia or minor ischemic stroke" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "P. Amarenco" 1 => "P.C. Lavallée" 2 => "L. Monteiro Tavares" 3 => "J. Labreuche" 4 => "G.W. Albers" 5 => "H. Abboud" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1056/NEJMoa1802712" "Revista" => array:6 [ "tituloSerie" => "N Engl J Med." "fecha" => "2018" "volumen" => "378" "paginaInicial" => "2182" "paginaFinal" => "2190" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/29766771" "web" => "Medline" ] ] ] ] ] ] ] ] 6 => array:3 [ "identificador" => "bib0035" "etiqueta" => "7" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Guidelines for the prevention of stroke in patients with stroke and transient ischemic attack: a guideline for healthcare professionals from the American Heart Association/American Stroke Association" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "W.N. Kernan" 1 => "B. Ovbiagele" 2 => "H.R. Black" 3 => "D.M. Bravata" 4 => "M.I. Chimowitz" 5 => "M.D. Ezekowitz" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1161/STR.0000000000000024" "Revista" => array:6 [ "tituloSerie" => "Stroke." "fecha" => "2014" "volumen" => "45" "paginaInicial" => "2160" "paginaFinal" => "2236" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/24788967" "web" => "Medline" ] ] ] ] ] ] ] ] 7 => array:3 [ "identificador" => "bib0040" "etiqueta" => "8" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Vascular effects of statins in stroke" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:2 [ 0 => "N. Delanty" 1 => "C.J. Vaughan" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1161/01.str.28.11.2315" "Revista" => array:6 [ "tituloSerie" => "Stroke." "fecha" => "1997" "volumen" => "28" "paginaInicial" => "2315" "paginaFinal" => "2320" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/9368582" "web" => "Medline" ] ] ] ] ] ] ] ] 8 => array:3 [ "identificador" => "bib0045" "etiqueta" => "9" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Estatinas y enfermedad cerebrovascular: nuevas perspectivas en la prevención del ictus" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:4 [ 0 => "L. Castilla-Guerra" 1 => "M.C. Fernández-Moreno" 2 => "J.M. López-Chozas" 3 => "M.D. Jiménez-Hernández" ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:5 [ "tituloSerie" => "Rev Neurol." "fecha" => "2007" "volumen" => "44" "paginaInicial" => "95" "paginaFinal" => "100" ] ] ] ] ] ] 9 => array:3 [ "identificador" => "bib0050" "etiqueta" => "10" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Lipid management in the prevention of stroke: review and updated meta-analysis of statins for stroke prevention" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:2 [ 0 => "P. Amarenco" 1 => "J. Labreuche" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1016/S1474-4422(09)70058-4" "Revista" => array:6 [ "tituloSerie" => "Lancet Neurol." "fecha" => "2009" "volumen" => "8" "paginaInicial" => "453" "paginaFinal" => "463" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/19375663" "web" => "Medline" ] ] ] ] ] ] ] ] 10 => array:3 [ "identificador" => "bib0055" "etiqueta" => "11" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Heart disease and stroke statistics—2016 update: a report from the American Heart Association" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "D. Mozaffarian" 1 => "E.J. Benjamin" 2 => "A.S. Go" 3 => "D.K. Arnett" 4 => "M.J. Blaha" 5 => "M. Cushman" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1161/CIR.0000000000000350" "Revista" => array:6 [ "tituloSerie" => "Circulation." "fecha" => "2016" "volumen" => "133" "paginaInicial" => "e38" "paginaFinal" => "360" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/26673558" "web" => "Medline" ] ] ] ] ] ] ] ] 11 => array:3 [ "identificador" => "bib0060" "etiqueta" => "12" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Serum cholesterol levels and six-year mortality from stroke in 350,977 men screened for the Multiple Risk Factor Intervention Trial" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:5 [ 0 => "H. Iso" 1 => "D.R. Jacobs Jr" 2 => "D. Wentworth" 3 => "J.D. Neaton" 4 => "J.D. Cohen" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1056/NEJM198904063201405" "Revista" => array:6 [ "tituloSerie" => "N Engl J Med." "fecha" => "1989" "volumen" => "320" "paginaInicial" => "904" "paginaFinal" => "910" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/2619783" "web" => "Medline" ] ] ] ] ] ] ] ] 12 => array:3 [ "identificador" => "bib0065" "etiqueta" => "13" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Cholesterol, diastolic blood pressure, and stroke: 13 000 strokes in 450 000 people in 45 prospective cohorts" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:1 [ 0 => "Prospective Studies Collaboration" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1016/s0140-6736(95)91487-0" "Revista" => array:6 [ "tituloSerie" => "Lancet." "fecha" => "1995" "volumen" => "346" "paginaInicial" => "647" "paginaFinal" => "653" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/7651043" "web" => "Medline" ] ] ] ] ] ] ] ] 13 => array:3 [ "identificador" => "bib0070" "etiqueta" => "14" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Cholesterol reduction and the risk for stroke in men" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:5 [ 0 => "D. Atkins" 1 => "B.M. Psaty" 2 => "T.D. Koepsell" 3 => "W.T. Longstreth" 4 => "E.B. Larson" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.7326/0003-4819-119-2-199307150-00008" "Revista" => array:6 [ "tituloSerie" => "Ann Intern Med." "fecha" => "1993" "volumen" => "119" "paginaInicial" => "136" "paginaFinal" => "145" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/8305001" "web" => "Medline" ] ] ] ] ] ] ] ] 14 => array:3 [ "identificador" => "bib0075" "etiqueta" => "15" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "The origin of the statins. 2004" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:1 [ 0 => "A. Endo" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1016/j.atherosclerosissup.2004.08.033" "Revista" => array:6 [ "tituloSerie" => "Atheroscler Suppl." "fecha" => "2004" "volumen" => "5" "paginaInicial" => "125" "paginaFinal" => "130" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/15531285" "web" => "Medline" ] ] ] ] ] ] ] ] 15 => array:3 [ "identificador" => "bib0080" "etiqueta" => "16" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Cholesterol Treatment Trialists’ (CTT) Collaborators. Efficacy and safety of cholesterol-lowering treatment: prospective meta-analysis of data from 90,056 participants in 14 randomised trials of statins" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "C. Baigent" 1 => "A. Keech" 2 => "P.M. Kearney" 3 => "L. Blackwell" 4 => "G. Buck" 5 => "C. Pollicino" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1016/S0140-6736(05)67394-1" "Revista" => array:6 [ "tituloSerie" => "Lancet." "fecha" => "2005" "volumen" => "366" "paginaInicial" => "1267" "paginaFinal" => "1278" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/16214597" "web" => "Medline" ] ] ] ] ] ] ] ] 16 => array:3 [ "identificador" => "bib0085" "etiqueta" => "17" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Efficacy and safety of more intensive lowering of LDL cholesterol: a meta-analysis of data from 170,000 participants in 26 randomised trials" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "Cholesterol Treatment Trialists’ (CTT) Collaboration" 1 => "C. Baigent" 2 => "L. Blackwell" 3 => "J. Emberson" 4 => "L.E. Holland" 5 => "C. Reith" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1016/S0140-6736(10)61350-5" "Revista" => array:6 [ "tituloSerie" => "Lancet." "fecha" => "2010" "volumen" => "376" "paginaInicial" => "1670" "paginaFinal" => "1681" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/21067804" "web" => "Medline" ] ] ] ] ] ] ] ] 17 => array:3 [ "identificador" => "bib0090" "etiqueta" => "18" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Cholesterol Treatment Trialists’ (CTT) Collaborators. The effects of lowering LDL cholesterol with statin therapy in people at low risk of vascular disease: meta-analysis of individual data from 27 randomised trials" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "B. Mihaylova" 1 => "J. Emberson" 2 => "L. Blackwell" 3 => "A. Keech" 4 => "J. Simes" 5 => "E.H. Barnes" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1016/S0140-6736(12)60367-5" "Revista" => array:6 [ "tituloSerie" => "Lancet." "fecha" => "2012" "volumen" => "380" "paginaInicial" => "581" "paginaFinal" => "590" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/22607822" "web" => "Medline" ] ] ] ] ] ] ] ] 18 => array:3 [ "identificador" => "bib0095" "etiqueta" => "19" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Efficacy and safety of statin therapy in older people: a meta-analysis of individual participant data from 28 randomised controlled trials" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:1 [ 0 => "Cholesterol Treatment Trialists’ Collaboration" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1016/S0140-6736(18)31942-1" "Revista" => array:6 [ "tituloSerie" => "Lancet." "fecha" => "2019" "volumen" => "393" "paginaInicial" => "407" "paginaFinal" => "445" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/30712900" "web" => "Medline" ] ] ] ] ] ] ] ] 19 => array:3 [ "identificador" => "bib0100" "etiqueta" => "20" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Statins in stroke prevention: present and future" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:3 [ 0 => "L. Castilla-Guerra" 1 => "M. Fernandez-Moreno" 2 => "M.A. Colmenero-Camacho" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.2174/1381612822666160510125229" "Revista" => array:6 [ "tituloSerie" => "Curr Pharm Des." "fecha" => "2016" "volumen" => "22" "paginaInicial" => "4638" "paginaFinal" => "4644" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/27160755" "web" => "Medline" ] ] ] ] ] ] ] ] 20 => array:3 [ "identificador" => "bib0105" "etiqueta" => "21" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Randomised trial of cholesterol lowering in 4,444 patients with coronary heart disease: the Scandinavian Simvastatin Survival Study (4S)" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:1 [ 0 => "Scandinavian Simvastatin Survival Study Group" ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:6 [ "tituloSerie" => "Lancet." "fecha" => "1994" "volumen" => "344" "paginaInicial" => "1383" "paginaFinal" => "1389" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/7968073" "web" => "Medline" ] ] ] ] ] ] ] ] 21 => array:3 [ "identificador" => "bib0110" "etiqueta" => "22" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Cholesterol and Recurrent Events Trial Investigators. The effect of pravastatin on coronary events after myocardial infarction in patients with average cholesterol levels" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "F.M. Sacks" 1 => "M.A. Pfeffer" 2 => "L.A. Moye" 3 => "J.L. Rouleau" 4 => "J.D. Rutherford" 5 => "T.G. Cole" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1056/NEJM199610033351401" "Revista" => array:6 [ "tituloSerie" => "N Engl J Med." "fecha" => "1996" "volumen" => "335" "paginaInicial" => "1001" "paginaFinal" => "1009" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/8801446" "web" => "Medline" ] ] ] ] ] ] ] ] 22 => array:3 [ "identificador" => "bib0115" "etiqueta" => "23" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Prevention of cardiovascular events and death with pravastatin in patients with coronary heart disease and a broad range of initial cholesterol levels" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:1 [ 0 => "The Long-Term Intervention with Pravastatin in Ischemic Disease (LIPID) Study Group" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1056/NEJM199811053391902" "Revista" => array:6 [ "tituloSerie" => "N Engl J Med." "fecha" => "1998" "volumen" => "339" "paginaInicial" => "1349" "paginaFinal" => "1357" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/9841303" "web" => "Medline" ] ] ] ] ] ] ] ] 23 => array:3 [ "identificador" => "bib0120" "etiqueta" => "24" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Myocardial Ischemia Reduction with Aggressive Cholesterol Lowering (MIRACL) Study Investigators. Effects of atorvastatin on early recurrent ischemic events in acute coronary syndromes: the MIRACL study: a randomized controlled trial" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "G.G. Schwartz" 1 => "A.G. Olsson" 2 => "M.D. Ezekowitz" 3 => "P. Ganz" 4 => "M.F. Oliver" 5 => "D. Waters" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1001/jama.285.13.1711" "Revista" => array:6 [ "tituloSerie" => "JAMA." "fecha" => "2001" "volumen" => "285" "paginaInicial" => "1711" "paginaFinal" => "1718" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/11277825" "web" => "Medline" ] ] ] ] ] ] ] ] 24 => array:3 [ "identificador" => "bib0125" "etiqueta" => "25" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "for the West of Scotland Coronary Prevention Study Group. Prevention of coronary heart disease with pravastatin in men with hypercholesterolemia" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "J. Shepherd" 1 => "S.M. Cobbe" 2 => "I. Ford" 3 => "C.G. Isles" 4 => "A.R. Lorimer" 5 => "P.W. MacFarlane" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1056/NEJM199511163332001" "Revista" => array:6 [ "tituloSerie" => "N Engl J Med." "fecha" => "1995" "volumen" => "333" "paginaInicial" => "1301" "paginaFinal" => "1307" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/7566020" "web" => "Medline" ] ] ] ] ] ] ] ] 25 => array:3 [ "identificador" => "bib0130" "etiqueta" => "26" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "MRC/BHF Heart Protection Study of cholesterol lowering with simvastatin in 20,536 high-risk individuals: a randomized placebo-controlled trial" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:1 [ 0 => "Heart Protection Collaborative Study Group" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1016/S0140-6736(02)09327-3" "Revista" => array:6 [ "tituloSerie" => "Lancet." "fecha" => "2002" "volumen" => "360" "paginaInicial" => "7" "paginaFinal" => "22" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/12114036" "web" => "Medline" ] ] ] ] ] ] ] ] 26 => array:3 [ "identificador" => "bib0135" "etiqueta" => "27" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "High-dose atorvastatin after stroke or transient ischemic attack" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:1 [ 0 => "The Stroke Prevention by Aggressive Reduction in Cholesterol Levels (SPARCL) Investigators" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1056/NEJMoa061894" "Revista" => array:6 [ "tituloSerie" => "N Engl J Med." "fecha" => "2006" "volumen" => "355" "paginaInicial" => "549" "paginaFinal" => "559" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/16899775" "web" => "Medline" ] ] ] ] ] ] ] ] 27 => array:3 [ "identificador" => "bib0140" "etiqueta" => "28" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Effects of intense low-density lipoprotein cholesterol reduction in patients with stroke or transient ischemic attack: the Stroke Prevention by Aggressive Reduction in Cholesterol Levels (SPARCL) trial" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "P. Amarenco" 1 => "L.B. Goldstein" 2 => "M. Szarek" 3 => "H. Sillesen" 4 => "A.E. Rudolph" 5 => "A. Callahan III" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1161/STROKEAHA.107.493106" "Revista" => array:6 [ "tituloSerie" => "Stroke." "fecha" => "2007" "volumen" => "38" "paginaInicial" => "3198" "paginaFinal" => "3204" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/17962589" "web" => "Medline" ] ] ] ] ] ] ] ] 28 => array:3 [ "identificador" => "bib0145" "etiqueta" => "29" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Hemorrhagic stroke in the stroke prevention by aggressive reduction in cholesterol levels study" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "L.B. Goldstein" 1 => "P. Amarenco" 2 => "M. Szarek" 3 => "A. Callahan 3rd" 4 => "M. Hennerici" 5 => "H. Sillesen" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1212/01.wnl.0000296277.63350.77" "Revista" => array:6 [ "tituloSerie" => "Neurology." "fecha" => "2008" "volumen" => "70" "paginaInicial" => "2364" "paginaFinal" => "2370" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/18077795" "web" => "Medline" ] ] ] ] ] ] ] ] 29 => array:3 [ "identificador" => "bib0150" "etiqueta" => "30" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Statins and the risk of intracerebral hemorrhage in patients with previous ischemic stroke or transient ischemic attack" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:4 [ 0 => "D. Gaist" 1 => "L.B. Goldstein" 2 => "L. Cea Soriano" 3 => "L.A. García Rodríguez" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1161/STROKEAHA.117.019141" "Revista" => array:6 [ "tituloSerie" => "Stroke." "fecha" => "2017" "volumen" => "48" "paginaInicial" => "3245" "paginaFinal" => "3251" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/29070714" "web" => "Medline" ] ] ] ] ] ] ] ] 30 => array:3 [ "identificador" => "bib0155" "etiqueta" => "31" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "China Kadoorie Biobank Collaborative Group, International Steering Committee, International Co-ordinating Centre Oxford, National Co-ordinating Centre, Beijing, Regional Co-ordinating Centres. Causal associations of blood lipids with risk of ischemic stroke and intracerebral hemorrhage in Chinese adults" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "L. Sun" 1 => "R. Clarke" 2 => "D. Bennett" 3 => "Y. Guo" 4 => "R.G. Walters" 5 => "M. Hill" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1038/s41591-019-0366-x" "Revista" => array:7 [ "tituloSerie" => "Nat Med." "fecha" => "2019" "volumen" => "25" "paginaInicial" => "569" "paginaFinal" => "574" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/30858617" "web" => "Medline" ] ] "itemHostRev" => array:3 [ "pii" => "S0272638615009403" "estado" => "S300" "issn" => "02726386" ] ] ] ] ] ] ] 31 => array:3 [ "identificador" => "bib0160" "etiqueta" => "32" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "ESC Scientific Document Group. 2019 ESC/EAS Guidelines for the management of dyslipidaemias: lipid modification to reduce cardiovascular risk" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "F. Mach" 1 => "C. Baigent" 2 => "A.L. Catapano" 3 => "K.C. Koskinas" 4 => "M. Casula" 5 => "L. Badimon" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1093/eurheartj/ehz455" "Revista" => array:6 [ "tituloSerie" => "Eur Heart J." "fecha" => "2020" "volumen" => "41" "paginaInicial" => "111" "paginaFinal" => "8819" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/31504418" "web" => "Medline" ] ] ] ] ] ] ] ] 32 => array:3 [ "identificador" => "bib0165" "etiqueta" => "33" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "IMPROVE-IT Investigators. Ezetimibe added to statin therapy after acute coronary syndromes" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "C.P. Cannon" 1 => "M.A. Blazing" 2 => "R.P. Giugliano" 3 => "A. McCagg" 4 => "J.A. White" 5 => "P. Theroux" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1056/NEJMoa1410489" "Revista" => array:6 [ "tituloSerie" => "N Engl J Med." "fecha" => "2015" "volumen" => "372" "paginaInicial" => "2387" "paginaFinal" => "2397" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/26039521" "web" => "Medline" ] ] ] ] ] ] ] ] 33 => array:3 [ "identificador" => "bib0170" "etiqueta" => "34" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Prevention of stroke with the addition of ezetimibe to statin therapy in patients with acute coronary syndrome in IMPROVE-IT (Improved Reduction of Outcomes: Vytorin Efficacy International Trial)" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "E.A. Bohula" 1 => "S.D. Wiviott" 2 => "R.P. Giugliano" 3 => "M.A. Blazing" 4 => "J.-G.-G. Park" 5 => "S.A. Murphy" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1161/CIRCULATIONAHA.117.029095" "Revista" => array:6 [ "tituloSerie" => "Circulation." "fecha" => "2017" "volumen" => "136" "paginaInicial" => "2440" "paginaFinal" => "2450" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/28972004" "web" => "Medline" ] ] ] ] ] ] ] ] 34 => array:3 [ "identificador" => "bib0175" "etiqueta" => "35" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Evolocumab and clinical outcomes in patients with cardiovascular disease" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "M.S. Sabatine" 1 => "R.P. Giugliano" 2 => "A.C. Keech" 3 => "N. Honarpour" 4 => "S.D. Wiviott" 5 => "S.A. Murphy" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1056/NEJMoa1615664" "Revista" => array:6 [ "tituloSerie" => "N Engl J Med." "fecha" => "2017" "volumen" => "376" "paginaInicial" => "1713" "paginaFinal" => "1722" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/28304224" "web" => "Medline" ] ] ] ] ] ] ] ] 35 => array:3 [ "identificador" => "bib0180" "etiqueta" => "36" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "ODYSSEY OUTCOMES Committees and Investigators. Alirocumab and cardiovascular outcomes after acute coronary syndrome" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "G.G. Schwartz" 1 => "P.G. Steg" 2 => "M. Szarek" 3 => "D.L. Bhatt" 4 => "V.A. Bittner" 5 => "R. Diaz" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1056/NEJMoa1801174" "Revista" => array:6 [ "tituloSerie" => "N Engl J Med." "fecha" => "2018" "volumen" => "379" "paginaInicial" => "2097" "paginaFinal" => "2107" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/30403574" "web" => "Medline" ] ] ] ] ] ] ] ] 36 => array:3 [ "identificador" => "bib0185" "etiqueta" => "37" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "IMPROVE-IT clinical implications. Should the "high-intensity cholesterol-lowering therapy" strategy replace the "high-intensity statin therapy"?" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:3 [ 0 => "L. Masana" 1 => "J. Pedro-Botet" 2 => "F. Civeira" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1016/j.atherosclerosis.2015.03.002" "Revista" => array:6 [ "tituloSerie" => "Atherosclerosis." "fecha" => "2015" "volumen" => "240" "paginaInicial" => "161" "paginaFinal" => "162" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/25795557" "web" => "Medline" ] ] ] ] ] ] ] ] 37 => array:3 [ "identificador" => "bib0190" "etiqueta" => "38" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Efficacy and safety of alirocumab and evolocumab: a systematic review and meta-analysis of randomized controlled trials" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "P. Guedeney" 1 => "G. Giustino" 2 => "S. Sorrentino" 3 => "B.E. Claessen" 4 => "A. Camaj" 5 => "D.N. Kalkman" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1093/eurheartj/ehz430" "Revista" => array:3 [ "tituloSerie" => "Eur Heart J." "fecha" => "2019" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/27141094" "web" => "Medline" ] ] ] ] ] ] ] ] 38 => array:3 [ "identificador" => "bib0195" "etiqueta" => "39" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "EUROASPIRE Investigators. Lifestyle and impact on cardiovascular risk factor control in coronary patients across 27 countries: results from the European Society of Cardiology ESC-EORP EUROASPIRE V registry" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "K. Kotseva" 1 => "G. De Backer" 2 => "D. De Bacquer" 3 => "L. Ryden" 4 => "A. Hoes" 5 => "D. Grobbee" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1177/2047487318825350" "Revista" => array:6 [ "tituloSerie" => "Eur J Prev Cardiol." "fecha" => "2019" "volumen" => "26" "paginaInicial" => "824" "paginaFinal" => "835" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/30739508" "web" => "Medline" ] ] ] ] ] ] ] ] 39 => array:3 [ "identificador" => "bib0200" "etiqueta" => "40" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Intensity of lipid lowering with statin therapy in patients with cerebrovascular disease versus coronary artery disease: insights from the PALM registry" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "Y. Xian" 1 => "A.M. Navar" 2 => "S. Li" 3 => "Z. Li" 4 => "J. Robinson" 5 => "S.S. Virani" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1161/JAHA.119.013229" "Revista" => array:6 [ "tituloSerie" => "J Am Heart Assoc." "fecha" => "2019" "volumen" => "8" "paginaInicial" => "e013229" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/31554462" "web" => "Medline" ] ] "itemHostRev" => array:3 [ "pii" => "S002252231832021X" "estado" => "S300" "issn" => "00225223" ] ] ] ] ] ] ] 40 => array:3 [ "identificador" => "bib0205" "etiqueta" => "41" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Metabolomics and lipidomics of ischemic stroke" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:1 [ 0 => "A. Au" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1016/bs.acc.2018.02.002" "Revista" => array:6 [ "tituloSerie" => "Adv Clin Chem." "fecha" => "2018" "volumen" => "85" "paginaInicial" => "31" "paginaFinal" => "69" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/29655461" "web" => "Medline" ] ] ] ] ] ] ] ] 41 => array:3 [ "identificador" => "bib0210" "etiqueta" => "42" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Targeted metabolomics" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:4 [ 0 => "L.D. Roberts" 1 => "A.L. Souza" 2 => "R.E. Gerszten" 3 => "C.B. Clish" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1002/0471142727.mb1030s99" "Revista" => array:6 [ "tituloSerie" => "Curr Protoc Mol Biol." "fecha" => "2012" "volumen" => "Chapter 30:Unit 30.2" "paginaInicial" => "1" "paginaFinal" => "24" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/22870856" "web" => "Medline" ] ] ] ] ] ] ] ] 42 => array:3 [ "identificador" => "bib0215" "etiqueta" => "43" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "A new rational approach to reach LDL-cholesterol concentration objectives after an acute coronary syndrome" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "N. Ribas" 1 => "L. Recasens" 2 => "S. Pérez" 3 => "V. Bazán" 4 => "J. Pedro-Botet" 5 => "S. Ruiz" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1016/j.arteri.2018.11.004" "Revista" => array:6 [ "tituloSerie" => "Clin Investig Arterioscler." "fecha" => "2019" "volumen" => "31" "paginaInicial" => "93" "paginaFinal" => "100" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/30711338" "web" => "Medline" ] ] ] ] ] ] ] ] 43 => array:3 [ "identificador" => "bib0220" "etiqueta" => "44" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Update of therapeutic planning tables oriented towards obtaining therapeutic objectives" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:2 [ 0 => "L. Masana" 1 => "N. Plana" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1016/j.arteri.2019.04.005" "Revista" => array:6 [ "tituloSerie" => "Clin Investig Arterioscler." 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Review article

Lipid-lowering treatment in secondary prevention of ischaemic cerebrovascular disease

Tratamiento hipolipemiante en la prevención secundaria de la enfermedad cerebrovascular isquémica

Elisenda Climenta,b, David Benaigesa,b,c, Juan Pedro-Boteta,b,c,

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86620@parcdesalutmar.cat

Corresponding author.

a Servicio Endocrinología y Nutrición, Hospital del Mar, Barcelona, Spain

b Departament de Medicina, Universitat Autònoma de Barcelona, Campus Universitari Mar, Barcelona, Spain

c Institut Hospital del Mar d’Investigacions Mèdiques (IMIM), Barcelona, Spain

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    "textoCompleto" => "<span class="elsevierStyleSections"><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0025">Introduction</span><p id="par0005" class="elsevierStylePara elsevierViewall">Data from the World Health Organisation 2016<a class="elsevierStyleCrossRefs" href="#bib0005"><span class="elsevierStyleSup">1&#44;2</span></a> confirm that stroke is the second cause of death after myocardial infarction&#46; It is worth noting that&#44; according to the National Institute of Statistics &#40;INE&#41; 2017&#44; it is already the leading of cause of death in women in Spain&#46;<a class="elsevierStyleCrossRef" href="#bib0015"><span class="elsevierStyleSup">3</span></a> The Global Burden of Disease Study 2016<a class="elsevierStyleCrossRef" href="#bib0020"><span class="elsevierStyleSup">4</span></a> estimated the incidence of stroke and risk of death from all causes excluding stroke to calculate the lifetime risk of a first ischaemic or haemorrhagic stroke in adults aged 25 or more&#46; The risk of ischaemic stroke was 18&#46;3 percent and the risk of haemorrhagic stroke was 8&#46;2 percent&#44; with significant geographical variation&#46;</p><p id="par0010" class="elsevierStylePara elsevierViewall">Patients with ischaemic stroke have a high risk of subsequent vascular events&#44; including recurrent stroke&#44; myocardial infarction and death from vascular causes&#46;<a class="elsevierStyleCrossRef" href="#bib0025"><span class="elsevierStyleSup">5</span></a> In this regard&#44; patients with a history of transient ischaemic attack or minor stroke were described to present a sustained risk of cardiovascular events during a 5-year follow-up period&#44; half of which occurred between the second and the fifth year&#46;<a class="elsevierStyleCrossRef" href="#bib0030"><span class="elsevierStyleSup">6</span></a> In fact&#44; the risk for the primary objective comprising stroke&#44; acute coronary syndrome or cardiovascular death was 12&#46;9&#37; and for isolated stroke it was 9&#46;5&#37;&#44; both at 5 years&#44; approximately double the rates per year of 6&#46;2&#37; and 5&#46;1&#37;&#44; respectively&#46;</p><p id="par0015" class="elsevierStylePara elsevierViewall">Although the vascular risk factors are the same for any site of atherosclerotic disease&#44; the impact of each is different according to the arterial territory affected&#46; Traditionally&#44; and unlike coronary heart disease&#44; the relationship between plasma cholesterol and stroke has been weak or non-existent&#44; with high blood pressure being the main risk factor for stroke<a class="elsevierStyleCrossRef" href="#bib0035"><span class="elsevierStyleSup">7</span></a> &#40;<a class="elsevierStyleCrossRef" href="#fig0005">Fig&#46; 1</a>&#41;&#46; However&#44; more recent clinical evidence has shown an increased risk of cerebrovascular disease with high levels of cholesterol linked to low density lipoproteins &#40;LDL&#41;&#44; as well as a decrease in this risk with lipid lowering treatment&#46;<a class="elsevierStyleCrossRefs" href="#bib0040"><span class="elsevierStyleSup">8&#44;9</span></a> Along these lines&#44; the meta-analysis by Amarenco and Labreuche<a class="elsevierStyleCrossRef" href="#bib0050"><span class="elsevierStyleSup">10</span></a> described that each mmol&#47;L decrease in LDL cholesterol was accompanied by a reduction in the relative risk &#40;RRR&#41; of stroke of 21&#46;1&#37; &#40;95&#37; confidence interval &#91;CI&#93;&#58; 6&#46;3&#8211;33&#46;5&#59; <span class="elsevierStyleItalic">P</span>&#8239;&#61;&#8239;&#46;009&#41;&#46;</p><elsevierMultimedia ident="fig0005"></elsevierMultimedia><p id="par0020" class="elsevierStylePara elsevierViewall">Together with mortality data&#44; we should not forget that cerebrovascular disease is the leading cause of acquired disability&#44;<a class="elsevierStyleCrossRef" href="#bib0055"><span class="elsevierStyleSup">11</span></a> and therefore has substantial socioeconomic and health repercussions&#46; However&#44; it is important to note that up to at least 80&#37; of recurrent cerebrovascular events could be prevented with appropriate therapeutic measures&#46; For this reason&#44; we considered it appropriate to conduct a narrative review of the impact of lipid-lowering therapy on secondary prevention of ischaemic stroke&#46;</p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0030">Hypercholesterolaemia&#44; cerebrovascular disease and mortality</span><p id="par0025" class="elsevierStylePara elsevierViewall">One of the first epidemiological studies to analyse the relationship between cholesterolaemia and cardiovascular mortality was published in 1989 by Iso et al&#46;<a class="elsevierStyleCrossRef" href="#bib0060"><span class="elsevierStyleSup">12</span></a> in the context of the Multiple Risk Factor Intervention Trial &#40;MRFIT&#41; involving 350&#44;977 men aged 35&#8211;57 years&#44; with no previous history of coronary heart disease&#46; The risk of death at 6 years of follow-up due to intracranial haemorrhage was 3 times higher in men with total cholesterol levels &#60;160&#8239;mg&#47;dL than in those with higher levels &#40;<span class="elsevierStyleItalic">P</span>&#8239;&#61;&#8239;&#46;05&#41;&#46; The inverse relationship between cholesterol levels and risk of death from haemorrhagic stroke was confined to patients with diastolic blood pressure &#8805;90&#8239;mmHg&#46; As for non-haemorrhagic stroke&#44; a positive and significant association was observed between cholesterol levels and risk of death from stroke&#46;</p><p id="par0030" class="elsevierStylePara elsevierViewall">Along the same lines&#44; the findings of the Prospective Studies Collaboration &#40;PSC&#41; of 1995<a class="elsevierStyleCrossRef" href="#bib0065"><span class="elsevierStyleSup">13</span></a> are worth noting&#44; which included 45 prospective cohorts comprising 450&#44;000 individuals with 13&#44;387 recorded strokes and 16 years of follow-up&#46; After adjusting for education level&#44; age&#44; sex&#44; diastolic blood pressure&#44; presence of coronary heart disease and ethnicity&#44; no association between cholesterolaemia and stroke risk was documented&#46; However&#44; it should be noted that in this study the results were not categorised according to different types of stroke &#40;ischaemic or haemorrhagic&#41;&#44; unlike the MRFIT study&#46;<a class="elsevierStyleCrossRef" href="#bib0060"><span class="elsevierStyleSup">12</span></a></p></span><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0035">Lipid-lowering treatment and reduction of risk of cerebrovascular disease</span><p id="par0035" class="elsevierStylePara elsevierViewall">In contrast to the findings of epidemiological studies&#44; the clinical evidence for the favourable effect of LDL cholesterol reduction in ischaemic cerebrovascular disease is more conclusive&#46; The role of lipid lowering therapy in the secondary prevention of ischaemic stroke before and after the statin era will be described below&#46;</p><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0040">Initial studies of the &#8220;pre-statin&#8221; era</span><p id="par0040" class="elsevierStylePara elsevierViewall">In 1993 Atkins et al&#46;<a class="elsevierStyleCrossRef" href="#bib0070"><span class="elsevierStyleSup">14</span></a> conducted one of the first meta-analyses to evaluate the effect of lipid lowering treatment prior to the introduction of statins&#44; including dietary hygiene measures&#44; cholestyramine&#44; niacin or clofibrate&#44; among others&#44; on the risk of cerebrovascular disease &#40;<a class="elsevierStyleCrossRef" href="#fig0010">Fig&#46; 2</a>&#41;&#46; With reference to fatal stroke&#44; the overall odds ratio &#40;OR&#41; associated with therapeutic strategies to reduce plasma cholesterol levels was 1&#46;32 &#40;95&#37; CI &#46;94&#8211;1&#46;86&#41;&#44; and the odds ratio &#40;OR&#41; for the 10 single intervention trials was 1&#46;34 &#40;CI &#46;91&#8211;1&#46;96&#41;&#46; Among the eight studies that included non-fatal episodes&#44; the likelihood rate of non-fatal stroke for participants in the active treatment arm compared to controls was 0&#46;88 &#40;CI &#46;70&#8211;1&#46;11&#41;&#44; and the likelihood rate of total stroke was 0&#46;98 &#40;CI &#46;80&#8211;1&#46;19&#41;&#46; In the three clofibrate trials&#44; this fibrate significantly increased the risk of fatal stroke &#40;OR 2&#46;64&#44; CI 1&#46;42&#8211;4&#46;92&#41; but not non-fatal stroke &#40;OR 0&#46;87&#44; CI &#46;61&#8211;1&#46;26&#41;&#46; Finally&#44; logistic regression analysis did not reveal a significant association between the magnitude of cholesterol reduction and the risk of fatal stroke&#46; Therefore&#44; the main conclusion of this meta-analysis was that lowering cholesterol levels with hygiene-dietary measures or with lipid lowering drug treatment other than statins did not decrease cerebrovascular disease-related morbidity and mortality in middle-aged males&#46;</p><elsevierMultimedia ident="fig0010"></elsevierMultimedia></span><span id="sec0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0045">Intervention studies with statins</span><p id="par0045" class="elsevierStylePara elsevierViewall">Since the introduction of lovastatin in 1987 as the first 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase inhibitor approved for use in humans&#44;<a class="elsevierStyleCrossRef" href="#bib0075"><span class="elsevierStyleSup">15</span></a> statins have become the most widely used lipid-lowering drugs&#44; with proven efficacy in cardiovascular prevention in all age groups&#44;<a class="elsevierStyleCrossRefs" href="#bib0080"><span class="elsevierStyleSup">16&#8211;19</span></a> mainly by reducing LDL cholesterol levels&#46; In the following years&#44; different studies have assessed the role of statins&#44; and their consequent lowering of cholesterol&#44; with the risk of a cerebrovascular event&#44; showing much more promising results than those obtained in the &#34;<span class="elsevierStyleItalic">pre-statin</span>&#34; era&#46; In fact&#44; statin therapy has been considered one of the most important advances in stroke prevention since the advent of aspirin or antihypertensive treatment&#46;<a class="elsevierStyleCrossRef" href="#bib0100"><span class="elsevierStyleSup">20</span></a></p><p id="par0050" class="elsevierStylePara elsevierViewall"><a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a> shows the main studies that have assessed the possible relationship between LDL cholesterol reduction with statins and the risk of stroke or transient ischaemic attack&#46; In most secondary prevention of cardiovascular disease studies&#44; such as the Simvastatin Survival Study Group &#40;4S&#41;&#44;<a class="elsevierStyleCrossRef" href="#bib0105"><span class="elsevierStyleSup">21</span></a> Cholesterol and Recurrent Event &#40;CARE&#41;&#44;<a class="elsevierStyleCrossRef" href="#bib0110"><span class="elsevierStyleSup">22</span></a> and Long Term Intervention with Pravastatin in Ischemic Disease &#40;LIPID&#41;&#44;<a class="elsevierStyleCrossRef" href="#bib0115"><span class="elsevierStyleSup">23</span></a> a significant reduction in stroke risk in patients with ischaemic heart disease was found&#44; which reached 50&#37; in the Myocardial Ischemia Reduction with Aggressive Cholesterol Lowering &#40;MIRACL&#41; Study<a class="elsevierStyleCrossRef" href="#bib0120"><span class="elsevierStyleSup">24</span></a> in patients with recent acute coronary syndrome&#46; In contrast&#44; in the West of Scotland Coronary Prevention Study &#40;WOSCOPS&#41;&#44;<a class="elsevierStyleCrossRef" href="#bib0125"><span class="elsevierStyleSup">25</span></a> a primary prevention study of cardiovascular disease&#44; showed a non-significant 11&#37; decrease in the risk of stroke during the 5 years of follow-up&#46;</p><elsevierMultimedia ident="tbl0005"></elsevierMultimedia><p id="par0055" class="elsevierStylePara elsevierViewall">Focussing on secondary prevention of cerebrovascular disease with statins&#44; the Heart Protection Study &#40;HPS&#41;<a class="elsevierStyleCrossRef" href="#bib0130"><span class="elsevierStyleSup">26</span></a> was the first study to assess the effect of simvastatin treatment on secondary prevention of stroke in patients with previous cerebrovascular disease&#46; A total of 20&#44;536 patients at high risk of vascular events were included with a 5-year follow-up&#46; Treatment with simvastatin significantly reduced the risk of vascular events &#40;RRR of 24&#37;&#44; <span class="elsevierStyleItalic">P</span>&#8239;&#60;&#8239;&#46;00001&#41; and stroke &#40;RRR of 27&#37;&#44; <span class="elsevierStyleItalic">P</span>&#8239;&#60;&#8239;&#46;00001&#41;&#46; This same study included 3280 randomly selected stroke patients &#40;none with transient ischaemic attack&#41; and 1822 stroke patients without established coronary heart disease&#46; The RRR of serious cardiovascular events was 19&#37; in all the stroke patients&#44; which rose to 23&#37; in the stroke patients without coronary heart disease&#46; However&#44; this study did not show a reduction in the risk of stroke among the patients with recurrent stroke &#40;10&#46;4&#37; of patients in the statin group had recurrent stroke compared to 10&#46;5&#37; of the patients in the placebo group&#41;&#46; Therefore&#44; in the patients with a previous stroke&#44; statins probably reduced the incidence of coronary events&#44; but there was no evidence that statins also reduced the incidence of recurrent stroke&#46;</p></span><span id="sec0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0050">Stroke prevention by aggressive reduction of cholesterol levels &#40;SPARCL&#41;</span><p id="par0060" class="elsevierStylePara elsevierViewall">As a result of the findings of the MIRACL study&#44;<a class="elsevierStyleCrossRef" href="#bib0120"><span class="elsevierStyleSup">24</span></a> the Stroke Prevention by Aggressive Reduction in Cholesterol Levels &#40;SPARCL&#41;<a class="elsevierStyleCrossRef" href="#bib0135"><span class="elsevierStyleSup">27</span></a> study was conducted&#44; the first clinical trial designed to confirm the benefits of statin therapy in the secondary prevention of stroke&#46; We included 4731 patients &#62;18 with a history of established or transient ischaemic stroke in the previous 1&#8211;6 months and who did not have hypercholesterolaemia or coronary heart disease&#46; Most were ischaemic strokes&#44; and some were haemorrhagic&#46; The patients received either atorvastatin 80&#8239;mg&#47;day &#40;n&#8239;&#61;&#8239;2365&#41; or placebo &#40;n&#8239;&#61;&#8239;2366&#41; and were followed for almost 5 years&#46; The primary objective of the study was to assess the incidence of fatal and non-fatal stroke&#46; A 16&#37; RRR was observed in recurrent stroke&#44; a 35&#37; RRR in severe coronary events and a 20&#37; RRR in severe cardiovascular events&#46; The superiority of atorvastatin over placebo was mainly in the patients with fatal stroke&#44; who experienced a 43&#37; reduction &#40;<span class="elsevierStyleItalic">P</span>&#8239;&#61;&#8239;&#46;03&#41;&#46; It would be unfair not to mention here the 66&#37; increase in the relative risk of haemorrhagic stroke in the patients who were randomised to atorvastatin&#46;</p><p id="par0065" class="elsevierStylePara elsevierViewall">On careful analysis of the results of the SPARCL study&#44; there are certain aspects worth noting&#46; Twenty-five percent of the patients who were assigned to the placebo arm ended up receiving statin treatment at some point in the study&#46; Therefore&#44; it could be argued that the results obtained underestimate the true clinical impact of high-dose statin therapy&#44; given that atorvastatin was compared to a control group where one in four patients also received the same treatment&#46; Therefore&#44; one might ask whether the SPARCL findings underestimate the real effect of intensive statin therapy&#44; or whether they underestimate the increased risk of intracerebral haemorrhage with statin therapy&#46;</p><p id="par0070" class="elsevierStylePara elsevierViewall">In order to answer these questions&#44; and address the issue of the actual benefits and risks of statin therapy in stroke patients&#44; Amarenco et al&#46;<a class="elsevierStyleCrossRef" href="#bib0140"><span class="elsevierStyleSup">28</span></a> re-analysed the data&#44; but this time reclassified the patients not according to the assigned treatment arm&#44; but according to the level of LDL cholesterol reduction&#46; This was possible because the methodological aspects of the study included 4 serial tests per patient and year&#46; The patients were classified into 3 categories&#58; no change in their LDL cholesterol&#44; a &#60;50&#37; decrease or a &#8805;50&#37; decrease in LDL cholesterol&#44; hypothesising that the latter group would indicate the true biological effect of intense LDL cholesterol reduction in recent stroke patients&#46; As expected&#44; most patients with a dramatic decrease in LDL cholesterol &#40;&#8805;50&#37;&#41; were in the atorvastatin group&#44; although not all participants in the atorvastatin group had such a marked therapeutic response&#46; Approximately one-third of them had a &#60;50&#37; decrease in LDL cholesterol&#44; and the study confirms that there were some people in the placebo group who took statins when an intense reduction in LDL cholesterol was noted&#46; Comparing the patients with a reduction in LDL cholesterol levels &#8805;50&#37;&#44; it was found that instead of an RRR of 16&#37; for recurrent stroke&#44; an RRR of 31&#37; was achieved &#40;for any subtype&#41;&#46; There were also reductions in the risk of serious coronary events &#40;RRR of 37&#37;&#41;&#44; and an RRR of 48&#37; in the need for any revascularisation procedure&#46; The main results of the SPARCL<a class="elsevierStyleCrossRef" href="#bib0135"><span class="elsevierStyleSup">27</span></a> study as well as the subsequent subanalysis<a class="elsevierStyleCrossRef" href="#bib0140"><span class="elsevierStyleSup">28</span></a> stratified by reduced LDL cholesterol levels are detailed in <a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a>&#46;</p><elsevierMultimedia ident="tbl0010"></elsevierMultimedia></span><span id="sec0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0055">Risk of intracerebral haemorrhage associated with statin treatment</span><p id="par0075" class="elsevierStylePara elsevierViewall">The second question in analysing the results of the SPARCL<a class="elsevierStyleCrossRef" href="#bib0135"><span class="elsevierStyleSup">27</span></a> study was whether the final results underestimated the increased risk of intracerebral haemorrhage from statins&#46; In this regard&#44; it should be noted that in the SPARCL<a class="elsevierStyleCrossRef" href="#bib0140"><span class="elsevierStyleSup">28</span></a> sub-analysis described in the above section&#44; no increase in haemorrhagic stroke was observed in the group with reduced cholesterol levels LDL&#8239;&#62;&#8239;50&#37;&#44; despite the fact that the atorvastatin group in the original analysis<a class="elsevierStyleCrossRef" href="#bib0135"><span class="elsevierStyleSup">27</span></a> presented an increased risk of haemorrhagic stroke&#46;</p><p id="par0080" class="elsevierStylePara elsevierViewall">These results are consistent with those subsequently described by Goldstein et al&#46;<a class="elsevierStyleCrossRef" href="#bib0145"><span class="elsevierStyleSup">29</span></a> in 2008&#44; where risk factors for intracerebral haemorrhage were analysed in the SPARCL study&#46; In this case&#44; male sex &#40;hazard ratio &#91;HR&#93;&#58; 2&#46;21&#44; 95&#37; CI&#58; 1&#46;20&#8211;4&#46;09&#59; <span class="elsevierStyleItalic">P</span>&#8239;&#61;&#8239;&#46;01&#41;&#44; age &#40;HR&#58; 1&#46;40&#44; 95&#37; CI&#58; 1&#46;08&#8211;1&#46;81&#59; <span class="elsevierStyleItalic">P</span>&#8239;&#61;&#8239;&#46;01&#41; and intracerebral haemorrhage as the form of presentation &#40;HR&#58; 8&#46;38&#44; 95&#37; CI&#58; 3&#46;78&#8211;18&#46;56&#59; <span class="elsevierStyleItalic">P</span>&#8239;&#60;&#8239;&#46;001&#41;&#44; in addition to poor blood pressure control&#44; were the factors associated with the risk of a haemorrhagic event&#46; Notably&#44; no quartile of LDL cholesterol was associated with an increased risk of intracerebral haemorrhage&#46; More recently&#44; Gaist et al&#46;<a class="elsevierStyleCrossRef" href="#bib0150"><span class="elsevierStyleSup">30</span></a> confirmed that statin use was not associated with an increased risk of intracranial haemorrhage in patients with a history of established or transient ischaemic stroke&#46;</p><p id="par0085" class="elsevierStylePara elsevierViewall">In a recent Mendelian randomisation study&#44;<a class="elsevierStyleCrossRef" href="#bib0155"><span class="elsevierStyleSup">31</span></a> each mmol&#47;L of genetically engineered LDL cholesterol was associated with RRRs of 0&#46;75 &#40;95&#37; CI &#46;60&#8211;&#46;95&#41; for ischaemic stroke and 1&#46;13 &#40;95&#37; CI &#46;91&#8211;1&#46;40&#41; for intracranial haemorrhage&#46; In the same study&#44; analysis of pharmacological reduction in LDL cholesterol confirmed that each mmol&#47;L decrease was accompanied by an RRR of 0&#46;80 &#40;95&#37; CI&#58; 0&#46;76&#8722;0&#46;84&#41; for ischaemic stroke and 1&#46;17 &#40;95&#37; CI&#58; 1&#46;03&#8211;1&#46;32&#41; for intracerebral haemorrhage&#46;</p><p id="par0090" class="elsevierStylePara elsevierViewall">In short&#44; the available evidence has not been able to demonstrate a real increased risk of intracranial haemorrhage secondary to statin therapy&#46;</p></span><span id="sec0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0060">Combined treatment</span><p id="par0095" class="elsevierStylePara elsevierViewall">The current joint guideline 2019 of the European Society of Cardiology &#40;ESC&#41; and the European Atherosclerosis Society &#40;EAS&#41;<a class="elsevierStyleCrossRef" href="#bib0160"><span class="elsevierStyleSup">32</span></a> for the management of dyslipidaemia recommends with a degree of evidence A intensive lipid lowering therapy to reduce LDL cholesterol levels in established or transient ischaemic stroke patients&#46; Although the therapeutic goals for LDL cholesterol can be achieved with statins in monotherapy in a substantial number of cases&#44; a significant proportion of patients at high&#47;very high risk or with elevated LDL cholesterol levels require additional drug therapy&#46; In this clinical situation&#44; where despite statin therapy at the maximum tolerated dose the therapeutic goal is not achieved&#44; the combination with ezetimibe is recommended&#44; and if still not achieved&#44; the addition of a PCSK9 inhibitor is recommended&#46;</p><p id="par0100" class="elsevierStylePara elsevierViewall">With regard to combination treatment with statins and ezetimibe&#44; the Improved Reduction of Outcomes&#58; Vytorin Efficacy International Trial &#40;IMPROVE-IT&#41;<a class="elsevierStyleCrossRef" href="#bib0165"><span class="elsevierStyleSup">33</span></a> provided clear evidence that reinforces the importance of reducing LDL cholesterol in cardiovascular prevention&#46; In this regard&#44; it should be stressed that the additional reduction in LDL cholesterol achieved with ezetimibe is of the same quality in terms of cardiovascular risk reduction&#44; as that obtained with statins in monotherapy&#46; Each mmol&#47;L &#40;38&#46;7&#8239;mg&#47;dL&#41; reduction in LDL cholesterol obtained with statins in monotherapy or with the statin plus ezetimibe combination is associated with an approximate reduction in the RR of cardiovascular disease of 20&#37;&#44; findings which are in fully in line with those of the Cholesterol Treatment Trialist Collaboration&#46;<a class="elsevierStyleCrossRef" href="#bib0085"><span class="elsevierStyleSup">17</span></a> In a complementary analysis of IMPROVE-IT&#44; Bohula et al&#46;<a class="elsevierStyleCrossRef" href="#bib0170"><span class="elsevierStyleSup">34</span></a> showed that simvastatin and ezetimibe combination therapy in patients stabilised after an acute coronary syndrome reduced the frequency of ischaemic stroke&#44; especially in patients with previous stroke&#46;</p><p id="par0105" class="elsevierStylePara elsevierViewall">Finally&#44; there is recent evidence regarding the beneficial effects of treatment with PCSK9 inhibitors in cardiovascular prevention&#46; The publication of the results of Further Cardiovascular Outcomes Research With PCSK9 Inhibition in Subjects With Elevated Risk &#40;FOURIER&#41;<a class="elsevierStyleCrossRef" href="#bib0175"><span class="elsevierStyleSup">35</span></a> with evolocumab and ODYSSEY Outcomes&#58; Evaluation of Cardiovascular Outcomes After an Acute Coronary Syndrome During Treatment with Alirocumab<a class="elsevierStyleCrossRef" href="#bib0180"><span class="elsevierStyleSup">36</span></a> support the theory that the lower the LDL cholesterol the better in patients at high&#47;very high cardiovascular risk&#44; and together with IMPROVE-IT<a class="elsevierStyleCrossRef" href="#bib0165"><span class="elsevierStyleSup">33</span></a> point to the use of high-intensity lipid-lowering therapies&#46;<a class="elsevierStyleCrossRef" href="#bib0185"><span class="elsevierStyleSup">37</span></a> These two studies were included in a recent systematic review and meta-analysis by Guedeney et al&#46;<a class="elsevierStyleCrossRef" href="#bib0190"><span class="elsevierStyleSup">38</span></a> which documented an RRR of ischaemic stroke of 22&#37; with treatment with PCSK9 inhibitors&#46;</p></span></span><span id="sec0045" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0065">The challenges</span><p id="par0110" class="elsevierStylePara elsevierViewall">Despite the availability of effective and potent therapeutic tools&#44; real-life clinical practice studies show that patients at high&#47;very high cardiovascular risk are under-treated and under-controlled&#46; For example&#44; the EUROASPIRE V registry<a class="elsevierStyleCrossRef" href="#bib0195"><span class="elsevierStyleSup">39</span></a> conducted in 27 countries with patients in secondary prevention found that 71&#37; had LDL cholesterol &#8805;1&#46;8&#8239;mmol&#47;L &#40;70&#8239;mg&#47;dL&#41; despite the fact that just over 80&#37; of the patients were treated with statins&#46; This highlights that undertreatment is one of the main barriers to overcome towards improving therapeutic performance&#46; Almost contemporaneously&#44; similar results were described in the PALM registry&#46;<a class="elsevierStyleCrossRef" href="#bib0200"><span class="elsevierStyleSup">40</span></a> Less use and intensity of statins was observed in subgroup analyses by age and LDL cholesterol levels&#44; although differences were not statistically significant in older patients and those with LDL&#8239;&#8805;&#8239;100&#8239;mg&#47;dL&#46; On the other hand&#44; no statistically significant differences in statin use and intensity of statin therapy were observed among patients with coronary artery disease and stroke versus coronary artery disease alone&#46; In this same study&#44; the median &#40;p25&#8211;p75&#41; LDL cholesterol levels were 90&#8239;mg&#47;dL &#40;73&#8211;114&#41;&#44; 88&#8239;mg&#47;dL &#40;69&#8211;111&#41; and 83&#8239;mg&#47;dL &#40;66&#8211;107&#41; for patients with cerebrovascular disease alone&#44; coronary artery disease and cerebrovascular disease&#44; or coronary artery disease alone&#44; respectively &#40;<span class="elsevierStyleItalic">P</span>&#8239;&#60;&#8239;&#46;001&#41;&#46; It should be noted that only 59&#46;2&#37; of patients with cerebrovascular disease presented LDL cholesterol levels &#60;100&#8239;mg&#47;dL&#44; and therefore&#44; most of the patients did not achieve the therapeutic goals&#46;</p><p id="par0115" class="elsevierStylePara elsevierViewall">Advances in analytical magnetic resonance imaging and mass spectrometry platforms have made substantial contributions to the field of metabolomics and lipidomics in general&#46;<a class="elsevierStyleCrossRef" href="#bib0205"><span class="elsevierStyleSup">41</span></a> These emerging technologies have become increasingly sophisticated through the development of new statistical methods&#44; bioinformatic tools and database resources&#46; More recently&#44; systems biology approaches have been applied to decipher biological and clinical complexities with the emergence of computational and mathematical models&#46; Thus&#44; the inclusion of metabolomics and lipidomics&#44; along with other &#34;omics&#34;&#44; is possible&#46;<a class="elsevierStyleCrossRef" href="#bib0210"><span class="elsevierStyleSup">42</span></a> Furthermore&#44; fluxomics is a relatively new and ever-expanding field that characterises the dynamic metabolic profile of the cell phenotype and involves a more comprehensive assessment of complex metabolic networks related to disease&#46; Fluxoma&#44; the set of metabolic flows in a metabolic system&#44; is a direct manifestation of the metabolic phenotype&#44; and therefore is key to understanding any disease with a strong metabolic component&#46; However&#44; more research is needed to unravel the causal mechanisms of ischaemic stroke and pave the way for new drug treatments to help us achieve the therapeutic goals set for our patients&#46;</p></span><span id="sec0050" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0070">Conclusions</span><p id="par0120" class="elsevierStylePara elsevierViewall">Cerebrovascular disease is one of the main causes of mortality in our population&#44; with hypercholesterolaemia being one of the modifiable risk factors described&#46; Previous studies have shown that lipid-lowering treatment&#44; both with statins and in combination with ezetimibe or PCSK9 inhibitors&#44; are effective in secondary prevention of ischaemic stroke&#44; by lowering LDL cholesterol levels&#46; However&#44; the main barrier in clinical practice remains the failure to achieve therapeutic goals in LDL cholesterol&#44; the result of undertreatment&#46; It has been documented that prior therapeutic planning<a class="elsevierStyleCrossRef" href="#bib0215"><span class="elsevierStyleSup">43</span></a> using updated Masana and Plana tables<a class="elsevierStyleCrossRef" href="#bib0220"><span class="elsevierStyleSup">44</span></a> and the use of computerised tools included in the clinical history<a class="elsevierStyleCrossRef" href="#bib0225"><span class="elsevierStyleSup">45</span></a> significantly improve the rate that therapeutic goals are met and thus achieve effective vascular prevention&#46;</p></span><span id="sec0055" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0075">Funding</span><p id="par0125" class="elsevierStylePara elsevierViewall">This research study received no specific subsidies from public sector agencies&#44; the commercial sector or non-profit organisations&#46;</p></span><span id="sec0060" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0080">Conflict of interests</span><p id="par0130" class="elsevierStylePara elsevierViewall">The authors have no conflict of interests to declare&#46;</p></span></span>"
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        "resumen" => "<span id="abst0005" class="elsevierStyleSection elsevierViewall"><p id="spar0040" class="elsevierStyleSimplePara elsevierViewall">Stroke is the second cause of death after myocardial infarction&#44; and the main cause of acquired disability&#46; Patients with ischaemic stroke have a higher risk of future vascular events&#44; including recurrent stroke&#44; myocardial infarction&#44; and death by vascular cause&#46; The initial epidemiological studies demonstrated a weak or non-existent relationship between cholesterolaemia and stroke&#46; Subsequently&#44; statin intervention trials showed a reduction in the risk of recurrence of cerebrovascular events&#46; The <span class="elsevierStyleItalic">Stroke Prevention by Aggressive Reduction in Cholesterol Levels</span> &#40;SPARCL&#41;&#44; the first clinical trial designed to assess effects of statin therapy in secondary stroke prevention&#44; highlighted the reduction of stroke recurrence with atorvastatin 80&#8239;mg&#47;daily in patients with a recent ischaemic established or transient stroke&#44; with a modest increase in the rate of haemorrhagic stroke&#46; Successive studies have also reported the benefits of statin therapy combined with ezetimibe or PCSK9 inhibitors in primary and secondary ischaemic stroke prevention&#46; Since 80&#37; of recurrent cerebrovascular events could be prevented&#44; it is considered of interest to carry out a narrative review of the benefits of lipid-lowering therapy in the secondary prevention of ischaemic cerebrovascular disease&#46;</p></span>"
      ]
      "es" => array:2 [
        "titulo" => "Resumen"
        "resumen" => "<span id="abst0010" class="elsevierStyleSection elsevierViewall"><p id="spar0045" class="elsevierStyleSimplePara elsevierViewall">El accidente cerebrovascular es la segunda causa de mortalidad despu&#233;s del infarto de miocardio y la principal causa de discapacidad adquirida&#46; Los pacientes con ictus isqu&#233;mico tienen un elevado riesgo de posteriores episodios vasculares&#44; incluyendo ictus recurrente&#44; infarto de miocardio y muerte de causa vascular&#46; Los primeros estudios epidemiol&#243;gicos mostraron una relaci&#243;n d&#233;bil o inexistente entre la colesterolemia y el ictus&#46; Posteriormente&#44; los estudios de intervenci&#243;n con estatinas revelaron una reducci&#243;n del riesgo de recurrencia de episodios cerebrovasculares&#46; El <span class="elsevierStyleItalic">Stroke Prevention by Aggressive Reduction in Cholesterol Levels</span> &#40;SPARCL&#41;&#44; primer ensayo cl&#237;nico dise&#241;ado para analizar los efectos de la terapia con estatinas en la prevenci&#243;n secundaria del ictus&#44; demostr&#243; que el tratamiento con atorvastatina 80&#8239;mg&#47;d&#237;a reduc&#237;a la recurrencia de ictus en pacientes con un accidente cerebrovascular isqu&#233;mico reciente establecido o transitorio&#44; con un modesto aumento en la tasa de ictus hemorr&#225;gico&#46; Estudios posteriores han recabado los beneficios de la terapia de estatinas&#44; con ezetimiba o inhibidores de PCSK9 tanto en la prevenci&#243;n primaria como secundaria del accidente cerebrovascular isqu&#233;mico&#46; Dado que el 80&#37; de los episodios cerebrovasculares recurrentes pueden prevenirse hemos considerado de inter&#233;s realizar una revisi&#243;n narrativa de los beneficios de la terapia hipolipemiante en la prevenci&#243;n secundaria de la enfermedad cerebrovascular isqu&#233;mica&#46;</p></span>"
      ]
    ]
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      0 => array:2 [
        "etiqueta" => "&#9734;"
        "nota" => "<p class="elsevierStyleNotepara" id="npar0005">Please cite this article as&#58; Climent E&#44; Benaiges D&#44; Pedro-Botet J&#46; Tratamiento hipolipemiante en la prevenci&#243;n secundaria de la enfermedad cerebrovascular isqu&#233;mica&#46; Clin Investig Arterioscler&#46; 2020&#59;32&#58;175&#8211;182&#46;</p>"
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          "en" => "<p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">Classic risk factors for vascular disease&#46;</p> <p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">AHT&#58; arterial hypertension&#59; LDL&#58; low density lipoproteins&#46;</p>"
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      1 => array:8 [
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        "etiqueta" => "Figure 2"
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        "figura" => array:1 [
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          "en" => "<p id="spar0015" class="elsevierStyleSimplePara elsevierViewall">Cholesterolaemia reduction and risk of stroke in the pre-statin era&#46;</p>"
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          "leyenda" => "<p id="spar0025" class="elsevierStyleSimplePara elsevierViewall">LDL&#58; low density lipoproteins&#59; NS&#58; not significant&#46;</p>"
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                  <table border="0" frame="\n
                  \t\t\t\t\tvoid\n
                  \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Study&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Baseline LDL cholesterol &#40;mg&#47;dL&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">LDL cholesterol reduction &#40;&#37;&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-head\n
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                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Established or transient ischaemic stroke reduction &#40;&#37;&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">4S<a class="elsevierStyleCrossRef" href="#bib0105"><span class="elsevierStyleSup">21</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">188&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">35&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">28 &#40;<span class="elsevierStyleItalic">P</span>&#8239;&#60;&#8239;&#46;01&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">CARE<a class="elsevierStyleCrossRef" href="#bib0110"><span class="elsevierStyleSup">22</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">139&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">28&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">32 &#40;<span class="elsevierStyleItalic">P</span>&#8239;&#60;&#8239;&#46;05&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">LIPID<a class="elsevierStyleCrossRef" href="#bib0115"><span class="elsevierStyleSup">23</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">150&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">25&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">19 &#40;<span class="elsevierStyleItalic">P</span>&#8239;&#60;&#8239;&#46;05&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">WOSCOPS<a class="elsevierStyleCrossRef" href="#bib0125"><span class="elsevierStyleSup">25</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">192&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">26&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">11 &#40;<span class="elsevierStyleItalic">P</span>&#8239;&#61;&#8239;NS&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">MIRACL<a class="elsevierStyleCrossRef" href="#bib0120"><span class="elsevierStyleSup">24</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">124&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">40&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">50 &#40;<span class="elsevierStyleItalic">P</span>&#8239;&#60;&#8239;&#46;05&#41;&nbsp;\t\t\t\t\t\t\n
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                  <table border="0" frame="\n
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                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">SPARCL<a class="elsevierStyleCrossRef" href="#bib0135"><span class="elsevierStyleSup">27</span></a>&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-head\n
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                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Sub-analysis<a class="elsevierStyleCrossRef" href="#bib0140"><span class="elsevierStyleSup">28</span></a> &#40;LDL cholesterol reduction &#8805;50&#37;&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">RRR of recurrent stroke&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">16&#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">31&#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
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                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
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                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#40;30&#37; non-fatal stroke and 33&#37; ischaemic stroke&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
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                  \t\t\t\t">RRR of severe coronary events&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">35&#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">RRR severe cardiovascular events&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">20&#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">48&#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
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                  \t\t\t\t">Increase in haemorrhagic stroke&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">No increase&nbsp;\t\t\t\t\t\t\n
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                    0 => array:2 [
                      "titulo" => "Anthology of stroke epidemiology in the 20th and 21st centuries&#58; assessing the past&#44; the present&#44; and envisioning the future"
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                          "etal" => false
                          "autores" => array:1 [
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                      "Revista" => array:6 [
                        "tituloSerie" => "Int J Stroke&#46;"
                        "fecha" => "2019"
                        "volumen" => "14"
                        "paginaInicial" => "223"
                        "paginaFinal" => "237"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/30794102"
                            "web" => "Medline"
                          ]
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            1 => array:3 [
              "identificador" => "bib0010"
              "etiqueta" => "2"
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                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Heart disease and stroke statistics&#8212;2017 update&#58; a report from the American Heart Association"
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                          "etal" => true
                          "autores" => array:6 [
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                            1 => "M&#46;J&#46; Blaha"
                            2 => "S&#46;E&#46; Chiuve"
                            3 => "M&#46; Cushman"
                            4 => "S&#46;R&#46; Das"
                            5 => "R&#46; Deo"
                          ]
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                        "fecha" => "2017"
                        "volumen" => "135"
                        "paginaInicial" => "e146"
                        "paginaFinal" => "e603"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/28122885"
                            "web" => "Medline"
                          ]
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                ]
              ]
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            2 => array:3 [
              "identificador" => "bib0015"
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                0 => array:1 [
                  "referenciaCompleta" => "Instituto Nacional de Estad&#237;stica 2017&#46; Defunciones seg&#250;n causa de muerte &#91;accessed 9 Nov 2019&#93;&#46; Available from&#58; <a target="_blank" href="https://www.ine.es/prodyser/espa_cifras/2019/files/assets/common/downloads/page0021.pdf">https&#58;&#47;&#47;www&#46;ine&#46;es&#47;prodyser&#47;espa&#95;cifras&#47;2019&#47;files&#47;assets&#47;common&#47;downloads&#47;page0021&#46;pdf</a>&#46;"
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              "identificador" => "bib0020"
              "etiqueta" => "4"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "GBD 2016 Lifetime Risk of Stroke Collaborators&#46; Global&#44; regional&#44; and country-specific lifetime risks of stroke&#44; 1990 and 2016"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
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                            0 => "V&#46;L&#46; Feigin"
                            1 => "G&#46; Nguyen"
                            2 => "K&#46; Cercy"
                            3 => "C&#46;O&#46; Johnson"
                            4 => "T&#46; Alam"
                            5 => "P&#46;G&#46; Parmar"
                          ]
                        ]
                      ]
                    ]
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                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1056/NEJMoa1804492"
                      "Revista" => array:6 [
                        "tituloSerie" => "N Engl J Med&#46;"
                        "fecha" => "2018"
                        "volumen" => "379"
                        "paginaInicial" => "2429"
                        "paginaFinal" => "2437"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/30575491"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
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            4 => array:3 [
              "identificador" => "bib0025"
              "etiqueta" => "5"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Global variation in the relative burden of stroke and ischemic heart disease&#47;clinical perspective"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:2 [
                            0 => "A&#46;S&#46; Kim"
                            1 => "S&#46;C&#46; Johnston"
                          ]
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                      ]
                    ]
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                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1161/CIRCULATIONAHA.111.018820"
                      "Revista" => array:6 [
                        "tituloSerie" => "Circulation&#46;"
                        "fecha" => "2011"
                        "volumen" => "124"
                        "paginaInicial" => "314"
                        "paginaFinal" => "323"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/21730306"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            5 => array:3 [
              "identificador" => "bib0030"
              "etiqueta" => "6"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Five year risk of stroke after tia or minor ischemic stroke"
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                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "P&#46; Amarenco"
                            1 => "P&#46;C&#46; Lavall&#233;e"
                            2 => "L&#46; Monteiro Tavares"
                            3 => "J&#46; Labreuche"
                            4 => "G&#46;W&#46; Albers"
                            5 => "H&#46; Abboud"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1056/NEJMoa1802712"
                      "Revista" => array:6 [
                        "tituloSerie" => "N Engl J Med&#46;"
                        "fecha" => "2018"
                        "volumen" => "378"
                        "paginaInicial" => "2182"
                        "paginaFinal" => "2190"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/29766771"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            6 => array:3 [
              "identificador" => "bib0035"
              "etiqueta" => "7"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Guidelines for the prevention of stroke in patients with stroke and transient ischemic attack&#58; a guideline for healthcare professionals from the American Heart Association&#47;American Stroke Association"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "W&#46;N&#46; Kernan"
                            1 => "B&#46; Ovbiagele"
                            2 => "H&#46;R&#46; Black"
                            3 => "D&#46;M&#46; Bravata"
                            4 => "M&#46;I&#46; Chimowitz"
                            5 => "M&#46;D&#46; Ezekowitz"
                          ]
                        ]
                      ]
                    ]
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                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1161/STR.0000000000000024"
                      "Revista" => array:6 [
                        "tituloSerie" => "Stroke&#46;"
                        "fecha" => "2014"
                        "volumen" => "45"
                        "paginaInicial" => "2160"
                        "paginaFinal" => "2236"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/24788967"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            7 => array:3 [
              "identificador" => "bib0040"
              "etiqueta" => "8"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Vascular effects of statins in stroke"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:2 [
                            0 => "N&#46; Delanty"
                            1 => "C&#46;J&#46; Vaughan"
                          ]
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                      ]
                    ]
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                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1161/01.str.28.11.2315"
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                        "tituloSerie" => "Stroke&#46;"
                        "fecha" => "1997"
                        "volumen" => "28"
                        "paginaInicial" => "2315"
                        "paginaFinal" => "2320"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/9368582"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            8 => array:3 [
              "identificador" => "bib0045"
              "etiqueta" => "9"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Estatinas y enfermedad cerebrovascular&#58; nuevas perspectivas en la prevenci&#243;n del ictus"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:4 [
                            0 => "L&#46; Castilla-Guerra"
                            1 => "M&#46;C&#46; Fern&#225;ndez-Moreno"
                            2 => "J&#46;M&#46; L&#243;pez-Chozas"
                            3 => "M&#46;D&#46; Jim&#233;nez-Hern&#225;ndez"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:5 [
                        "tituloSerie" => "Rev Neurol&#46;"
                        "fecha" => "2007"
                        "volumen" => "44"
                        "paginaInicial" => "95"
                        "paginaFinal" => "100"
                      ]
                    ]
                  ]
                ]
              ]
            ]
            9 => array:3 [
              "identificador" => "bib0050"
              "etiqueta" => "10"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Lipid management in the prevention of stroke&#58; review and updated meta-analysis of statins for stroke prevention"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:2 [
                            0 => "P&#46; Amarenco"
                            1 => "J&#46; Labreuche"
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                      ]
                    ]
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                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1016/S1474-4422(09)70058-4"
                      "Revista" => array:6 [
                        "tituloSerie" => "Lancet Neurol&#46;"
                        "fecha" => "2009"
                        "volumen" => "8"
                        "paginaInicial" => "453"
                        "paginaFinal" => "463"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/19375663"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            10 => array:3 [
              "identificador" => "bib0055"
              "etiqueta" => "11"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Heart disease and stroke statistics&#8212;2016 update&#58; a report from the American Heart Association"
                      "autores" => array:1 [
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                          "etal" => true
                          "autores" => array:6 [
                            0 => "D&#46; Mozaffarian"
                            1 => "E&#46;J&#46; Benjamin"
                            2 => "A&#46;S&#46; Go"
                            3 => "D&#46;K&#46; Arnett"
                            4 => "M&#46;J&#46; Blaha"
                            5 => "M&#46; Cushman"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1161/CIR.0000000000000350"
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                        "tituloSerie" => "Circulation&#46;"
                        "fecha" => "2016"
                        "volumen" => "133"
                        "paginaInicial" => "e38"
                        "paginaFinal" => "360"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/26673558"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            11 => array:3 [
              "identificador" => "bib0060"
              "etiqueta" => "12"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Serum cholesterol levels and six-year mortality from stroke in 350&#44;977 men screened for the Multiple Risk Factor Intervention Trial"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:5 [
                            0 => "H&#46; Iso"
                            1 => "D&#46;R&#46; Jacobs Jr"
                            2 => "D&#46; Wentworth"
                            3 => "J&#46;D&#46; Neaton"
                            4 => "J&#46;D&#46; Cohen"
                          ]
                        ]
                      ]
                    ]
                  ]
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                    0 => array:2 [
                      "doi" => "10.1056/NEJM198904063201405"
                      "Revista" => array:6 [
                        "tituloSerie" => "N Engl J Med&#46;"
                        "fecha" => "1989"
                        "volumen" => "320"
                        "paginaInicial" => "904"
                        "paginaFinal" => "910"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/2619783"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            12 => array:3 [
              "identificador" => "bib0065"
              "etiqueta" => "13"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Cholesterol&#44; diastolic blood pressure&#44; and stroke&#58; 13 000 strokes in 450 000 people in 45 prospective cohorts"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:1 [
                            0 => "Prospective Studies Collaboration"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1016/s0140-6736(95)91487-0"
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                        "tituloSerie" => "Lancet&#46;"
                        "fecha" => "1995"
                        "volumen" => "346"
                        "paginaInicial" => "647"
                        "paginaFinal" => "653"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/7651043"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            13 => array:3 [
              "identificador" => "bib0070"
              "etiqueta" => "14"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Cholesterol reduction and the risk for stroke in men"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:5 [
                            0 => "D&#46; Atkins"
                            1 => "B&#46;M&#46; Psaty"
                            2 => "T&#46;D&#46; Koepsell"
                            3 => "W&#46;T&#46; Longstreth"
                            4 => "E&#46;B&#46; Larson"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.7326/0003-4819-119-2-199307150-00008"
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                        "tituloSerie" => "Ann Intern Med&#46;"
                        "fecha" => "1993"
                        "volumen" => "119"
                        "paginaInicial" => "136"
                        "paginaFinal" => "145"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/8305001"
                            "web" => "Medline"
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                    ]
                  ]
                ]
              ]
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            14 => array:3 [
              "identificador" => "bib0075"
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              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "The origin of the statins&#46; 2004"
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                          "autores" => array:1 [
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                        "tituloSerie" => "Atheroscler Suppl&#46;"
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                        "volumen" => "5"
                        "paginaInicial" => "125"
                        "paginaFinal" => "130"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/15531285"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            15 => array:3 [
              "identificador" => "bib0080"
              "etiqueta" => "16"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Cholesterol Treatment Trialists&#8217; &#40;CTT&#41; Collaborators&#46; Efficacy and safety of cholesterol-lowering treatment&#58; prospective meta-analysis of data from 90&#44;056 participants in 14 randomised trials of statins"
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                            5 => "C&#46; Pollicino"
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                        ]
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                    ]
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                  "host" => array:1 [
                    0 => array:2 [
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                        "paginaFinal" => "1278"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/16214597"
                            "web" => "Medline"
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                0 => array:2 [
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                      "titulo" => "Efficacy and safety of more intensive lowering of LDL cholesterol&#58; a meta-analysis of data from 170&#44;000 participants in 26 randomised trials"
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                            5 => "C&#46; Reith"
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                        "paginaFinal" => "1681"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/21067804"
                            "web" => "Medline"
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                ]
              ]
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                0 => array:2 [
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                    0 => array:2 [
                      "titulo" => "Cholesterol Treatment Trialists&#8217; &#40;CTT&#41; Collaborators&#46; The effects of lowering LDL cholesterol with statin therapy in people at low risk of vascular disease&#58; meta-analysis of individual data from 27 randomised trials"
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                        "paginaFinal" => "590"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/22607822"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
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              "identificador" => "bib0095"
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              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Efficacy and safety of statin therapy in older people&#58; a meta-analysis of individual participant data from 28 randomised controlled trials"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:1 [
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                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/30712900"
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                      "titulo" => "Statins in stroke prevention&#58; present and future"
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                        ]
                      ]
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                      "doi" => "10.2174/1381612822666160510125229"
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                        "tituloSerie" => "Curr Pharm Des&#46;"
                        "fecha" => "2016"
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                        "paginaInicial" => "4638"
                        "paginaFinal" => "4644"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/27160755"
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              "identificador" => "bib0105"
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                0 => array:2 [
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                    0 => array:2 [
                      "titulo" => "Randomised trial of cholesterol lowering in 4&#44;444 patients with coronary heart disease&#58; the Scandinavian Simvastatin Survival Study &#40;4S&#41;"
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                        "tituloSerie" => "Lancet&#46;"
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                        "volumen" => "344"
                        "paginaInicial" => "1383"
                        "paginaFinal" => "1389"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/7968073"
                            "web" => "Medline"
                          ]
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            21 => array:3 [
              "identificador" => "bib0110"
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                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Cholesterol and Recurrent Events Trial Investigators&#46; The effect of pravastatin on coronary events after myocardial infarction in patients with average cholesterol levels"
                      "autores" => array:1 [
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                            1 => "M&#46;A&#46; Pfeffer"
                            2 => "L&#46;A&#46; Moye"
                            3 => "J&#46;L&#46; Rouleau"
                            4 => "J&#46;D&#46; Rutherford"
                            5 => "T&#46;G&#46; Cole"
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                        ]
                      ]
                    ]
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                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1056/NEJM199610033351401"
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                        "tituloSerie" => "N Engl J Med&#46;"
                        "fecha" => "1996"
                        "volumen" => "335"
                        "paginaInicial" => "1001"
                        "paginaFinal" => "1009"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/8801446"
                            "web" => "Medline"
                          ]
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                      ]
                    ]
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                ]
              ]
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            22 => array:3 [
              "identificador" => "bib0115"
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                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Prevention of cardiovascular events and death with pravastatin in patients with coronary heart disease and a broad range of initial cholesterol levels"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:1 [
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                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1056/NEJM199811053391902"
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                        "tituloSerie" => "N Engl J Med&#46;"
                        "fecha" => "1998"
                        "volumen" => "339"
                        "paginaInicial" => "1349"
                        "paginaFinal" => "1357"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/9841303"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            23 => array:3 [
              "identificador" => "bib0120"
              "etiqueta" => "24"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Myocardial Ischemia Reduction with Aggressive Cholesterol Lowering &#40;MIRACL&#41; Study Investigators&#46; Effects of atorvastatin on early recurrent ischemic events in acute coronary syndromes&#58; the MIRACL study&#58; a randomized controlled trial"
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                            1 => "A&#46;G&#46; Olsson"
                            2 => "M&#46;D&#46; Ezekowitz"
                            3 => "P&#46; Ganz"
                            4 => "M&#46;F&#46; Oliver"
                            5 => "D&#46; Waters"
                          ]
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                      ]
                    ]
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                  "host" => array:1 [
                    0 => array:2 [
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                        "paginaInicial" => "1711"
                        "paginaFinal" => "1718"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/11277825"
                            "web" => "Medline"
                          ]
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                      ]
                    ]
                  ]
                ]
              ]
            ]
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              "identificador" => "bib0125"
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              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "for the West of Scotland Coronary Prevention Study Group&#46; Prevention of coronary heart disease with pravastatin in men with hypercholesterolemia"
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                        0 => array:2 [
                          "etal" => true
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                            2 => "I&#46; Ford"
                            3 => "C&#46;G&#46; Isles"
                            4 => "A&#46;R&#46; Lorimer"
                            5 => "P&#46;W&#46; MacFarlane"
                          ]
                        ]
                      ]
                    ]
                  ]
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                    0 => array:2 [
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                        "tituloSerie" => "N Engl J Med&#46;"
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                        "volumen" => "333"
                        "paginaInicial" => "1301"
                        "paginaFinal" => "1307"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/7566020"
                            "web" => "Medline"
                          ]
                        ]
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                    ]
                  ]
                ]
              ]
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              "identificador" => "bib0130"
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                0 => array:2 [
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                    0 => array:2 [
                      "titulo" => "MRC&#47;BHF Heart Protection Study of cholesterol lowering with simvastatin in 20&#44;536 high-risk individuals&#58; a randomized placebo-controlled trial"
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                        0 => array:2 [
                          "etal" => false
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                      ]
                    ]
                  ]
                  "host" => array:1 [
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                        "tituloSerie" => "Lancet&#46;"
                        "fecha" => "2002"
                        "volumen" => "360"
                        "paginaInicial" => "7"
                        "paginaFinal" => "22"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/12114036"
                            "web" => "Medline"
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                    ]
                  ]
                ]
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              "identificador" => "bib0135"
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              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "High-dose atorvastatin after stroke or transient ischemic attack"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:1 [
                            0 => "The Stroke Prevention by Aggressive Reduction in Cholesterol Levels &#40;SPARCL&#41; Investigators"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1056/NEJMoa061894"
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                        "tituloSerie" => "N Engl J Med&#46;"
                        "fecha" => "2006"
                        "volumen" => "355"
                        "paginaInicial" => "549"
                        "paginaFinal" => "559"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/16899775"
                            "web" => "Medline"
                          ]
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              "identificador" => "bib0140"
              "etiqueta" => "28"
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                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Effects of intense low-density lipoprotein cholesterol reduction in patients with stroke or transient ischemic attack&#58; the Stroke Prevention by Aggressive Reduction in Cholesterol Levels &#40;SPARCL&#41; trial"
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                            3 => "H&#46; Sillesen"
                            4 => "A&#46;E&#46; Rudolph"
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                        ]
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                    0 => array:2 [
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                        "paginaInicial" => "3198"
                        "paginaFinal" => "3204"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/17962589"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
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              "identificador" => "bib0145"
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              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Hemorrhagic stroke in the stroke prevention by aggressive reduction in cholesterol levels study"
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                            4 => "M&#46; Hennerici"
                            5 => "H&#46; Sillesen"
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                        ]
                      ]
                    ]
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                  "host" => array:1 [
                    0 => array:2 [
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                        "tituloSerie" => "Neurology&#46;"
                        "fecha" => "2008"
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                        "paginaInicial" => "2364"
                        "paginaFinal" => "2370"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/18077795"
                            "web" => "Medline"
                          ]
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                    ]
                  ]
                ]
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              "identificador" => "bib0150"
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                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Statins and the risk of intracerebral hemorrhage in patients with previous ischemic stroke or transient ischemic attack"
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                        "paginaFinal" => "3251"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/29070714"
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              "identificador" => "bib0155"
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                0 => array:2 [
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                    0 => array:2 [
                      "titulo" => "China Kadoorie Biobank Collaborative Group&#44; International Steering Committee&#44; International Co-ordinating Centre Oxford&#44; National Co-ordinating Centre&#44; Beijing&#44; Regional Co-ordinating Centres&#46; Causal associations of blood lipids with risk of ischemic stroke and intracerebral hemorrhage in Chinese adults"
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                        "tituloSerie" => "Nat Med&#46;"
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                        "paginaFinal" => "574"
                        "link" => array:1 [
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                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/30858617"
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                          "pii" => "S0272638615009403"
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              "identificador" => "bib0160"
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                0 => array:2 [
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                    0 => array:2 [
                      "titulo" => "ESC Scientific Document Group&#46; 2019 ESC&#47;EAS Guidelines for the management of dyslipidaemias&#58; lipid modification to reduce cardiovascular risk"
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                    0 => array:2 [
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                        "volumen" => "41"
                        "paginaInicial" => "111"
                        "paginaFinal" => "8819"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/31504418"
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              "identificador" => "bib0165"
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                0 => array:2 [
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                    0 => array:2 [
                      "titulo" => "IMPROVE-IT Investigators&#46; Ezetimibe added to statin therapy after acute coronary syndromes"
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                        "paginaInicial" => "2387"
                        "paginaFinal" => "2397"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/26039521"
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                0 => array:2 [
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                    0 => array:2 [
                      "titulo" => "Prevention of stroke with the addition of ezetimibe to statin therapy in patients with acute coronary syndrome in IMPROVE-IT &#40;Improved Reduction of Outcomes&#58; Vytorin Efficacy International Trial&#41;"
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                        "paginaFinal" => "2450"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/28972004"
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                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Evolocumab and clinical outcomes in patients with cardiovascular disease"
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                        "paginaFinal" => "1722"
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              "identificador" => "bib0180"
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                0 => array:2 [
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                    0 => array:2 [
                      "titulo" => "ODYSSEY OUTCOMES Committees and Investigators&#46; Alirocumab and cardiovascular outcomes after acute coronary syndrome"
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                          "etal" => true
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                        ]
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                      "titulo" => "IMPROVE-IT clinical implications&#46; Should the &#34;high-intensity cholesterol-lowering therapy&#34; strategy replace the &#34;high-intensity statin therapy&#34;&#63;"
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                      "titulo" => "Efficacy and safety of alirocumab and evolocumab&#58; a systematic review and meta-analysis of randomized controlled trials"
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                          "etal" => true
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                            4 => "A&#46; Camaj"
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                        "fecha" => "2019"
                        "link" => array:1 [
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                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/27141094"
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                ]
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                          "etal" => true
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                            1 => "A&#46;M&#46; Navar"
                            2 => "S&#46; Li"
                            3 => "Z&#46; Li"
                            4 => "J&#46; Robinson"
                            5 => "S&#46;S&#46; Virani"
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                      ]
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                        "tituloSerie" => "J Am Heart Assoc&#46;"
                        "fecha" => "2019"
                        "volumen" => "8"
                        "paginaInicial" => "e013229"
                        "link" => array:1 [
                          0 => array:2 [
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                      "titulo" => "Metabolomics and lipidomics of ischemic stroke"
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                          "autores" => array:1 [
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                        "link" => array:1 [
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                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/29655461"
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                      "titulo" => "Targeted metabolomics"
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                        "paginaInicial" => "1"
                        "paginaFinal" => "24"
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                      "titulo" => "A new rational approach to reach LDL-cholesterol concentration objectives after an acute coronary syndrome"
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                        "tituloSerie" => "Clin Investig Arterioscler&#46;"
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                    0 => array:2 [
                      "titulo" => "Update of therapeutic planning tables oriented towards obtaining therapeutic objectives"
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                            3 => "G&#46; V&#225;zquez"
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Article information

ISSN: 25299123
Original language: English

DOI:10.1016/j.artere.2020.07.001

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Year/Month	Html	Pdf	Total

2024 November	11	2	13
2024 October	21	6	27
2024 September	35	17	52
2024 August	35	11	46
2024 July	31	9	40
2024 June	34	8	42
2024 May	32	13	45
2024 April	32	16	48
2024 March	40	6	46
2024 February	49	4	53
2024 January	47	6	53
2023 December	62	14	76
2023 November	49	21	70
2023 October	71	23	94
2023 September	76	4	80
2023 August	33	2	35
2023 July	61	5	66
2023 June	61	7	68
2023 May	78	8	86
2023 April	71	3	74
2023 March	93	15	108
2023 February	71	12	83
2023 January	56	13	69
2022 December	61	5	66
2022 November	40	12	52
2022 October	38	16	54
2022 September	27	12	39
2022 August	15	5	20
2022 July	7	4	11
2022 June	11	8	19
2022 May	14	8	22
2022 April	18	4	22
2022 March	11	5	16
2022 February	10	0	10

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