Assessment of acute stroke treatment, hypertension, and post discharge medication prescription among Lebanese patients with ischemic stroke: Results of a crosssectional study

Keywords: AVC ischémique, Hypertension, Prise en charge, Suivi, Observance Acute Ischemic stroke, Hypertension, Management, Post discharge, Adherence Unité de recherche

Objectives: Stroke, the most common neurologic disorder and the major cause of disability and death after heart disease causing 11.8% of the total deaths worldwide, is defined as a rapidly developing clinical signs of focal disturbance of cerebral function lasting more than 24 hour. This study aims to assess appropriateness of hypertension treatment in acute stroke and its adherence with the choice of medications tailored according to blood pressure readings and investigate the degree of physician adherence with the international guidelines for post-stroke discharge medications among Lebanese hospitals.

Patients and Methods:

This was a pilot study performed in three Lebanese hospitals where medical records of ischemic stroke patients were used to collect required data. The study enrolled ischemic stroke patients older than 18 years of age, admitted to intensive care unit or internal medicine department. Patients with hemorrhagic stroke were excluded. Statistical analysis was done using IBM Statistical Package for the Social Science software. The significance level is p-value ≤ 0.05.

Results:

Out of 200 patients with stroke, 64.7 % were males. The difference of systolic blood pressure (SBP) from baseline, 2 hour, and after 24 hour showed significant decrease by mean value 25.18±33.45 (P<0.001), and 6.44 ± 22.11 (P = 0.019) respectively. Also, diastolic blood pressure (DBP) showed significant decrease between baseline and after 24 hour by a mean value 12.17 ± 13.63 (P value < 0.001). Labetalol and amlodipine were administered to patients with significantly higher baseline blood pressure (p < 0.001). Change in SBP from baseline after 2 hour of drug administration was significantly higher with labetalol (p = 0.028 for patients eligible for reperfusion), amlodipine (p = 0.014), and nitroglycerine (p = 0.044). As for the change in SBP after 24 hour, it was significantly higher with labetalol just for patients not eligible for reperfusion (p < 0.001), and amlodipine (p = 0.006). As for the change in DBP, it was significantly lower after 24 hour on labetalol administration for patients not eligible for reperfusion (p < 0.001) and it was also lower 2 hour after administration of ramipril (p = 0.001) and 24 h (p = 0.021). Concerning post discharge medications adherence, antithrombotic drugs showed the highest percentage (73 %) followed by antihypertensive and lipid lowering agents by comparable results (47.5 % and 40.7 % respectively). The physician adherence for the three medications together showed (30.4 %).

4 Conclusion: Secondary prevention for critical diseases such as stroke appears to be inadequate in the study area. This study reveals the gap between American Stroke Association guideline recommendations and the clinical practice and states the impact of such a difference on patients' health.

Résumé

L'AVC ischémique aigu est une cause majeure de mortalité et de handicap et demeure un problème majeur de santé mondiale. Le respect des recommandations internationales est essentiel lors de la prise en charge d'un AVC ischémique pendant la phase aiguë afin de prévenir les complications précoces et les récidives. Cette étude est la première au Liban à évaluer le respect des directives dans la prise en charge aiguë et post AVC ischémique et à évaluer son impact sur la mortalité hospitalière. Quant à l'évaluation des divers médicaments prescrits après l'hospitalisation, tels que les anti-thrombotiques, les antihypertenseurs, les hypolipémiants, et la mesure de la pression artérielle à différents moments à l'hôpital a été effectuée à l'aide d'une feuille de collecte de données.

Les résultats de cette étude ont mis en évidence que les recommandations internationales étaient peu respectées, ce qui explique les taux de mortalité élevés chez les patients victimes d'AVC au Liban. Nos résultats ont montré que la majorité des patients prenaient des antihypertenseurs non recommandés par les directives comme le Labétalol ou la Nicardipine.

Le Labétalol était réservé aux patients présentant une tension artérielle moyenne initiale de 205/104 mm Hg tandis que d'autres agents étaient administrés à une tension artérielle initiale inférieure comprise entre 175 et 140/93 et 85 mm Hg. Il faut dire que la majorité n'a pas eu d'hospitalisation en Stroke Unit, pas de thrombolyse ni thrombectomie; fautre de structure et de disponibilité de ces traitements au Liban.

Résumé

Objectifs: L'accident vasculaire cérébral, le trouble neurologique le plus courant et la principale cause de handicap et de décès après la maladie cardiaque, causant 11,8 % du total des décès dans le monde, est défini comme un signe clinique en développement rapide de perturbation focale de la fonction cérébrale durant plus de 24 heures. Cette étude vise à évaluer la pertinence du traitement de l'hypertension en cas d'AVC aigu et d'étudier le degré d'adhésion des médecins aux directives internationales sur les médicaments de sortie après un AVC dans les hôpitaux libanais.

Patients et Méthodes: Il s'agissait d'une étude pilote réalisée dans des hôpitaux libanais où les dossiers médicaux des patients victimes d'un AVC ischémique ont été utilisés pour recueillir les données requises. L'étude a recruté des patients atteints d'un AVC ischémique âgés de plus de 18 ans, admis en unité de soins intensifs ou en service de médecine. Les patients victimes d'AVC hémorragique en ont été exclus. L'analyse statistique a été effectuée à l'aide du logiciel IBM Statistical Package pour le logiciel de sciences sociales. Le niveau de signification est la valeur p ≤ 0,05.

Résultats: Sur 200 patients victimes d'AVC, 64,7% étaient des hommes. La différence de pression artérielle systolique par rapport à la ligne de base, 2 heures et après 24 heures a montré une diminution significative de la valeur moyenne de 25,18 ± 33,45 (p <0,001) et de 6,44 ± 22,11 (p = 0,019) respectivement. En outre, la pression artérielle diastolique a également montré une diminution significative entre la ligne de base et après 24 heures d'une valeur moyenne de 12,17 ± 13,63 (valeur p <0,001). Le labétalol et l'amlodipine ont été administrés à des patients dont la tension artérielle initiale était significativement plus élevée (p <0,001). La variation de la PAS par rapport à la valeur initiale après 2 heures d'administration du médicament était significativement plus élevée avec le labétalol (p = 0,028 pour les patients éligibles à la reperfusion), l'amlodipine (p = 0,014) et la nitroglycérine (p = 0,044). Quant à la variation de la PAS après 24 heures, elle était significativement plus élevée avec le labétalol uniquement pour les patients non éligibles à la reperfusion (p <0,001), et de même pour l'amlodipine (p = 0,006). Quant à la DBP, elle a subi une forte baisse significative après 24 heures d'administration de labétalol pour les patients non éligibles à la reperfusion (p <0,001) et ceci était remarquable 2 heures après l'administration de ramipril (p = 0,001) comme après 24 heures (p = 0,021). En ce qui concerne la prescription des médicaments après la sortie de l'hôpital, les médicaments anti-thrombotiques sont les plus prescrits (73%) suivis des antihypertenseurs et des hypolipidémiants (47,5% et 40,7% respectivement). L'observance des malades pour les trois médicaments pris ensemble était de 30,4%.

Conclusion:

La prévention secondaire des accidents vasculaires cérébraux semble inadéquate dans la zone d'étude. Cette étude révèle l'écart entre les recommandations internationales et la pratique clinique et indiquer l'impact sur la mortalité et la morbidité des patients.

ACKNOWLEDGMENTS

My Ph.D., an important achievement and milestone in my life, a dream of my parents, cost me time, effort and a lot of sacrifices. Thank you God and everyone who helped me achieve it. A great thanks to Prof. Hassan Hosseini, my French supervisor, who ideated this project, supported it with a remarkable optimism. Thank you for the confidence that you placed in me to work on it. Thank you for being so patient, bearing with me and giving me all the tips and advices to reach this point. I really appreciate your help and time all over these three years, despite your multiple tasks and narrow time.

To my Lebanese supervisor, Prof. Pascale Salameh, I want to tell you that you were not just a thesis director, you were a great guide and mentor who was always there to teach and orient me in every step. Thank you for everything you taught me, still teach me and will teach me. You are an ideal person to follow as you always give a hope to me and all those who are around you. You are a great person who teaches from her deep heart without any boundaries.

I am so grateful equally to Professors Jerome Hodel, Mikael Mazighi, Amal Al Hajje, and Samar Rachidi who accepted to be part of the jury and evaluate my thesis. I really appreciate the time that you devoted to me. To my parents, I fulfilled your dream about obtaining a PhD degree with your continuous help and support especially my mother. My mom I would like to thank you even my words cannot fully express my appreciation to your help for my kids when I was not able to be around to take care for them. Without your unconditional love and support, I couldn't have done my PhD. I love you until the end of times.

To my husband, I also wanted to thank you for staying by my side, believing in me and supporting me in every step. My husband you were supporting me from the first day we get married, starting with my Master degree, helping me pass the American Board Exam, and finally accepting my time away from home to pursue my PhD degree. You were always there motivating, helping, and pushing me to fulfill my degree. I love you so much!! Finally, to my kids I am really sorry if I was not able to be beside you during times you needed me and eventually I am around to be there always for you.

LIST OF TABLES

LIST OF FIGURES

INTRODUCTION

Stroke is the most common neurologic disorder and a major cause of disability and death, with an overall growing incidence particularly in low to middle income countries [1]. symptoms last for less than 24 hours this is defined as transient ischemic attack (TIA). This updated definition wasn't adopted by many practitioners since it caused confusion.

Therefore, the patient's clinical status (nature and duration of deficits) must remain the basis of stroke and TIA definitions because this is what matters most and has been the main outcome of prognostic and therapeutic studies. Further, definitions focused on the clinical deficit allow inclusion of all affected persons and reduce the risk of mis-diagnosis [3].

Stroke is classified as either ischemic or hemorrhagic, with the majority being of ischemic origin [4]. The pathophysiology of ischemic stroke involves occlusion of an intracranial or extracranial carotid blood vessels that in most cases impair blood flow and leads to infarction of brain tissue supplied by that blood vessel. The vessel occlusion can occur due to a local vessel obstruction typically caused by atherosclerotic plaque, or secondary to embolization of a clot from the heart to a brain vessel as exemplified by atrial fibrillation [5].

Epidemiology and Burden of Stroke

Worldwide, stroke is the second most common cause of mortality. In 2015, stroke deaths accounted for 11.8% of total deaths worldwide, making stroke the second leading global cause of death behind heart disease [1].

Globally, the incidence of stroke due to ischemia is 68 %, while the incidence of hemorrhagic stroke (intracerebral hemorrhage and subarachnoid hemorrhage combined) is 32 % [6].In the United States, the proportion of all strokes due to ischemia, intracerebral hemorrhage, and subarachnoid hemorrhage is 87, 10, and 3 % respectively [4]. This shows that globally, there is a higher incidence of hemorrhagic stroke in low-and middle-income countries. In general, stroke is a disease of aging with most strokes occurring in people older than 65 years of age [4]. Aging is the strongest non-modifiable risk factor for ischemic stroke, and older stroke patients have higher mortality and morbidity and poorer prognosis than their young counterparts. Several aging related changes in the brain have been identified that are associated with an increase in vulnerability to ischemic stroke in the elderly. These changes include age-related alterations in cerebral blood vessels, a reduction in cerebral blood flow with age, and an increase in blood brain barrier permeability [START_REF] Chen | Ischemic stroke in the elderly: an overview of evidence[END_REF].

Gender

The relationship of sex to stroke risk depends on age. In early adulthood (up until age of 45), males have a higher incidence of ischemic stroke than females [4]. In middle age (ages of 45 -54 years), the rates of ischemic stroke begin to increase in women, concomitant with the onset of menopause and a decline of female sex hormones [START_REF] Christensen | Stroke in Women[END_REF].

After middle age (55 years and older), stroke rates continue to increase in women, reaching a stroke incidence that is comparable to males. In elderly females beyond the age of 85, a higher risk of stroke is reported in females. Overall, more strokes occur in women than men, because of the longer life span of women compared with men [4]. A study performed in Europe found that the risk of stroke increased by 9% per year in men and 10% per year in women [14]. The reasons behind these findings have not been fully elucidated.

Race

There are well-documented racial disparities in stroke. Blacks are at twice the risk of incident stroke when compared with their white counterparts and have higher mortality associated with stroke. Hispanic/Latino Americans also have an increased risk of stroke in some cohorts.

According to the REGARDS study (REasons for Geographic And Racial Differences in Stroke), one reason for the racial disparities could be the higher prevalence of stroke risk factors, such as hypertension, obesity, and diabetes mellitus, among blacks. However, these additional risk factors do not completely explain the increased risk seen in these racial-ethnic groups. Black race has been identified as a factor in the relationship between rurality and stroke risk, but this could be attributed to issues with access to health care [15].

1.3.2 Modifiable Risk Factors 1.3.2.

Hypertension

Hypertension (HTN) is the most important modifiable risk factor for stroke, with a strong, direct, linear, and continuous relationship between blood pressure and stroke risk. In INTERSTROKE, hypertension was the most important stroke risk factor: using a definition of hypertension that included both a history of hypertension and a blood pressure measurement of 160/90 mm Hg, the population attributable risk, or proportion of strokes in the population attributable to hypertension, was 52%. For ischemic stroke, the population attributable risk was 45% [START_REF] O'donnell | Risk factors for ischaemic and intracerebral haemorrhagic stroke in 22 countries (the INTERSTROKE study): a case-control study[END_REF].

The mechanism of stroke due to hypertension is complex and generally occurs due to longstanding hypertension. During this long period, a series of changes take place in the cardiovascular and cerebrovascular system. These changes, such as vascular remodeling, altered cerebral blood flow (CBF) auto regulation, inflammation, and oxidative stress contribute to the pathogenesis of stroke in hypertension [START_REF] O'donnell | Risk factors for ischaemic and intracerebral haemorrhagic stroke in 22 countries (the INTERSTROKE study): a case-control study[END_REF].

Vascular Remodeling

Sustained elevations in blood pressure have profound effects on the structure of cerebral blood vessels. Two types of remodeling are described, inward eutrophic or inward hypertrophic remodeling, depending on whether the media cross-sectional area is enlarged. In hypertrophic remodeling, the media thickens to encroach into the lumen, resulting in increased media cross-sectional area and media/lumen ratio. The size of vascular smooth muscle cells (VSMCs) increases and there is accumulation of extracellular matrix proteins, such as collagen and fibronectin, in the vessel wall. In eutrophic remodeling, smooth muscle cells undergo a rearrangement that leads to a reduction in the outer and inner diameters, whereas media/lumen ratio is increased and cross-sectional area is unaltered. In this case, the change in VSMCs size is negligible, and the reduction in lumen is due to a reorganization of cellular and acellular material in the vascular wall, accompanied by enhanced apoptosis in the outer regions of the blood vessel. Remodeling is damaging because it reduces the vessels' lumen and increases vascular resistance, and has emerged as a potential risk factor for cardiovascular events and cerebrovascular disease.

Moreover, longstanding HTN leads to arterial stiffening by inducing the deposition of collagen and elastin fragmentation in the walls of large arteries. Arterial stiffening leads to an increased pulse pressure which is a good predictor of stroke and cognitive decline [17].

Altered Cerebral Autoregulation

Cerebral auto regulation is a homeostatic process that regulates and maintains cerebral blood flow (CBF) constant across a range of blood pressures. The original conceptualization was proposed by Lassen as a triphasic curve consisting of the lower limit, the plateau and the upper limit. In healthy adults, the limits are between 50 and 150 mm Hg cerebral perfusion pressure (CPP) or 60 and 160 mm Hg mean arterial pressure (MAP), where CPP = MAPintracranial pressure (ICP). This homeostatic mechanism ensures that as MAP or CPP increases, resistance increases (vasoconstriction) in the small cerebral arteries. Conversely, this process maintains constant CBF by decreasing cerebrovascular resistance or vasodilation when MAP or CPP decreases [START_REF] Armstead | Cerebral Blood Flow Autoregulation and Dysautoregulation[END_REF].

Cerebral blood flow (CBF) reductions impair neuronal function and, if prolonged induce brain damage. HTN induces profound alterations of the regulatory mechanism, which, in concert with the structural changes described above, compromise the blood supply to the brain. HTN alters cerebrovascular auto regulation leading to a shift of the pressure-flow relationship to the right, such that higher pressures are needed to maintain the same level of cerebral perfusion. The lateral shift may be also associated with a reduction in resting CBF, resulting in a downward displacement of the curve. These alterations reduce cerebral perfusion at each level of blood pressure, compromising the ability of the brain to maintain adequate CBF in the face of hypotension or arterial occlusion. The mechanisms of the effects of HTN on auto regulation are not completely understood and has been shown that the self-regulation is lost during a stroke [START_REF] Faraco | Hypertension: a harbinger of stroke and dementia[END_REF].

Oxidative Stress

Oxidative stress is a condition in which generation of Reactive Oxygen Species exceeds the capacity of the antioxidant defense system. There is compelling evidence that oxidative stress play a critical part in the pathogenesis of hypertension, and stroke as a long-term complication. In the cerebral circulation, angiotensin II has been implicated in reactive oxygen species (ROS) particularly superoxide generation via activation of the enzyme NADPH oxidase. Peroxynitrite is the product of the reaction between nitric oxide and the radical superoxide. It can induce DNA damage and lipid peroxidation, change protein function.

Peroxynitrite exerts deleterious effects on cerebral blood vessels, which can account for the cerebrovascular dysfunction induced by Ang II [START_REF] Yu | From hypertension to stroke: mechanisms and potential prevention strategies[END_REF].

Diabetes

It is well known that diabetes causes various microvascular and macrovascular complications, one of which is stroke. Diabetes is a major risk factor for stroke and is associated with an increase in overall stroke mortality. Compared with nondiabetic patients, diabetic patients have at least twice the risk for stroke, and approximately 20% of diabetic patients will die from stroke, making it one of the leading causes of death in this population.

Diabetes duration has also been shown to increase the risk of ischemic stroke disease, with every year of diabetes duration increasing the risk by 3% [START_REF] Banerjee | Duration of diabetes and risk of ischemic stroke: the Northern Manhattan Study[END_REF].

There is a significant association between elevated glucose levels (fasting, postprandial, and glycated hemoglobin) and the incidence of stroke, independent of other traditional cardiovascular risk factors in patients with type 2 diabetes [START_REF] Kuusisto | Non-insulin-dependent diabetes and its metabolic control are important predictors of stroke in elderly subjects[END_REF].

Among diabetics numerous risk factors play a role together to promote the development of ischemic stroke. These risk factors can be classified as diabetes-specific factors such as hyperglycemia and vascular risk factors such as hypertension and dyslipidemia. In addition to these also genetic, demographic, and lifestyle factors contribute in varying degrees to the overall risk of the subjects with diabetes mellitus [START_REF] Banerjee | Duration of diabetes and risk of ischemic stroke: the Northern Manhattan Study[END_REF].

Hyperglycemia contributes to the pathogenesis of stroke through several possible pathways. The possible pathways include: increased polyol pathway flux, increased advanced glycation end product formation, activation of protein kinase C isoforms, and increased hexosamine pathway flux [START_REF] Baliga | Diabetes and stroke: part one--risk factors and pathophysiology[END_REF].

These pathogenic pathways lead to the generation of reactive oxygen species which may lead to endothelial dysfunction by reducing the bioavailability of endothelium-derived nitric oxide (NO). The formation of Advanced Glycosylation End Products accelerates the atherosclerotic process by promoting low-density lipoprotein (LDL) uptake and oxidation leading to foam cell formation. These complex changes lead to the typical diabetic milieu that is characterized by a chronic state of low-grade inflammation, endothelial dysfunction, hypercoagulability, dyslipidemia and insulin resistance. Moreover, there is a higher prevalence and incidence of cardiometabolic risk factors such as obesity, hypertension, and dyslipidemia in patients with diabetes that add on to stroke risk [START_REF] Baliga | Diabetes and stroke: part one--risk factors and pathophysiology[END_REF].

There are clear differences in stroke patterns between patients with diabetes and those without diabetes. Patients with diabetes have a higher proportion of ischemic stroke compared to hemorrhagic strokes. Also, lacunar stroke is the most common stroke type. This may be due to the higher prevalence of microvascular disease and the co-existence of hypertension seen in this patient group [START_REF] Kuusisto | Non-insulin-dependent diabetes and its metabolic control are important predictors of stroke in elderly subjects[END_REF].

Atrial Fibrillation (AF)

The most disabling consequence of atrial fibrillation (AF) is ischemic stroke. In the setting of AF, a thrombus originating from the heart travels to the brain's vascular system resulting in the occlusion of a brain blood vessel and damage to the brain tissue. As described above, this is known as a cardioembolic stroke. The mechanism of thrombus formation in AF is a multifactorial process that includes changes in flow, atrial anatomy, prothrombotic alterations in blood constituents, and inflammation [START_REF] Castellano | Mechanisms of Stroke in Atrial Fibrillation[END_REF].

The failure of fibrillating atria to contract results in an increase in atrial pressure, atrial stretch, and dilation which lead to blood stasis. Also, the erratic atrial wall motion and abnormal blood flow lead to injury of the endothelium of the fibrillating atria, thus leading to activation of the clotting cascade with platelet adhesion and aggregation. Activated platelets provide a catalytic surface for assembling plasma factors of the prothrombinase complex and subsequent thrombin formation, fibrin generation, and thus thrombus consolidation.

Attached to each atrium is an appendage. The left atrium and particularly the left atrial appendage (LAA) is the source of cardioembolic emboli in most cases of AF. As noted by Blackshear and Odell who identified that the LAA is the source of up to 90% of left atrial thrombi in nonvalvular AF and 57% in valvular AF [START_REF] Abrich | Left atrial appendage exclusion during mitral valve surgery and stroke in atrial fibrillation[END_REF].

This is due to the morphology of the LAA, a frequently long, narrow, and hooked extension of the left atrium which creates an anatomic environment for blood stasis and thrombus formation.

It was previously thought that blood stasis was the sole mechanism of stroke in AF, however recent evidence also indicates that patients with AF are in a hypercoagulable state.

Platelet activation is enhanced in patients with AF as determined by increased plasma levels of platelet derived b-thromboglobulin and platelet factor. In addition, in patients with AF, elevated levels of coagulation parameters such as thrombin-antithrombin III complex, D-dimers, fibrinogen, prothrombin fragments 1 and 2, and von Willebrand factor (vWF) have been described, indicating a hypercoagulable state [START_REF] Khan | The prothrombotic state in atrial fibrillation: pathophysiological and management implications[END_REF].

Dyslipidemia

The relationship between lipids and stroke is complex. In most, but not all, observational studies, there is an association between higher total and LDL cholesterol levels and increased ischemic stroke risk [START_REF] Menet | Hyperlipidemia in Stroke Pathobiology and Therapy: Insights and Perspectives[END_REF].

The reason for these differences between studies could be explained by the differential association with ischemic stroke subtypes. The strongest association is between lipids and large artery atherosclerosis, while dyslipidemia is less likely to play a major role in the pathogenesis of other ischemic stroke subtypes. In a case-control study, the association between cholesterol and ischemic stroke risk was strongest for large artery atherosclerosis (OR=3.2) [START_REF] Watanabe | Shizukiyo Ishikawa High-Density Lipoprotein Cholesterol and Risk of Stroke Subtypes: Jichi Medical School Cohort Study[END_REF].

The association between dyslipidemia and large artery atherosclerotic stroke subtype was also shown in two other Japanese studies [START_REF] Cui | High serum total cholesterol levels is a risk factor of ischemic stroke for general Japanese population: the JPHC study[END_REF][START_REF] Imamura | LDL cholesterol and the development of stroke subtypes and coronary heart disease in a general Japanese population: the Hisayama study[END_REF].

There is strong evidence that LDL, along with other factors, play a fundamental role in the development of atherosclerosis. Atherosclerotic lesions or plaques may protrude into the lumen of the arteries, causing occlusion thus limiting blood flow. These plaques can rupture leading to thrombosis, thus completely blocking blood flow. These processes usually occur in the large intracranial and extracranial cerebral blood vessels therefore, leading to ischemic stroke [START_REF] Cui | High serum total cholesterol levels is a risk factor of ischemic stroke for general Japanese population: the JPHC study[END_REF].

Cigarette smoking

Cigarette smoking is an independent predictor of cerebrovascular disease in both men and women. Smokers have a relative risk of ischemic stroke of 1.92 times higher as compared to non-smokers. Cigarette smoking increases heart rate, blood pressure, the risk of thrombus formation, and the development of atherosclerosis. Also, smoking increases blood viscosity, fibrinogen and platelet aggregation, and decreases high density lipoprotein (HDL) cholesterol [START_REF] Amiri | Smoking habits and incidence of cardiovascular diseases in men and women: findings of a 12 year follow up among an urban Eastern-Mediterranean population[END_REF]. In addition, according to a study conducted by Al Hajje et al., waterpipe and cigarette smoking were observed to have a stronger association with stroke in current smokers than non-smokers among Lebanese population [START_REF] El-Hajj | Cigarette and Waterpipe Smoking are Associated with the Risk of Stroke in Lebanon[END_REF].

Physical inactivity

It is well documented that physical activity exerts a beneficial protective effect on reduction of stroke risk and recurrence throughout life including in older adults. In the Nurses' Health Study and the Women's Health Initiative, mild exercise such as walking was associated with reduced risk, and in postmenopausal women, slow walking speed was a strong independent predictor of increased risk of stroke. In a longitudinal study of older, multiethnic, urban-dwelling stroke free individuals, greater exercise intensity was found to be associated with lowering stroke risk for men. A meta-analysis report of physical activity and stroke risk concluded that moderately and highly active adults had a lower risk of stroke than low-activity adults. Moderately active adults had a 20% stroke risk reduction and in highly active adults, a 27% risk reduction [START_REF] Larry B Goldstein | Physical activity and the risk of stroke[END_REF].

Possible mechanisms activated in physical activity to reduce risk include reduction in plasma fibrinogen, decrease aggregability of platelets, lowering blood pressure and reducing weight. Despite the documented benefits of an active life as demonstrated in a number of longitudinal studies, sedentary lifestyles continue to be an increasing trend. For stroke, the benefits of even light to moderate activities results in an important health benefits in the pathway to stroke reduction [START_REF] Larry B Goldstein | Physical activity and the risk of stroke[END_REF].

Alcohol Consumption

The association between alcohol intake and stroke morbidity and mortality is Jshaped. Light and moderate alcohol consumption is associated with reduced risk of stroke, while heavy alcohol consumption is associated with an increased risk [START_REF] Rantakömi | Alcohol consumption and the risk of stroke among hypertensive and overweight men[END_REF].

Heavy alcohol use likely increases the risk of stroke by increasing the risk of hypertension, atrial fibrillation, cardiomyopathy, and diabetes [START_REF] Chjen | Associations between alcohol intake and diabetic retinopathy risk: a systematic review and meta-analysis[END_REF][START_REF] Briasoulis | Alcohol consumption and the risk of hypertension in men and women: a systematic review and meta-analysis[END_REF][START_REF] Kodama | Alcohol consumption and risk of atrial fibrillation: a meta-analysis[END_REF].

A recent systematic review and meta-analysis included [START_REF] Menet | Hyperlipidemia in Stroke Pathobiology and Therapy: Insights and Perspectives[END_REF] All the symptoms need not be present to diagnose stroke. Any of the above-mentioned symptoms can be present and is helpful is diagnosing ischemic as well as hemorrhagic stroke.

For complete assessment of a stroke patient it is recommended to use the NIH stroke scale (NIHSS) as illustrated in Figure 1.

Total Score

Place in the order section of patient's chart MD Signature

Treatment of Ischemic Stroke

The goal of therapy in acute ischemic stroke is to preserve and maintain tissue perfusion to avoid infarction. Therapy should be targeted to restore blood flow to the compromised regions and improve collateral flow. Restoring blood flow can minimize the effects of ischemia only if performed quickly. The treatment of ischemic stroke is divided into acute stroke care and secondary prevention [START_REF] Hui | Ischemic Stroke. StatPearls. Treasure Island[END_REF]. In the acute phase, treatment is aimed at reperfusion of the ischemic tissue with IV thrombolytic or mechanical thrombectomy, management of blood pressure, and avoiding complications. After the acute phase, treatment is aimed at reducing the risk of recurrent stroke by determining the most likely etiology and directing treatment towards the cause(s).

Acute Stroke Care

The main goals of treatment in the acute phase of ischemic stroke are: acute reperfusion and management of blood pressure.

Acute Reperfusion

For acute reperfusion two strategies are available: IV thrombolytics and mechanical thrombectomy. Mechanical thrombectomy should be considered in all patients, even if fibrinolytic therapy is administered. The AHA/ASA guidelines do not recommend observation for a clinical response after IV alteplase administration even if mechanical thrombectomy is considered a treatment option [4].

Endovascular thrombectomy in the first six hours is much better than standard medical care in patients with large vessel occlusion in the arteries of the proximal anterior circulation [START_REF] Hui | Ischemic Stroke. StatPearls. Treasure Island[END_REF].

In acute stroke, ischemia is rarely complete at presentation. During acute ischemic stroke (AIS) there are two regions of ischemia the core and the penumbra. The core, where the blood clot occurs, receives roughly 10% to 25% of normal blood flow, leading to infarction and tissue necrosis [START_REF] Liu | Targeting ischemic penumbra: part I -from pathophysiology to therapeutic strategy[END_REF].

The penumbra, which is the ischemic tissue surrounding the core, can receive blood from collateral circulation, delaying completion of the infarct. These neurons are salvageable if reperfused in time. Thrombolysis with IV alteplase can lyse the clot and restore blood flow to the ischemic penumbra. IV alteplase is the only FDA approved treatment for patients with AIS [START_REF] Hui | Ischemic Stroke. StatPearls. Treasure Island[END_REF]. Alteplase is a recombinant tissue-type plasminogen activator (rt-PA). The advent of alteplase has dramatically revolutionized the treatment of AIS since it improves patients' outcomes and resolves their neurologic deficits [START_REF] Dhillon | Alteplase: a review of its use in the management of acute ischaemic stroke[END_REF]. Despite its benefits, alteplase use is not without risks. The most feared side effect of alteplase is symptomatic intracerebral hemorrhage (sICH). To reduce the rate of this side effect, patients with AIS are carefully selected and a strict eligibility criterion is in place. Table 1 lists the inclusion/ exclusion criteria.

Its FDA approval was based on the results of the National Institute of Neurological Disorders and Stroke (NINDS) trials which showed that IV rt-PA administration within 3 hours of ischemic stroke symptoms onset improved clinical outcomes compared to placebo [START_REF] Wardlaw | Recombinant tissue plasminogen activator for acute ischaemic stroke: an updated systematic review and meta-analysis[END_REF]. An alteplase dose of 0.9 mg/kg was used in the NINDS trial. And the total dose of alteplase is divided into a 10% bolus and 90% as an infusion over 60 minutes [47][48].

While FDA labeling still indicates that patients eligible for IV rt-PA should be treated within 3 hours, the AHA/ASA treatment guidelines recommend that IV rt-PA also be also showed benefit of IV tPA in functional outcomes. However, the rate of symptomatic intracerebral hemorrhage was significantly higher in the IV rt-PA group, but no difference in mortality rate was observed. Therefore, IV rt-PA is considered safe in this extended time window [START_REF] Hacke | Thrombolysis with alteplase 3 to 4.5 hours after acute ischemic stroke[END_REF].

Although IV alteplase may be administered up to 4.5 hours after stroke onset, several trials have shown that earlier administration correlates with better outcomes [START_REF] Turc | Intravenous thrombolysis for acute ischemic stroke[END_REF].

"Time is brain" during AIS and timely reperfusion is of utmost importance. Nearly 2 to 10 million neurons are lost during each minute of untreated stroke [START_REF] Saver | Time is brain--quantified[END_REF].

Thus, shorter door-to-needle times of IV rt-PA administration can save more neurons and improve functional outcomes. A meta-analysis of several studies supports this conclusion [START_REF] Emberson | Effect of treatment delay, age, and stroke severity on the effects of intravenous thrombolysis with alteplase for acute ischaemic stroke: a meta-analysis of individual patient data from randomised trials[END_REF].

Based on this, the AHA/ASA recommend a door-to-needle time of < 60 minutes for IV rt-PA administration once the patient arrives at the hospital [START_REF] Turc | Intravenous thrombolysis for acute ischemic stroke[END_REF].

Despite the clear data that support its timely use, utilization of IV rt-PA remains significantly low in both developed and developing countries [START_REF] Sayed | Acute stroke care and thrombolytic therapy use in a tertiary care center in Lebanon[END_REF]. The utilization of thrombolytic therapy for acute stroke patients in the developing countries is low (less than 1% to 3%) compared to developed countries (up to 10%) [START_REF] Wasay | Utilization and outcome of thrombolytic therapy for acute stroke in Pakistan[END_REF]. In Lebanon, the results showed that around 10.3%

of the acute ischemic stroke patients who met the eligible criteria received rt-PA administration [START_REF] Sayed | Acute stroke care and thrombolytic therapy use in a tertiary care center in Lebanon[END_REF] .

Results from Get with the Guidelines Stroke program revealed that only 7% of all stroke patients arrived within a time period eligible for IV rt-PA, and only 77% of patients eligible for rt-PA were given rt-PA within 2 hours of symptom onset [START_REF] Schwamm | Get With the Guidelines-Stroke is associated with sustained improvement in care for patients hospitalized with acute stroke or transient ischemic attack[END_REF]. Combination of both previous ischemic stroke and diabetes mellitus IV alteplase has numerous limitations including a low potential to recanalize occluded vessels with a large (>8 mm) thrombus [START_REF] Riedel | The importance of size: successful recanalization by intravenous thrombolysis in acute anterior stroke depends on thrombus length[END_REF], resulting in a poor recanalization rate (13% to 50%) in large vessel occlusion stroke and a low rate of benefit in the patients having the most disabling strokes [START_REF] Khandelwal | Acute Ischemic Stroke Intervention[END_REF].

To overcome these limitations, alternative therapies have been studied. Tenecteplase is one of these alternative therapies.

Tenecteplase (TNK) is a genetically engineered variant of rt-PA that has a longer halflife and is more fibrin specific than rt-PA. TNK has properties which make it a faster and more complete thrombolytic agent and, at the same time, with less bleeding complications and early reocclusions [START_REF] Bhaskar | Reperfusion therapy in acute ischemic stroke: dawn of a new era?[END_REF].

Furthermore, TNK can be given as a one-time bolus without need for an infusion [START_REF] Bivard | Review of stroke thrombolytics[END_REF].

In the Tenecteplase versus Alteplase for Acute Ischemic Stroke (TAAIS) trial, 75

patients, who arrived <6 hour after the onset of ischemic stroke, were randomly assigned to receive either rt-PA (0.9 mg/kg) or TNK (0.1 mg/kg or 0.25 mg/kg). Patients treated with TNK had greater reperfusion rates and better clinical outcomes at 24 hour than rt-PA patients, while no significant differences in intracranial bleeding or other serious adverse events were noted between the groups. Although TNK has shown promising results, IV rt-PA is still recommended as the standard of care. had hypertension (defined as SBP greater than 140 mmHg) within the first two days of the acute stroke [START_REF] Hong | Rivaroxaban vs Warfarin Sodium in the Ultra-Early Period After Atrial Fibrillation-Related Mild Ischemic Stroke: A Randomized Clinical Trial[END_REF].

Another study, the IST trial recruited 19,435 patients and reported an incidence of hypertension of 80% [START_REF]The International Stroke Trial (IST): a randomised trial of aspirin, subcutaneous heparin, both, or neither among 19435 patients with acute ischaemic stroke. International Stroke Trial Collaborative Group[END_REF].

It is unclear whether this rise in BP is a protective mechanism to increase perfusion to the ischemic area or whether it's due to chronic hypertension or other pathological mechanisms. Under normal physiological conditions, cerebral autoregulation maintains adequate and stable cerebral blood flow despite fluctuations in mean arterial pressure (MAP). This is achieved by the small arteries and arterioles of the cerebral vasculature which constrict or dilate in response to changes in the systemic blood pressure. However, in patients with AIS cerebral autoregulation may be impaired [START_REF] Jordan | Cerebral autoregulation and acute ischemic stroke[END_REF].

Blood Pressure as a Prognostic Factor in AIS Results of several observational studies have revealed a U-shaped relationship between blood pressure and poor outcomes. Both very high and very low baseline blood pressures were associated with poor outcomes. The results of an analysis from the IST which evaluated more than 17,000 patients with ischemic stroke revealed that early death increased by 17.9% for every 10 mm Hg below 150 mm Hg (P<0.0001) and by 3.8% for every 10 mm Hg above 150 mm Hg (P=0.016). Moreover, the rate of recurrent ischemic stroke within 14 days increased by 4.2% for every 10mm Hg increase in SBP (P=0.023). Low SBP was associated with a severe clinical stroke (total anterior circulation syndrome) and an excess of deaths from coronary heart disease (P=0.002) [START_REF] Rasmussen | Blood Pressure Thresholds and Neurologic Outcomes After Endovascular Therapy for Acute Ischemic Stroke: An Analysis of Individual Patient Data From 3 Randomized Clinical Trials[END_REF].

Should high BP be treated?

Several studies have shown that BP declines within the first several hours to days following ischemic stroke without administration of antihypertensives [START_REF] Mcmanus | Blood Pressure in Acute Ischemic Stroke[END_REF][START_REF] Schrader | The ACCESS Study: evaluation of Acute Candesartan Cilexetil Therapy in Stroke Survivors[END_REF].

One of the most controversial questions that remain unanswered is whether high blood pressure in the setting of acute ischemic stroke should be treated. The rationale for lowering BP is to reduce or prevent cerebral edema and limit hemorrhagic transformation of the infarct. However, lowering BP too much in AIS worsens hypoperfusion and leads to the expansion of the ischemic core.

When to treat high blood pressure?

Treatment of the rise in blood pressure in the acute phase of ischemic stroke depends on whether the patient is eligible for acute reperfusion or not. The treatment of hypertension for patients ineligible for thrombolysis is controversial, and no strict blood pressure goals are recommended. Current AHA/ASA guidelines state that, in patients with BP < 220/120 mmHg who did not receive IV rt-PA or undergo mechanic thrombectomy and have no comorbid condition requiring antihypertensive treatment (for example, aortic dissection, acute coronary event, or acute heart failure), treatment of hypertension within the first 48 to 72 hours is not considered effective to prevent death or dependency [START_REF] Powers | Guidelines for the Early Management of Patients With Acute Ischemic Stroke: A Guideline for Healthcare Professionals From the American Heart Association/American Stroke Association[END_REF].

Furthermore, multiple trials have shown that treating hypertension in the acute phase of ischemic stroke does not improve outcomes. The Scandinavian Candesartan Acute Stroke Trial (SCAST) [START_REF] Sandset | The angiotensinreceptor blocker candesartan for treatment of acute stroke (SCAST): a randomised, placebocontrolled, double-blind trial[END_REF] with SBP values between 141 and 150 mm Hg up to 24 hours after thrombolysis [START_REF] Ahmed | Relationship of blood pressure, antihypertensive therapy, and outcome in ischemic stroke treated with intravenous thrombolysis: retrospective analysis from Safe Implementation of Thrombolysis in Stroke-International Stroke Thrombolysis Register (SITS-ISTR)[END_REF].

Choice of Antihypertensive

In the acute phase of stroke, there is a lack of evidence to suggest a specific antihypertensive agent over the others. However, it's preferable to use agents that are reversible, titratable and carry a low risk of increased intracranial pressure. The AHA/ASA guidelines suggest the use of IV nicardipine, labetalol, or clevidipine [START_REF] Powers | Guidelines for the Early Management of Patients With Acute Ischemic Stroke: A Guideline for Healthcare Professionals From the American Heart Association/American Stroke Association[END_REF].

Table 2 provides the dosing of these agents. Intravenous nitroprusside is considered if blood pressure is not controlled on the aforementioned agents. It is considered a second line agent due to its risk of increased intracranial pressure.

Table 2. Choice of antihypertensive agents [66] Patient otherwise eligible for acute reperfusion therapy except that BP is >185/110 mmHg Antipyretics such as acetaminophen may be used to lower temperature but induction of hypothermia is not supported [START_REF] Powers | Guidelines for the Early Management of Patients With Acute Ischemic Stroke: A Guideline for Healthcare Professionals From the American Heart Association/American Stroke Association[END_REF]. Common sources of infection should be ruled out, such as pneumonia and urinary tract infections.

Treatment of Hyperglycemia

Glucose level should be maintained in the range of 140 to 180 mg/dL in the first 24 hours.

Hypoglycemia defined by levels less than 60 mg/dL should be treated to achieve normoglycemia as hypoglycemia decreases the repair of the brain which can be explained by the fact that the brain is dependent on oxidative pathways that require glucose for metabolism, and the metabolic demand of the brain is high. However, hyperglycemia decreases reperfusion due to oxidation of nitric oxide-dependent mechanisms and subsequent loss of vascular tone and is associated with an increase in mortality [START_REF] Zhu | Stress Hyperglycemia and Outcome of Non-diabetic Patients After Acute Ischemic Stroke[END_REF].

Hyperglycemia in the acute stroke should be treated with the rapid acting insulin to achieve the target blood glucose level [START_REF] Powers | Guidelines for the Early Management of Patients With Acute Ischemic Stroke: A Guideline for Healthcare Professionals From the American Heart Association/American Stroke Association[END_REF]. [START_REF] Powers | Guidelines for the Early Management of Patients With Acute Ischemic Stroke: A Guideline for Healthcare Professionals From the American Heart Association/American Stroke Association[END_REF]. In addition, statins should be continued if the patients were already on statins prior to the ischemic stroke.

Anticoagulants

Anticoagulation therapy is not routinely indicated for acute stroke management due to the associated risk of intra or extra-cranial bleeding regardless of the benefits they provide.

Controversy exists over the timing for initiation of anticoagulation, the efficacy of the treatment in relation to stroke etiology, the ideal dose of anticoagulants, and the use of novel anticoagulants [START_REF] Whiteley | Targeted use of heparin, heparinoids, or low-molecular-weight heparin to improve outcome after acute ischaemic stroke: an individual patient data meta-analysis of randomised controlled trials[END_REF][START_REF] Paciaroni | Efficacy and safety of anticoagulant treatment in acute cardioembolic stroke: a meta-analysis of randomized controlled trials[END_REF]. Current AHA/ASA 2018 guidelines provide against the use of anticoagulation in acute ischemic stroke regardless of the extent of stenosis [START_REF] Powers | Guidelines for the Early Management of Patients With Acute Ischemic Stroke: A Guideline for Healthcare Professionals From the American Heart Association/American Stroke Association[END_REF] . Usually, if the size of the stroke is small to moderate, anticoagulation can be started within 7-14 days and delayed for a couple of weeks if small hemorrhagic transformation after acute stroke was documented [START_REF] Paciaroni | Early Recurrence and Major Bleeding in Patients With Acute Ischemic Stroke and Atrial Fibrillation Treated With Non-Vitamin-K Oral Anticoagulants (RAF-NOACs) Study[END_REF][START_REF] Paciaroni | Hemorrhagic Transformation in Patients With Acute Ischemic Stroke and Atrial Fibrillation: Time to Initiation of Oral Anticoagulant Therapy and Outcomes[END_REF].

Deep Vein Thrombosis Prophylaxis

Intermittent pneumatic compression is recommended for all immobile patients unless there are contraindications. Although prophylactic heparin is often used for immobile patients, the benefit is not clear in stroke patients [START_REF]Efficacy and safety of very early mobilisation within 24 h of stroke onset (AVERT): a randomised controlled trial[END_REF].

Dual Antiplatelet Therapy (DAPT)

Stroke is common during the first few weeks after TIA or minor ischemic stroke. The risk of another stroke occurring after a TIA or minor stroke is high, with approximately 10 to 20% of patients having a stroke within 3 months after the index event; most of these strokes occur within the first 2 days [START_REF] Lovett | Early risk of recurrence by subtype of ischemic stroke in population-based incidence studies[END_REF].

Therefore, antiplatelet therapy is indicated for patients with AIS within 24 to 48 hours after onset. And for those treated with IV alteplase, aspirin administration is generally delayed until 24 hours later.

Results from two trials using dual antiplatelet therapy (aspirin plus clopidogrel) have

shown benefit compared to aspirin alone in patients with minor stroke. The CHANCE trial was a randomized, double-blind, placebo-controlled trial conducted in China which recruited 5170 patients. These patients were assigned within 24 hours after the onset of minor ischemic stroke or high-risk TIA to combination therapy with clopidogrel and aspirin (clopidogrel at an initial maximum dose of 300 mg, followed by 75 mg per day for 90 days, plus aspirin at a dose of 75 mg per day for the first 21 days) or to placebo plus aspirin (75 mg per day for 90 days). Stroke occurred in 8.2% of patients in the clopidogrel-aspirin group, as compared with 11.7% of those in the aspirin group (hazard ratio, 0.68; 95% confidence interval, 0.57 to 0.81; P<0.001). Moderate or severe hemorrhage occurred in seven patients (0.3%) in the clopidogrel-aspirin group and in eight (0.3%) in the aspirin group (P = 0.73).

The authors concluded that the combination of clopidogrel and aspirin is superior to aspirin alone for reducing the risk of stroke in the first 90 days with no increase in the risk of hemorrhage [START_REF] Wang | Clopidogrel with aspirin in acute minor stroke or transient ischemic attack[END_REF].

The CHANCE trial was conducted on Chinese population; therefore its results cannot be generalized to the general population. Another trial, the POINT trial, tested the combination of aspirin and clopidogrel in an international population. The POINT trial enrolled 4811 patients with minor ischemic stroke or high-risk TIA. These patients were randomized to receive either clopidogrel at a loading dose of 600 mg on day 1, followed by 75 mg per day, plus aspirin (at a maximum dose of 325 mg per day) or the same range of doses of aspirin alone. Major ischemic events occurred in 121 of 2432 patients (5.0%) receiving clopidogrel plus aspirin and in 160 of 2449 patients (6.5%) receiving aspirin plus placebo (hazard ratio, 0.75; 95% confidence interval [CI], 0.59 to 0.95; P = 0.02), with most events occurring during the first week after the initial event. Major hemorrhage occurred in 23 patients (0.9%) receiving clopidogrel plus aspirin and in 10 patients (0.4%) receiving aspirin plus placebo (hazard ratio, 2.32; 95% CI, 1.10 to 4.87; P = 0.02). According to a previous study, patients with minor ischemic stroke or high-risk TIA who received a combination of clopidogrel and aspirin had a lower risk of major ischemic events but a higher risk of major hemorrhage at 90 days than those who received aspirin alone [START_REF] Johnston | Clopidogrel and Aspirin in Acute Ischemic Stroke and High-Risk TIA[END_REF].

The AHA/ASA guidelines recommend administering dual antiplatelet therapy (aspirin plus clopidogrel) for patients presenting within 24 hours with minor stroke for a treatment duration of 21 days [START_REF] Powers | Guidelines for the Early Management of Patients With Acute Ischemic Stroke: A Guideline for Healthcare Professionals From the American Heart Association/American Stroke Association[END_REF].

Secondary Prevention

Up to 25% of strokes are recurrent strokes. The case mortality rate after an initial stroke is 22% whereas in recurrent stroke the rate goes up to 41% [START_REF] Dhamoon | Recurrent stroke and cardiac risks after first ischemic stroke: the Northern Manhattan Study[END_REF].

Therefore, it is important to prevent recurrent stroke. As stated earlier, there are modifiable risk factors for stroke such as hypertension, diabetes mellitus, dyslipidemia, smoking, and physical inactivity. These risk factors are amenable for secondary prevention by the use of pharmacological therapy. Moreover, atrial fibrillation is a major cause of cardioembolic stroke; therefore, the use of anticoagulants as prevention is an important strategy for this type of ischemic stroke. The following section will review the different strategies implemented to prevent ischemic stroke [START_REF] Dhamoon | Recurrent stroke and cardiac risks after first ischemic stroke: the Northern Manhattan Study[END_REF].

Antihypertensive Therapy

Hypertension is the most common modifiable risk factor for stroke. The prevalence of premorbid hypertension in patients with recent stroke is approximately 70% [START_REF] Lovett | Early risk of recurrence by subtype of ischemic stroke in population-based incidence studies[END_REF].

Hypertension increases the risk of recurrent stroke and several meta-analyses have shown that antihypertensives decrease the risk of recurrent stroke by approximately 30%.

Although the evidence for using antihypertensive treatment to prevent recurrent stroke in stroke patients with elevated BP is compelling, questions remain about when precisely after an index stroke to initiate it, what specific agent to use, which BP goal to aim for, and whether the treatment approach should vary by index stroke etiology and baseline level of BP.

The AHA/ASA guidelines recommend resumption of antihypertensive therapy for previously treated, neurologically stable patients with known hypertension for prevention of recurrent stroke. In addition, antihypertensive therapy should be initiated for previously untreated, neurologically stable patients with any type of stroke or TIA who have a blood pressure that is above target. Generally, they are started or restarted 24 to 48 hours after ischemic stroke onset and during hospitalization.

Monotherapy is recommended when blood pressure is <20/10 mmHg above goal.

According to hypertension guidelines the choice of drug is as follows: for adults who experience a stroke or TIA, treatment with a thiazide diuretic, ACE inhibitor, or ARB, or combination treatment consisting of a thiazide diuretic plus ACE inhibitor, is useful [START_REF] Whelton | ACC/AHA/AAPA/ABC/ACPM/AGS/APhA/ASH/ASPC/NMA/PCNA Guideline for the Prevention, Detection, Evaluation, and Management of High Blood Pressure in Adults: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines[END_REF].

This recommendation is based on several randomized controlled trials (RCTs) and systematic reviews [START_REF] Liu | Science EOT dataset[END_REF][START_REF]Randomised trial of a perindopril-based blood-pressure-lowering regimen among 6,105 individuals with previous stroke or transient ischaemic attack[END_REF][START_REF] Sacco | Aspirin and extended-release dipyridamole versus clopidogrel for recurrent stroke[END_REF]. Beta blockers have shown that they do not reduce stroke risk compared to other antihypertensives and are not recommended unless there is a compelling indication for them [START_REF] Wiysonge | Betablockers for hypertension[END_REF].

Despite the recommendations for choice of antihypertensives, calcium channel blockers have not shown statistical difference from angiotensin inhibitors and diuretics [START_REF] Chen | The effects of calcium channel blockers in the prevention of stroke in adults with hypertension: a meta-analysis of data from 273,543 participants in 31 randomized controlled trials[END_REF][START_REF] Wang | Comparative Effectiveness of Blood Pressure-lowering Drugs in Patients who have Already Suffered From Stroke: Traditional and Bayesian Network Meta-analysis of Randomized Trials[END_REF].

According to hypertension guidelines a BP goal of less than 130/80 mm Hg is recommended for adult patients who have had a stroke or TIA [START_REF] Whelton | ACC/AHA/AAPA/ABC/ACPM/AGS/APhA/ASH/ASPC/NMA/PCNA Guideline for the Prevention, Detection, Evaluation, and Management of High Blood Pressure in Adults: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines[END_REF].

Anticoagulant Therapy (non-Cardioembolic Stroke)

Anticoagulation is not recommended for prevention of stroke in patients with noncardioembolic stroke based on the results of several studies comparing aspirin with warfarin.

The WARSS study enrolled 2206 patients with recent (within 30 days) ischemic stroke without evidence of cardioembolic source. It compared aspirin 325 mg with warfarin with a target INR of 1.4 to 2.8. There were no significant differences between the groups in terms of efficacy or bleeding risk [START_REF] Hankey | Warfarin-Aspirin Recurrent Stroke Study (WARSS) trial: is warfarin really a reasonable therapeutic alternative to aspirin for preventing recurrent noncardioembolic ischemic stroke?[END_REF].

Another trial, the WASID trial compared warfarin and aspirin in those with recent stroke and documented 50 to 99% intracranial stenosis (who had no evidence of significant carotid or cardio-embolic disease) and revealed no benefit from warfarin in terms of stroke recurrence which was similar in both groups (HR 1.04, 95% CI 0.73 to 1.48). However, there was an increased hemorrhage rate and increased mortality [START_REF] Chimowitz | Comparison of warfarin and aspirin for symptomatic intracranial arterial stenosis[END_REF].

The SPIRIT trial included 1316 patients with TIA or minor stroke. The trial was terminated early due to increased bleeding, although it did involve a high target INR (3 to 4.5). The ESPRIT trial enrolled 1038 patients with recent ischemic stroke. It compared aspirin with warfarin (target INR 2 -3). There was no difference in rate of the primary outcome between treatment groups although ischemic events were lower following warfarin (HR 0.73, 95% CI 0.52 to 1.01) but major hemorrhage rate was higher (HR 2.56, 95% CI 1.48 to 4.43) [START_REF] Halkes | Medium intensity oral anticoagulants versus aspirin after cerebral ischaemia of arterial origin (ESPRIT): a randomised controlled trial[END_REF].

Anticoagulant Therapy (Cardioembolic Stroke)

Due to the thromboembolic risk associated with atrial fibrillation (AF), chronic oral anticoagulation is recommended for most AF patients. However, such therapy is associated with an increased risk of bleeding and recommendations for its use must take both benefit and risk into account. Scoring algorithms are now commonly employed to help predict stroke risk and identify those with atrial fibrillation most likely to benefit from anticoagulant treatment. The CHA2DS2-VASc score is available to calculate whether a patient with non-rheumatic atrial fibrillation requires anticoagulation. This score is endorsed by the American and European guidelines [START_REF] January | AHA/ACC/HRS Focused Update of the 2014 AHA/ACC/HRS Guideline for the Management of Patients With Atrial Fibrillation: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines and the Heart Rhythm Society[END_REF].

The most recent update in the atrial fibrillation guidelines recommend that for men with a CHA2DS2-VASc score of 2 or greater and women with a CHA2DS2-VASc score of 3 or greater, oral anticoagulation should be administered. Options include: vitamin K antagonists such as warfarin and the direct-acting oral anticoagulants (DOACs) also known as nonvitamin K oral anticoagulants (NOACs). The NOACs include rivaroxaban, apixaban, edoxaban (direct factor Xa inhibitors) and dabigatran (direct thrombin inhibitor). Oral anticoagulants might be reasonable for men with CHA2DS2-VASc score of 1 and women with CHA2DS2-VASc score of 2 [START_REF] January | AHA/ACC/HRS Focused Update of the 2014 AHA/ACC/HRS Guideline for the Management of Patients With Atrial Fibrillation: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines and the Heart Rhythm Society[END_REF].

NOACs are preferred over warfarin in patients with non-valvular AF (valvular heart disease is defined as moderate-to-severe mitral stenosis or a mechanical heart valve).

Warfarin remains the drug of choice in patients with valvular AF [START_REF] January | AHA/ACC/HRS Focused Update of the 2014 AHA/ACC/HRS Guideline for the Management of Patients With Atrial Fibrillation: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines and the Heart Rhythm Society[END_REF].

Statins

Statins are the most commonly prescribed lipid lowering therapy. Numerous trials have been published on their beneficial effects on low-density lipoprotein cholesterol (LDL-C), cardiovascular disease events, and mortality. Also, the benefits of statin treatment have been shown for primary and secondary stroke prevention. Interestingly, epidemiologic and observational studies have not shown a clear association between cholesterol levels and all causes of stroke [93].

Moreover, non-statin drugs (such as fibrates and bile acid sequestrants) have shown no significant impact on stroke incidence even though they lowered cholesterol levels. This suggests that statins have an extra non-lipid lowering mechanism by which they decrease the risk of initial and recurrent stroke. This mechanism has not been fully elucidated. However, it has been proposed that statins' pleiotropic effects play a role in stroke prevention. These effects include plaque stabilization, antithrombotic effects, reduction in inflammation, improving endothelial function and slowing carotid arterial disease progression.

The Heart Protection Study (HPS) [START_REF]MRC/BHF Heart Protection Study of cholesterol lowering with simvastatin in 20,536 highrisk individuals: a randomised placebo-controlled trial[END_REF] provided the first evidence of the benefit of statin therapy in secondary stroke prevention. Patients with high risk of vascular events (n=20,536) were included in the study. Simvastatin treatment significantly reduced the risk of vascular events and those events that cause strokes. This effect was also noted in patients with relatively low levels of LDL-C (<116 mg/dL). The HPS included 3280 randomly chosen stroke patients and 1822 stroke patients without established CHD. In all stroke patients, there was a 19% RRR of major vascular events, and in the stroke patients without established CHD, the reduction in the risk of major vascular events was 23%. However, the HPS did not find a reduction in stroke risk among patients with recurrent cerebrovascular disease (10.4% of patients in the statin group had a recurrent stroke as compared with 10.5% of patients in the placebo group). This finding has been related to the late inclusion of patients at a mean of 4.3 years after their stroke or TIA, at a moment when patients were less likely to have a stroke event and more likely to have a coronary event. Therefore, in patients with a prior stroke, statins likely reduced the incidence of coronary events, but there was no proof that statins reduced the incidence of recurrent strokes. On the basis of these results, and despite the fact that evidence of the benefits of statins in the secondary prevention of stroke was lacking, the Food and Drug Administration approved simvastatin for stroke patients, independently of any measurement of LDL-C.

To address whether statins are beneficial for secondary stroke prevention The Stroke Prevention by Aggressive Reduction in Cholesterol Levels (SPARCL) trial [START_REF] Amarenco | Results of the Stroke Prevention by Aggressive Reduction in Cholesterol Levels (SPARCL) trial by stroke subtypes[END_REF] was designed.

The SPARCL trial randomly assigned 80 mg/day of either placebo or atorvastatin to 4731 patients with a history of non-disabling stroke or TIA in the preceding 1-6 months and with no CHD. Patients were required to have a baseline LDL-C of 100 to 190 mg/dL (2.6 to 4.9 mmol/L). The mean baseline LDL-C and total cholesterol levels were about 133 and 212 mg/dL. Patients with hemorrhagic stroke were included if they were deemed to be at risk for ischemic stroke or CHD. Patients were excluded if they had atrial fibrillation, other cardiac sources of embolism, or subarachnoid hemorrhage. After 5 years of follow up, atorvastatin reduced fatal or nonfatal stroke (11.2 versus 13.1 percent, adjusted hazard ratio

[HR] 0.84, 95% CI 0.71-0.99, absolute risk reduction at five years 2.2 percent, 95% CI 0.2-4.2 percent), despite a small increase in the incidence of hemorrhagic stroke.

Moreover, a meta-analysis reviewed the literature through January 2011 and found that statins significantly reduced the risk of major cerebrovascular events (i.e., fatal and nonfatal strokes and transient ischemic attacks) compared with controls, both in patients with established cerebrovascular disease (odds ratio [OR] 0.83, 95% CI 0.75-0.91) and in those without prior cerebrovascular disease (OR 0.80, 95% CI 0.71-0.91) [START_REF] Naci | Comparative effects of statins on major cerebrovascular events: a multiple-treatments meta-analysis of placebo-controlled and activecomparator trials[END_REF].

In conclusion, statin therapy reduced the risk of secondary ischemic stroke regardless of pretreatment blood cholesterol levels and therefore the ACC/AHA guidelines recommend high-intensity statin for patients with TIA or ischemic stroke of atherosclerotic origin [START_REF] Grundy | AHA/ACC/AACVPR/AAPA/ABC/ACPM/ADA/AGS/APhA/ASPC/NLA/PCNA Guideline on the Management of Blood Cholesterol: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines[END_REF].

For patients unable to tolerate high intensity statins, moderate intensity statin therapy is given instead.

Antiplatelet Therapy

Antiplatelet agents are used both during the acute phase of ischemic stroke and for secondary prevention. Specifically, antiplatelet agents are recommended for most stroke subtypes except cardio-embolic stroke. However, several questions remain unanswered: should a single agent or a combination of two or more agents be used, how long should maintenance treatment be continued for and when is the exact time to initiate treatment after an ischemic stroke.

Aspirin

The most commonly used antiplatelet agent is aspirin. Aspirin irreversibly inhibits cyclooxygenase, thus preventing the conversion of arachidonic acid to thromboxane A2 (TXA2). Thromboxane A2 is a vasoconstrictor and stimulator of platelet aggregation. Platelets are inhibited for their full life cycle (5-7 days) after exposure to aspirin. Aspirin also inhibits prostacyclin activity and this inhibits platelet aggregation. Aspirin reduces recurrent AIS rather than reducing neurologic symptoms after the index stroke. This is why aspirin is not recommended as a substitute for acute stroke treatment in patients who are otherwise eligible for IV alteplase or mechanical thrombectomy.

Both the CAST [START_REF] Hong | Rivaroxaban vs Warfarin Sodium in the Ultra-Early Period After Atrial Fibrillation-Related Mild Ischemic Stroke: A Randomized Clinical Trial[END_REF] and IST trials [START_REF]The International Stroke Trial (IST): a randomised trial of aspirin, subcutaneous heparin, both, or neither among 19435 patients with acute ischaemic stroke. International Stroke Trial Collaborative Group[END_REF] provided data on the acute use of aspirin after AIS. The CAST trial showed that 160 mg/day of aspirin reduced the risk of stroke recurrence and death in the first 28 days. In IST, 300 mg/day of aspirin reduced stroke recurrence within 14 days; however, had no effect on early mortality. In both of these trials there was a small increase in the risk of hemorrhagic transformation. When aspirin is initiated within 48 hours of AIS, the data showed a small but statistically significant decline in risk of mortality and morbidity. The AHA/ASA guidelines recommend the administration of aspirin is in patients with AIS within 24 to 48 hours after onset and for those treated with IV alteplase, aspirin administration is generally delayed until 24 hours later.

Several meta-analyses have shown the benefits of aspirin for secondary prevention. A meta-analysis of 16 placebo-controlled trials (17,000 individuals at high average risk) aspirin showed a reduction of about a fifth in total stroke (2•08% vs 2•54% per year, p=0•002) [START_REF] Baigent | Aspirin in the primary and secondary prevention of vascular disease: collaborative meta-analysis of individual participant data from randomised trials[END_REF].

In a pooled analysis of Clopidogrel is given orally at a dose of 75 mg per day. Loading patients with AIS with 375 mg followed by 75 mg was considered safe with no increase in the risk of hemorrhagic transformation [102].

ASA Plus Dipyridamole

Dipyridamole has platelet-inhibiting properties due to inhibition of adenosine re-uptake and platelet phosphodiesterase (PDE). For secondary stroke prevention, it has also been suggested that the beneficial effects of dipyridamole are due to a combination of both indirect anti-inflammatory effects from leukotriene inhibition and antithrombotic effect when used in combination with aspirin. This study demonstrated that the combination of aspirin 25 mg and dipyridamole 200 mg provided a significant risk reduction of secondary strokes by 37% when compared to placebo and 18% when compared to aspirin monotherapy [103].

The open-label ESPRIT trial enrolled patients with TIA/stroke within 6 months and reported that there was an ARR of 1% for recurrent AIS in patients taking aspirin plus dipyridamole as compared to subjects on aspirin monotherapy [104].

The ESPRIT trial reported unexpected 42% reduction in major bleeding with the combination. In the non-inferiority PROFESS trial, where subjects were randomized to receive either aspirin plus dipyridamole or clopidogrel, no significant difference was found in the recurrent-stroke risks between the two treatments [START_REF] Sacco | Aspirin and extended-release dipyridamole versus clopidogrel for recurrent stroke[END_REF].

OBJECTIVES

The first objective was to assess the adherence to international acute treatment guidelines of ischemic stroke in Lebanese hospitals and its impact on in-hospital mortality.

The second objective was to assess appropriateness of hypertension treatment in acute stroke and its adherence with the choice of medications tailored according to blood pressure readings.

The third objective was to investigate the degree of physician adherence with the international guidelines for post-stroke discharge medications among Lebanese hospitals. supportive treatment should be instituted for all patients with stroke to ensure maximal perfusion and oxygenation of the brain. However, the in-hospital mortality is still high despite guidelines implementation. Moreover, studies that assess the adherence to treatment guidelines and its impact on the outcomes of ischemic stroke are limited.

Overview of The Manuscripts

Thus, this is the first study that was conducted in Lebanon to assess guidelines adherence in the acute management of ischemic stroke and evaluate its impact on in-hospital mortality.

Conclusion

The study findings highlighted that adherence to guidelines was suboptimal in the majority of the subjects that might explain the high death rates among stroke patients. The adherence to the various strategic treatment arms was not the same where it was high for the early performance of brain imaging and low for the emergency reperfusion. There are various reasons that explain the in-adherence to the guidelines in Lebanese hospitals due to the limited stroke units and even such units are mainly restricted in university hospitals. In addition, the financial issues play a major role in the choice of the treatment regimens due to the lack of reimbursement by social security or insurance.

Future research perspective

The findings of this study raised the need to assess the guidelines adherence to hypertension treatment in acute ischemic stroke matched according to blood pressure levels. Treatment of hypertension in acute ischemic stroke is still controversial since it has been documented that both high and low blood pressures are associated with detrimental consequences. Thus, we conducted another study to assess appropriateness of hypertension treatment in acute stroke and evaluate the adherence with the choice of medications tailored according to blood pressure readings. this study aims to assess appropriateness of hypertension treatment in acute stroke and its adherence with the choice of medications tailored according to blood pressure readings.

Conclusion

This study demonstrates an evaluation of guidelines adherence to the treatment of hypertension in acute stroke. Our results showed that the majority of the patients received agents that were not recommended by the guidelines like labetalol or nicardipine. Labetalol was reserved for patients presenting with a high baseline blood pressure while other agents were given at much lower baseline blood pressure. Moreover, Labetalol, Amlodipine, and Nitroglycerine were the most effective medications on lowering systolic blood pressure and Labetalol and Ramipril were effective on lowering the diastolic blood pressure. In addition, the subjects were overtreated for hypertension and a minority of the patients presented with blood pressure levels that required anti-hypertensive therapy. The study findings highlight the fact that the anti-hypertensive medications used in this study were not in accordance with the guidelines recommendations where Amlodipine and Trinitrine (nitroglycerine) are highly used. However, recommended agents by the guidelines as Labetalol and Nicardipine were underutilized. This can be explained by the lack of original diagnosis of stroke where in most cases it can be confused with other hypertensive or neurological conditions which explains the use of such agents especially nitrates. Arch et al. identified that around 20% of stroke cases are misdiagnosed which increases the administration of hypertensive agents and antiplatelet therapy [113]. Our results show that Labetalol was highly used at higher baseline blood pressures compared to Amlodipine and Trinitrine which support that the choice of antihypertensive medications is highly related with the baseline blood pressure.

Another major finding is the lack of adherence in terms of the initiation of antihypertensive medications tailored according to the blood pressure levels. However, the majority of the patients received antihypertensive medications even though they do not meet the criteria for treatment. Almost all patients who were eligible for blood pressure treatment received antihypertensive medication which sheds light that the guidelines were broadly followed for patients who required blood pressure treatment and that undertreatment rate was 10 %. A possible reason this patient did not receive treatment could be due to the isolated elevation of DBP of 120 mmHg, and SBP of 180 mmHg. Our results are consistent with a study done in

Cameroon showing an undertreatment rate of 9.7% [114].

extent and nature of adherence, we conducted this study. Hence, the aim of this study is to investigate the physician adherence to post discharge stroke treatment guidelines including an assessment of prescribing the following medications as anti-thrombotic, antihypertensive, and lipid lowering agents upon hospital discharge. In addition, the study evaluates the change in blood pressure at different time intervals post anti-hypertensive administration among in-patients.

Conclusion

The results of this article highlight that non-adherence to post-discharge stroke medications is highly prevalent and that the international expert guidelines are also documented to be non-implemented in Lebanon probably because the recommended resources are not compatible with the resources available. The study concludes that the majority of the patients were not prescribed all the recommended medications upon discharge that emphasize a major gap in the adherence with the treatment guidelines. Furthermore, the study showed that systolic blood pressure is lowered from baseline, 2 hours, and 24 hours post treatment and diastolic blood pressure showed significant decrease only between baseline and 24 hours after treatment. In addition, further lowering in blood pressure was not associated with better therapeutic outcomes.

The findings of this study can be interpreted by the fact that physicians are unaware about the recommendations for secondary prevention after stroke [120] or the guidelines do not fit with patients' complex conditions and are poorly adapted to general practice [121,122].

options. One of the striking findings in this study is the limited use of reperfusion therapy whether thrombectomy performance or administration of recombinant tissue plasminogen activator (rt-PA) although they are the main stay of acute treatment in acute stroke due to the limited availability of stroke units in Lebanon. Reperfusion therapy is the main stay of therapy, however, it is underutilized. The reason behind this limited use of reperfusion therapy is multi-factorial and can be due to either physician reluctant in the administration of this high-risk drug or patients are presenting beyond the time frame for eligibility criteria for drug administration. Furthermore, physicians concern about the risk of hemorrhage and the insecurity to use such a high-risk intravenous drug with poor physician compensation are associated also with restricted use of rt-PA. rt-PA should be utilized as a cornerstone in the treatment of all acute stroke patients as it allows for a fast recovery, shortens hospital stay, and decreases mortality rate. In addition, this study highlights that most of the patients were not treated according to the guidelines recommendations that can explain the reason for a high degree of complications post stroke. In this study, some areas in the acute treatment guidelines were applied to most of the patients as the performance of early diagnostic imaging, controlling diabetes, and lowering temperature in febrile conditions. However, other strategic treatment option was not performed according to the guideline's recommendations in most of the patients as treatment of hypertension. Hypertension, the most common symptom diagnosed in ischemic stroke, was not treated in accordance with guidelines recommendations. Our results showed that the majority of the patients received agents that were not recommended by the guidelines like vasodilator (Nitroglycerin). A major contributing factor to this result can be explained either by lack or delay in stroke diagnosis when patients are admitted to emergency department. In addition, in other cases there is confusion between diagnosis of ischemic stroke patients presenting with hypertension and hypertensive emergencies or other neurological disorders. Furthermore, our results highlighted that acute ischemic stroke patients were prescribed anti-hypertensive medications that were not recommended by the guidelines and antihypertensive drugs were prescribed albeit that the blood pressure readings were not high enough to recommend hypertension management. Another important area that should be addressed is to enhance patient awareness through addressing patients' belief and intentions. Targeting patient knowledge alone is not adequate to enhance adherence but there is strong evidence which supports the fact that addressing patients' belief plays a synergistic effect in enhancing further treatment adherence [125].

In addition, encompassing and encouraging physician-patient communication plays a vital role in raising the level of awareness which increases the need to ask patients about their feelings and concerns. Thus, certain diseases can be missed by physicians due to the lack of proper communication and some patients rate that their relationship with physicians as poor because of their malpractice and miscommunication [126].

Thus, the findings of our study raise the need to conduct a future study in Lebanon to assess patient educational level about stroke and identify the factors associated with inadequate knowledge and in-adherence to medications. Accordingly, the key issues that are responsible for in-adherence with the guidelines should be addressed to ensure and optimize the application of the guidelines in every clinical situation. Thus, based upon a thorough revision of all the factors that may play a role with physicians in-adherence with the guidelines, a theoretical framework is being built as depicted below to clearly identify and manipulate the gaps.

Measuring and Improving Physician

One of the factors that may play a role in physician noncompliance could be related to physician attitudes toward the guideline leading to rejection. The attitudes can be explained by the lack of motivation, lack of self-efficacy, and lack of outcome expectancy. Behavior is another factor that can impede guidelines in-adherence which can be related to the limitations of the guideline by itself or its implementation strategy, external barriers related to the inefficiencies in the hospital or health care delivery system, or to differences in the patient's clinical status.

Another important aspect that interferes with guidelines in-adherence is the physician knowledge represented by lack of awareness and lack of familiarity. The vast growth and expansion of research makes it difficult for physicians to be aware of guidelines implementation and critically apply to practice [130,131]. It has been highlighted that awareness to the guidelines does not guarantee familiarity with the recommendation and its application correctly where lack of familiarity is more common than lack of awareness [132].

Physician attitude is another factor that can hinder adherence to the guidelines manifested by lack of self-efficacy and lack of outcome. Low self-efficacy manifested by lack of confidence in ability to follow guidelines recommendations is highly associated with in-adherence [133].Outcome expectancy plays a major role in guidelines adherence since if the physician has a negative belief that the recommendation set by the guidelines won't lead to an improved outcome adherence to the guidelines will be low [134]. Thus, if physician's belief that the therapeutic intervention set by the guidelines won't play a role in the clinical setting, the adherence rate will be low.

Behavior factor also influences the degree of adherence since appropriate knowledge and positive attitude are not enough to ensure adherence to guidelines if there are external barriers [135]. The barriers that may be encountered and that limit the ability to adhere to the guidelines pertain to patient, guideline, or environmental factors. Physicians usually document that the guidelines are not easy to follow or not convenient sometimes to apply on patients with multiple concomitant disease states and are polypharmacy.

In addition, lack of agreement with specific guidelines or the concept of guidelines in general can lead to in-adherence, although it is considered inferior factor compared to other factors [136].

Thus, the findings of our study raise the need to conduct a future study in Lebanon to assess and identify the barriers associated with guidelines in-adherence among physicians and then implementing measure to improve adherence based on the theoretical framework. -Lack of familiarity -Lack of awareness 6. LIMITATIONS AND STRENGTHS

Limitations

The major limitation of this study was its retrospective nature which can miss some data as the prescribed medications upon post discharge that could have been used in the study.

Availability of incomplete data introduced information bias and affected the quality of the data obtained concerning acute and post discharge management as well as other factors that could affect the physician's approach to therapy like past medical history or past medication history or even the medications the patient may have taken at home just before admission.

This also influenced our ability to include multivariable analysis as we were not able to account for confounding factors like age, gender, past medical history and the use of combination medications in the study. Another limitation was lack of hospital randomization since the researchers didn't have access to most hospitals due to the time needed to get an Institutional Review Boards approval; this may limit the sample and its external validity. In addition, the study enrolled a small sample size due to issues encountered with recruitment and finding stroke patients. The data collection phase also presented many biases, one of which was the selection bias as the patients were not randomly picked from the lists but in the order of their hospital identification numbers.

Strengths

This trial is the first of its kind in Lebanon that evaluates the adherence to both post discharge medications and acute stroke treatment guidelines among Lebanese physicians. The study is multi-center conducted in different hospitals (Makassed General Hospital, Rafic Hariri University Hospital, and Ain W Zein Medical Village) in Lebanon and from various regions of Lebanon. Moreover, the data collection sheet used is structured and facilitates the collection of different kinds of information. Also, a statistician supervised all data entry and analysis.

This study is vital as it assessed the guidelines adherence for acute hypertension management which is a controversial area closely linked with detrimental consequences associated with either extremely low or high blood pressure. The strengths of this study presents an introduction to the massive difference between clinical practice and guideline recommendations in acute settings were such issues can impose serious consequences. It also assessed rates of overtreatment and their effect on the stroke complications.

Clinical Implications

* An evaluation of the guideline adherence and practice variations helps to fine tune the optimal care to ensure that the highest possible standard of practice is implemented.

* Proper assessments of the relationship between the process of adherence to the guidelines and outcomes with a comprehensive set of process indicators will improve the quality of the care.

* It is highly recommended to develop a specialty based clinical practice guidelines that can be applied on a national level considering the local needs to provide the best possible and evidence-based stroke care.

Lebanese Situation

Acute and post-stroke guidelines in-adherence is high among Lebanese physicians which is due to variety of factors. Most of the Lebanese hospitals lack the specialized Stroke Units which hinders the acute guidelines adherence and the utility of alteplase. In addition, financial issues play a vital role in poor adherence with the guidelines since there is insufficient funds allocated for the management of critical conditions as stroke and physicians do not receive extra reimbursement when prescribing high-risk drugs as alteplase. There are other barriers that pertain to physicians including lack of physician awareness or lack of familiarity, lack of outcome expectancy, or the inertia of previous practice, or external barriers. Some of the Lebanese physicians do not receive grants or funds to attend international conferences to update and keep abreast of the new management options that limits the professional development and minimize the adherence with the guidelines. There is also striking occurrence of immigration of qualified physicians due to the financial crises and political scenarios Lebanon is witnessing that influenced the quality of medical case in Lebanese hospitals.

The limited prescription of alteplase among ischemic stroke Lebanese patients can be explained also by the fact that most of the patients either present beyond the time frame window for the use of alteplase or patients do not recall the time for symptom onset.

Furthermore, Lebanon is a country where the medical insurance is expensive and restricted to patients of high-socioeconomic status. Also, the national social security fund is limited and doesn't grant approval for all therapeutic management strategies listed in the guidelines which further explains the low adherence with the guidelines. In Lebanon, there is mainly lack of public health policy due to certain factors as political that shows to interfere with the choice of the medications for the past years.

The

  PhD chapter is closed now. It is time to open a new page, with new objectives and new challenges. INTRODUCTION ............................................................................................................................................ 1.1 EPIDEMIOLOGY AND BURDEN OF STROKE ......................................................................................................................1.2 ETIOLOGY ............................................................................................................................................................... 1.2.1 Large-Vessel Atherosclerosis ....................................................................................................................... 1.2.2 Cardioembolic Stroke .................................................................................................................................. 1.2.3 Small Vessel Disease (Lacunar Stroke) ........................................................................................................1.3 RISK FACTORS OF STROKE ........................................................................................................................................... 1.3.1 Non-modifiable Risk Factors ....................................................................................................................... 1.3.2 Modifiable Risk Factors ............................................................................................................................... 1.3.3 Other risk factors ........................................................................................................................................ 1.4 CLINICAL PRESENTATION OF ISCHEMIC STROKE ............................................................................................................... 1.5 TREATMENT OF ISCHEMIC STROKE ............................................................................................................................... 1.5.1 Acute Stroke Care ........................................................................................................................................ 1.5.2 Secondary Prevention ................................................................................................................................. 2. OBJECTIVES .................................................................................................................................................. 3. OVERVIEW OF THE MANUSCRIPTS ...............................................................................................................

7 .

 7 CONCLUSION ..................................................................................................................................................... ACKNOWLEDGMENTS ........................................................................................................................................... CONFLICT OF INTEREST .......................................................................................................................................... REFERENCES .......................................................................................................................................................... APPENDICES .......................................................................................................................................................... APPENDIX A: ARTICLE ONE .............................................................................................................................................. APPENDIX B: ARTICLE TWO ........................................................................................................................................... APPENDIX C: ARTICLE THREE ......................................................................................................................................... APPENDIX D: DATA COLLECTION SHEET.............................................................................................................................

Figure

  Figure 1: National Institute of Health Stroke Scale Neurological Assessment Flow Sheet[43]

administered to eligible patients 3

 3 to 4.5 hours after stroke, based on results of the European Cooperative Acute Stroke Study III (ECASS III) trial. In 2008 the ECASS III trial studied IV rt-PA versus placebo in the 3 to 4.5 hour time window from onset of stroke symptoms. This trial

1. 5 . 1 . 5

 515 Treatment of Dyslipidemia High-intensity statins through either atorvastatin 40-80 mg daily or rosuvastatin 20-40 mg daily are recommended for patients who are 75 years old or younger and who have clinical atherosclerotic cardiovascular disease

Finally, aspirin plus

  dipyridamole is less well tolerated than other antiplatelet therapy, primarily because of headaches, leading to declining popularity over the years. Moreover, dipyridamole is contraindicated in patients with coronary artery disease. New recommendation is promiosinhg for the use of Ticagrelor. Ticagrelor Ticagrelor has been recently used in combination with aspirin and shows a promising treatment option which is even a more effective DAPT combination, without non-responders and without a clinically unacceptable risk of severe bleeding events. Ticagrelor has unique pharmacological property since it is a reversible binding, direct-acting, oral P2Y12 receptor antagonist that prevents adenosine diphosphate-mediated P2Y12 dependent platelet activation and aggregation [105]. Ticagrelor has a faster onset and achieves greater and more consistent platelet inhibition than clopidogrel, which requires metabolism to its active form [106, 107]. Although data are not yet sufficient to make routine therapeutic recommendations based on the pharmacogenomics of antiplatelet drug activity [108, 109], Ticagrelor could be used when clopidogrel is contraindicated or patients have resistance to clopidogrel.

3. 1

 1 First Manuscript 3.1.1 Introduction Acute medical management is the one of the most influential factors on mortality rate and functional outcomes post-ischemic stroke. Implementing acute ischemic stroke management protocols decrease the risk of stroke-related complications and improve outcomes. Acute

3. 2

 2 Second Manuscript 3.2.1 Introduction Majority of ischemic stroke patients present with elevated blood pressure within 1 hour of symptom onset [110]. The elevation in blood pressure can affect the choice of subsequent treatment options where hypertension can affect thrombolytic eligibility and cause a delay in the administration of IV tissue plasminogen activator (IV tPA)[111]. Appropriate treatment of hypertension is extremely crucial in patients who have door-to-treatment times less than the recommended 60 minutes where timely and thus are eligible for IV tPA[112]. Due to the controversial areas surrounding hypertension management in acute ischemic stroke, thus

  Adherence with International Guidelines Clinical practice guidelines (CPGs) are systematically developed statements that assist clinicians in making decisions about appropriate patient care for specific clinical circumstances[127]. Guidelines development is a cornerstone in the management of critical illness as their implementation should improve quality of care by decreasing inappropriate variation, decrease mortality by expediting the application of effective advances to everyday practice, and should exert a positive impact on clinical workflow [128, 129]. Clinical practice guidelines are formulated based upon solid evidence that incorporates complicated clinical knowledge which is considered challenging to clearly comprehend and apply the guidelines in a proper manner into clinical tasks. The application of guidelines in the clinical setting is being hindered by many factors that impede the guidelines implementation. It is extremely important to identify and remove the road-blocks responsible for guidelines in-adherence.

Figure 3 .

 3 Figure 3. Theoretical framework responsible for guidelines in-adherence

  .1 STRATEGIES TO ENHANCE PATIENT ADHERENCE AND EDUCATION ......................................................................................

3.1 FIRST MANUSCRIPT ......................................................................................................................................... 3.1.1 Introduction ........................................................................................................................................... 3.1.2 Conclusion .............................................................................................................................................. 3.1.3 Future research perspective................................................................................................................... 3.2 SECOND MANUSCRIPT .............................................................................................................................................. 3.2.1 Introduction ................................................................................................................................................ 3.2.2 Conclusion ................................................................................................................................................... 3.2.3 Future research perspective ........................................................................................................................ 3.3 THIRD MANUSCRIPT .................................................................................................................................................. 3.3.1 Introduction ................................................................................................................................................ 3.3.2 Conclusion ................................................................................................................................................... 4. DISCUSSION ....................................................................................................................................................... 5. RESEARCH PROGRAMS ...................................................................................................................................... 55.2. MEASURING AND IMPROVING PHYSICIAN ADHERENCE WITH INTERNATIONAL GUIDELINES .................................................... 6. LIMITATIONS AND STRENGTHS .......................................................................................................................... 6.1 LIMITATIONS ........................................................................................................................................................... 6.2 STRENGTHS............................................................................................................................................................. 6.3 CLINICAL IMPLICATIONS ............................................................................................................................................. 6.4 LEBANESE SITUATION ................................................................................................................................................

Table 1 :

 1 Criteria for the use of Alteplase...

................................................................................................................... Table 2. Choice of antihypertensive agents .................................................................................................................

  According to the World Health Organization stroke is defined as "rapidly developing clinical signs of focal (or global) disturbance of cerebral function lasting more than 24 hours and leading to death, with no apparent cause other than that of vascular origin." Although the WHO definition is widely used, it relies heavily on clinical symptoms and is now considered

outdated by the American Heart Association and American Stroke Association (AHA/ASA) due to significant advances in the 'nature, timing, clinical recognition of stroke and its mimics, and imaging findings that require an updated definition. Thus, a new definition was proposed by AHA/ ASA

[2]

. The AHA/ ASA statement defined central nervous system infarction as "brain, spinal cord, or retinal cell death attributable to ischemia, based on pathological, imaging, or other objective evidence of cerebral, spinal cord, or retinal focal ischemic injury in a defined vascular distribution; or clinical evidence of cerebral, spinal cord, or retinal focal ischemic injury based on symptoms persisting ≥24 hours or until death, and other etiologies excluded." More specifically, ischemic stroke is defined as "an episode of neurological dysfunction caused by focal cerebral, spinal, or retinal infarction." On the other hand, if

  Other risk factorsSeveral other risk factors of stroke have been proposed but are considered to play an inferior role. Some of these risk factors include oral contraceptive use, inflammatory processes,

	1.3.3 migraine, sleep apnea syndrome, prothrombin activator inhibitor complex deficiency,
	hypotension,	high	C-reactive	protein,	certain	infections	as	Chlamydia
	pneumoniae, Helicobacter pylori, Legionella pneumophilia, chronic bronchitis, periodontal
	disease, and hyperuricemia [39-42].
								0.90
	(95% CI, 0.85-0.95) for < 1 drink/day, 0.92 (95% CI, 0.87-0.97) for 1 to 2 drinks/day, 1.08
	(95% CI, 1.01-1.15) for > 2 to 4 drinks/day, and 1.14 (95% CI, 1.02-1.28) for > 4 drinks/day
	[38].

prospective studies with data on ischemic stroke (25 studies), intracerebral hemorrhage (11 studies), and/or subarachnoid hemorrhage (11 studies) published through September 1, 2016. Light and moderate alcohol consumption was associated with a lower risk of ischemic stroke, whereas high and heavy drinking was associated with an increased risk; the overall RRs were 1.4 Clinical presentation of ischemic stroke Clinical presentation of stroke depends on the area of the brain affected by occlusion of the arteries. AHA/ASA have popularized the FAST algorithm to diagnose stroke in the prehospital setting. FAST acronym stands for facial droop, arm weakness, slurred speech and time of onset. Another easy way to remember to signs of stroke is the 6S method

[START_REF] Chugh | Acute Ischemic Stroke: Management Approach[END_REF]

. Stroke: 6S Method to Diagnose Stroke 1. Sudden (symptoms usually start suddenly) 2. Slurred Speech (speech is not clear, as if drunk) 3. Side Weak (face, arm or leg or all three can get weak) 4. Spinning (vertigo) 5. Severe headache 6. Seconds (note the time when the symptoms start and rush to the hospital) Befast: Balance (loss of balance/dizziness), Eyes (disturbance of vision in one or both eyes), Face (facial droop), Arm (weakness)and Speech (slurred) test.

1: National Institute of Health Stroke Scale Neurological Assessment Flow Sheet [43]

	To be completed by physician		DATE: TIME:		DATE: TIME:
		Description/ Score		SCORE	SCORE
	Category	UN= Untestable	Scoring Key	▼▼▼	▼▼▼
	1a. Level of Consciousness	Alert	0
	(Alert, drowsy, etc.)	Drowsy	1
		Stuporous	2
		Coma	3
	1b. Level of Consciousness	Answers both correctly	0
	Questions (Month, age)	Answers one correctly	1
		Incorrect	2
	1c. Level of Consciousness	Obeys both correctly	0
	Commands (Open/close eyes,	Obeys one correctly	1
	squeeze and let go)	Incorrect	2
	2. Best Gaze	Normal	0
	(Eyes open -patient follow	Partial gaze palsy	1
	examiners finger / face)	Forced Deviation	2
	3. Visual	No visual loss	0
	(Introduce visual stimulus, or threat	Partial hemianopia	1
	to patient's visual field quadrants)	Complete hemianopia	2
		Bilateral hemianopia	3
	4. Facial Palsy	Normal	0
	(Show teeth, raise eyebrows and	Minor	1
	squeeze eyes shut)	Partial	2
		Complete	3
	5. Motor, Arm: Left / Right		Left / Right
		No drift	0	0
		Drift	1	1
		Can't resist gravity	2	2
		No effort against gravity	3	3
		No movement	4	4
		Amputation, joint fusion (explain)	UN	UN
	6. Motor, Leg: Left / Right		Left / Right
		No drift	0	0
		Drift	1	1
		Can't resist gravity	2	2
		No effort against gravity	3	3
		No movement	4	4
		Amputation, joint fusion (explain)	UN	UN
	7. Limb Ataxia	Absent	0
	(Finger-nose, heel down shin)	Present in one limb	1
		Several limbs	2
		Amputation, joint fusion (explain)	UN
	8. Sensory	Normal	0
	(Pin prick to face, arm [trunk] and	Partial Loss	1
	leg-compare side to side)	Severe Loss	2
	9. Best Language	No aphasia	0
		Mild to moderate aphasia	1
		Severe aphasia	2
		Mute	3
	10. Dysarthria	Normal articulation	0
	(Evaluate speech clarity by patient	Mild to mod. dysarthria	1
	repeating listed words)	Near to unintelligible or worse	2
		Intubated or other physical barrier	UN
	11. Extinction or inattention	No neglect	0
	(Use information from prior testing	Partial neglect	1
	to identify neglect or double	Complete neglect	2
	simultaneous stimuli)
	NIH STROKE SCALE NEUROLOGICAL		APPLY PATIENT LABEL HERE
	ASSESSMENT FLOW SHEET
	FORM ID ED 405	Approved: __________	Original -Medical Record

Table 1 : Criteria for the use of Alteplase [4] Inclusion Criteria

 1

	Diagnosis of ischemic stroke causing measurable neurological deficit
	Treatment within 4.5 hours
	Age ≥18 years
	Exclusion Criteria
	Current intracranial hemorrhage
	Subarachnoid hemorrhage
	Ischemic stroke within 3 months
	Severe head trauma within 3 months
	History of intracranial hemorrhage
	Coagulopathy (platelet count<100,000, activated partial thromboplastin time
	(aPTT) >40 second, or prothrombin time (PT) >15 second)
	Active internal bleeding
	Intracranial/intraspinal surgery within 3 months
	Intra-axial intracranial neoplasm
	Current severe uncontrolled hypertension (systolic ≥185 mmHg or diastolic ≥110
	mmHg)
	Gastrointestinal malignancy or gastrointestinal bleed within 21 days
	Therapeutic doses of low molecular weight heparin received within 24 hours (eg,
	to treat venous thromboembolsim and acute coronary syndrome); this exclusion
	does not apply to prophylactic doses
	Current use of a direct thrombin inhibitor or direct factor Xa inhibitor with
	evidence of anticoagulant effect by laboratory tests such as aPTT, international
	normalized ratio (INR), or appropriate factor Xa activity assays
	Additional exclusion criteria Between 3 and 4.5 hours:
	Age >80 years
	Oral anticoagulant use regardless of INR
	Severe stroke (national institute of health stroke scale (NIHSS) score >25)

  1.5.1.2 Blood Pressure Management in Acute Ischemic Stroke Abnormal Blood Pressure Most patients with acute ischemic stroke present with elevated blood pressure. This has been shown in two large studies: the Chinese Acute Stroke Trial (CAST) and the International Stroke Trial (IST). The CAST trial enrolled 21,106 patients and from those 75%

  The European Stroke Prevention Study-2 (ESPS-2) compared aspirin monotherapy, dipyridamole monotherapy, aspirin-dipyridamole combination therapy, and placebo in 6602 patients with ischemic stroke/ TIA [103].

  Strategies to Enhance Patient Adherence and EducationFuture research programs should be based upon assessing knowledge and awareness about warning symptoms of stroke, risk factors, and disease etiology through a scale that should be validated and adapted to the Lebanese population. The scale should incorporate also awareness about the acute and rapid measures that should be performed directly in response to stroke symptoms. It is well known from previous literature that stroke can be prevented through appropriate awareness directed on identifying and modifying associated risk factors, initiating prophylactic measures, and increasing patient's education. Thus, prospective study can be done to assess and evaluate the knowledge about stroke and highlight the major gaps in stroke awareness. Thus, results from the future study can raise the need for implementing educational programs directed towards the community to improve patients' quality of life, prevent health-care professionals from being overwhelmed when stroke cases present to the emergency room at an early stage. As shown in the below figure, a future study can be conducted to focus on enhance patient education about awareness through simplifying regimen characteristics through, imparting knowledge, modifying patient beliefs, enhancing patient and family communication, and evaluating medication adherence.

	understanding is associated with favorable outcome represented by enhanced medication
	adherence, improved satisfaction, and enriched recall [124].
		Imparting
	5. Research Programs	Knowledge
	Enhancing Patient and Family Communication 5.1 Figure 2. Framework representing the interventions to enhance patient education and ensure Simplifying Regimen Characteristics Modifying Evaluating Patient Beliefs Adherence
	adherence to medications
	One of the factors that can impact adherence to medications is the simplifying treatment
	characteristics. The prescribed treatment regimens should be simple and tailored according
	to patient's daily life activities. Different adherence aids can be provided to help patient's
	memory as medication boxes and alarms[123].
	A cornerstone in minimizing and preventing disease progression in general and stroke
	specifically is through imparting appropriate knowledge. Ensuring adequate patient

Acknowledgments

We are grateful to all the hospitals who participated in this study and to the whole team (nurses, computer and laboratory technicians, clerical workers, and information technology staff). We would also like to thank Professors Pascale Salameh and Hassan Hosseini for their assistance and continuous support in every single detail. All persons who helped us in data collection in Lebanese hospitals.

Future research perspective

The study findings reflected by the suboptimal adherence for hypertension management in acute stroke which raised the need to assess the guidelines adherence among stroke survivors. Effective secondary prevention is a cornerstone in stroke management since it minimizes complications and optimizes therapeutic outcomes. In addition, post stroke treatment adherence as it is associated with recued disability and mortality. Furthermore, assessment of post-ischemic stroke management is vital since there are different medications prescribed for stroke survivor patients tailored to treat the underlying risk factors and concomitant disease states.

Third manuscript

Introduction

Guidelines adherence to stroke secondary preventive medications is subjected to challenges. Success of preventative measures and the reduction in stroke recurrence risk requires implementation of lifestyle factors, and initiation of medications immediately after the event and continuing the medications over the long-term period [115]. Early implementation of effective secondary prevention measures aimed at reducing blood pressure through antihypertensive medications, improving the lipid panel through statins, controlling glycemic level through antidiabetic drugs, and improving blood flow through anti-thrombotics is recommended to reduce the risk of further stroke events [START_REF] Amarenco | Results of the Stroke Prevention by Aggressive Reduction in Cholesterol Levels (SPARCL) trial by stroke subtypes[END_REF][116][117][118].

Despite the growing evidence on the effectiveness of pharmacotherapies for the treatment and prevention of stroke, nonadherence to medications among stroke survivors remains a concern and is associated with adverse outcomes [119]. In order to better understand the Barriers to the suboptimal guidelines adherence include, but are not limited to, lack of early symptoms recognition and delayed presentation after symptoms onset, financial constraints imposed on most of the Lebanese population, lack of drug and imaging modality availability (CTs), and provider related barriers (knowledge, experience, and fear of serious complications) [START_REF] Sayed | Acute stroke care and thrombolytic therapy use in a tertiary care center in Lebanon[END_REF]. In addition, there are other potential perceived barriers behind physician in-adherence can be lack of physician agreement with the recommendations due to lack of applicability or lack of evidence, environmental factors such as organizational constraints, and guideline factors such as unclear or ambiguous guideline recommendations.

Discussion

This study conducted over a two-year period highlighted that adherence to acute and post stroke treatment guidelines was suboptimal across different management strategies. Inadherence with the guidelines will be associated with a high degree of mortality since compliance with the treatment minimizes the development of complications. Our study was the first of its kind in Lebanon to date that assesses the adherence of Lebanese physicians to post discharge medications and acute stroke treatment guidelines. The insights described in this study allow the consideration of changes that could be manipulated in clinical practice to implement treatment guidelines.

Our findings highlight that guidelines were not applied that can be due to physician's unawareness to the treatment guidelines, unavailability of the medications at the Lebanese hospitals, and avoidance of drug prescription due to both fear from polypharmacy in stroke patients who are mainly elderly and the costs associated with some effective treatment Another important aspect is that some hospitals restrict their formulary to some but not all pharmacological categories which pose an obligation on the physicians to treat patients with the available medications that depict the in-adherence with the guideline recommendations.

CONCLUSION

This study reveals the gap between AHA/ASA guideline recommendations and the clinical practice and the alarming rate of hypertension overtreatment. The key barrier for guidelines in-adherence in Lebanese stroke patients was the absence of social security insurance. In addition, increased concerns about medications costs and side effects in poly-pharmacy conditions also represented a major adherence barrier. It highlights the need for specified programs that monitor the conformity with guidelines and encourages hospitals and health care providers to implement the guidelines for providing optimal care. Adherence to the guidelines prevent the possible development of complications that could be life threatening like hemorrhage or neurological damage. It also highlights the fact the important role of a clinical pharmacist to promote and maintain adequate utilization of medications in both acute settings and upon discharge.

Conflict of interest

The authors have no conflict of interest to disclose.

Appendices

Appendix A: Article One