Atorvastatin in Acute Stroke Treatment
Atorvastatin in Acute Stroke Treatment
Recent clinical trials and meta-analyses of b-hydroxy-bmethylglutaryl coenzyme A (HMG-CoA)
 reductase inhibitors (statins) have demonstrated a significant reduction in ischemic stroke
 in patients with a history of coronary artery disease, both with and without elevations of
 serum cholesterol. Recent data suggest that statins have other beneficial properties in
 addition to the retardation of atherosclerosis. Asahi et al demonstred that Statins increased
 eNOS and tPA mRNA levels but did not change mRNA levels of PAI-1 and that In eNOS knockout
 mice, atorvastatin reduced the volume of ischemic tissue and improved neurologic outcomes
 after arterial occlusion by blood clot emboli. In addition to their lipid-lowering effects,
 it has been speculated that statins may also have beneficial effects on cerebral circulation
 and brain parenchyma during ischaemic stroke and reperfusion. Aslanyan et al reported that
 statin use was associated with reduced mortality at 1 month during the follow-up.

 In patients with recent stroke or TIA and without known coronary heart disease, 80 mg of
 atorvastatin per day reduced the overall incidence of strokes and of cardiovascular events,
 despite a small increase in the incidence of hemorrhagic stroke period .

 Recently the investigators group reported that lacunar strokes compared to nonlacunar ones
 exhibited significantly lower plasma levels of TNF-α and IL1-β, P-selectin and ICAM-1 24-72 h
 and 7-10 days after stroke onset (4). At extracranial arterial territories, inflammation
 plays a crucial role mediating all the stages of the atherosclerosis process . Similarly,
 thrombosis and defective fibrinolysis may also contribute to the progression of
 atherosclerotic lesions . Interestingly, both mechanisms might have a relevant role in the
 pathogenesis of intracranial large artery atherosclerosis and ischemic stroke Moreover our
 group showed that Patients with cardioembolic and atherothrombotic stroke subtypes showed
 significantly higher median plasma levels of TNF-α, IL-6, IL-1β whereas the lacunar subtype
 showed significantly lower median plasma levels of TNF-α, IL-6 and IL-1β and that
 immunoinflammatory marker plasma levels are significantly related to ischemic lesion volume.

 A meta-analysis showed that statins may possess antithrombotic property because these drugs
 were reported to reduce periprocedural infarction in patients undergoing percutaneous
 coronary intervention .

 This clinical benefit was detected after median, 0.5 days of treatment with statins
 (indicating that statins could potentially exert an antithrombotic effect even earlier than
 supposed from pharmacological studies.

 Violi et al recently showed the first evidence that atorvastatin acutely and simultaneously
 decreases oxidative stress and platelet activation by directly inhibiting platelet Nox2 and
 ultimately platelet isoprostanes and thromboxane A2 so providinf a rationale for the use of
 statins to prevent or modulate coronary thrombosis.

 Whereas recent data suggest that inflammatory reactions are involved in the pathogenesis and
 progression of cerebral ischaemia , no study has evaluated effects of atorvastatin 80 mg/day
 after a recent stroke on stroke outcome and on immunoinflammatory markers so to evaluate
 acute antithrombotic and anti-inflammatory effects of atorvastatin also in acute
 cerebrovascular event setting.

 On this basis the primary objective of the study was to evaluate the separate effects of
 atorvastatin in vivo on immunoinflammatory markers and on stroke prognosis in patients with
 recent acute ischemic stroke classified as atherothrombotic.
Material and Methods The investigators will enroll patients with a diagnosis of acute
 ischemic stroke admitted to the Internal Medicine Department at the University of Palermo
 between November 2011 and October 2014. The controlsubjects were patients admitted, in the
 same period, to our Internal Medicine Department for any cause different from acute
 cardiovascular and cerebrovascular events or exclusion criteria. Every subject with ischemic
 stroke was matched for age (±3 years), sex, and cardiovascular risk factor prevalence with
 one control subject

 Study Hypothesis and Patient Population:

 The primary hypothesis of the study is that treatment with 80 mg of atorvastatin per day
 administered early at admission after acute ischemic stroke would reduce immunoinflammatory
 activation of the acute phase and that this immunoinflammatory modulation could have a
 possible effect on prognosis of ischemic stroke evaluated by some outcome indicators.

 Eligible patients are men and women over 18 years of age who had an acute ischemic stroke
 Patients with inflammatory or infectious diseases, cancer, hematological diseases and severe
 renal or liver failure, as well as those who were under treatment with anti-inflammatory will
 be excluded Stroke was defined by focal neurological signs or symptoms thought to be of
 vascular origin that persisted for >24 h, confirmed by brain CT and/or MRI in baseline
 conditions Cardiovascular risk factors will be evaluated for both subjects and controls on
 the basis of the following criteria: type 2 diabetes will be determined using a clinically
 based algorithm that considered age at onset, presenting weight and symptoms, family history,
 onset ofinsulin treatment, and history of ketoacidosis. Atrial fibrillation will be diagnosed
 when present on the admission ECG. Hypertension was present when a patient had received
 antihypertensive treatment before admission or when hypertension was diagnosed during the
 hospital stay by repeated detection of blood pressure ≥160/95 mmHg. Hypercholesterolemia was
 defined as total serum cholesterol ≥200 mg/dl or on the basis of a clinical history of
 hypercholesterolemia or statin treatment.

 The studyIs pending of approvationby the Ethics Committee of the "Policlinico P. Giaccone" of
 Palermo. Written informed consent wasobtained for all patients.

 The type of acute ischemic stroke will be classified according to the TOAST classification
 (Adams et al., 1993): 1) Large Artery Athero- Sclerosis (LAAS); 2) CardioEmbolic Infarct
 (CEI); 3) LACunar infarct (LAC); 4) stroke of Other Determined Etiology (ODE); 5) stroke of
 UnDetermined Etiology (UDE).

 • Large artery atherosclerosis (LAAS) These patients will have clinical and brain imaging
 findings of either significant (≥50%) stenosis or occlusion of a major brain artery or branch
 cortical artery, presumably due to atherosclerosis. Clinical findings include those of
 cerebral cortical impairment (aphasia, neglect, restricted motor involvement, etc.) or brain
 stem or cerebellar dysfunction. Cortical or cerebellar lesions and brain stem or subcortical
 hemispheric infarcts greater than 1.5 cm in diameter on CT or MRI are considered to be of
 potential large artery atherosclerotic origin. Supportive evidence by duplex imaging or
 arteriography of a stenosis of greater than 50% of an appropriate intracranial or
 extracranial artery is needed. Diagnostic studies should exclude potential sources of
 cardiogenic embolism.

 Patient evaluation and blood sample collection All the ischemic stroke patients will undergo:
 medical history with recordi ng of potential stroke risk factors, blood and coagulation
 tests, 12-lead ECG, 24 h electrocardiography monitoring, trans-thoracic echocardiography,
 carotid ultrasound, brain CT or MRI at admission (repeated between the third and the seventh
 days of stroke onset).

 Blood samples will be obtained in the non-fasting state. After 10 min of rest in the supine
 position, vital signs were recorded and blood samples were collected from the antecubital
 vein. EDTA-anticoagulated peripheral blood was drawn from each patient within 12 h from
 symptom onset. Serum and plasma were immediately separated by centrifugation and stored in
 aliquots at -80 °C until analysis.

 The investigators will evaluate plasma levels of IL-1β, TNF-α, IL-6 and IL-10, Eselectin,
 P-selectin, sICAM-1 and sVCAM-1 as markers of immunoinflammatory activation, VWF plasma
 levels as a marker of endothelial dysfunction, TPA-antigen and PAI-1 plasma levels as
 thrombotic/ fibrinolytic markers.

 These laboratory evaluation will be done at 72 h and at one week after symptom onset.

 IL-1β, TNF-α, IL-6 and IL-10 and VWFantigen were measured using a sandwich ELISA (Human
 IL-1β, TNF-α, IL-6 and IL-10 Quantikine, R&D Systems (VWF ELISA kitdurian, Instrumentation
 Laboratory, Milano, Italy); VCAM-1, ICAM-1, E-selectin, P-selectin, PAI-1 and TPAantigen will
 be measured by commercial bioimmunoassay (Human sICAM-1, sVCAM-I, sE-selectin and sP-selectin
 Parameter, Quantikine, R&D Systems, Gentaur AssayMax Human Plasminogen Activator Inhibitor-1
 (PAI-1) ELISA Kit, Gentaur AssayMax Tissue Plasminogen Activator (TPA) ELISA Kit).

 The minimum detectable concentrations for the diagnostic tests were: TNF alpha: 1.6 pg/mL,
 IL-1β: b1 pg/mL; IL-6:b0.70 pg/mL; IL-10: N3.9 pg/mL; ICAM-1:b0.35 ng/mL;VCAM-1:0.6 ng/mL;
 E-Selectin: b0.1 ng /mL; P-Selectin:b0.5 ng/mL; vWF:1.0%;TPA: 0.3 pg/ml; PAI-1: b50 pg/ml.
 Intra-assay and inter-assay coefficients of variation were: TNF alpha: 4.2% and 4.6%; IL-1β:
 3.3% and 4.2%; IL-6: 1.6% and 3.3%; IL-10: 4.3% and 7.5%; ICAM-1: 4.8% and 6.1%; VCAM-1: 3.5%
 and 7.7%; ESelectin: 4.8% and 5.7%; P-Selectin: 4.9% and 8.8%; vWF: 5% and 10%; TPA: 4.8% and
 5%; PAI-1: 5.7% and 8.3%.

 As outcome indicators the investigators will use evaluation of acute neurological deficit by
 means National Institutes of Health Stroke Scale, at 72 hours and 7 days after admission and
 evaluation of disability at 7 days after admission by means modified Rankin Scale
 Neurological deficit score on admission was evaluated by the NIHSS. The National Institutes
 of Health Stroke Scale, or NIH Stroke Scale (NIHSS) is a tool used by healthcare providers to
 objectively quantify the impairment caused by a stroke. The NIHSS is composed of 11 items,
 each of which scores a specific ability between a 0 and 4. For each item, a score of 0
 typically indicates normal function in that specific ability, while a higher score is
 indicative of some level of impairment. The individual scores from each item are summed in
 order to calculate a patient's total NIHSS score. The maximum possible score is 42, with the
 minimum score being a 0 Disability at 7 days was evaluated by modified Rankin Scale (mRS)
 that is a commonly used scale for measuring the degree of disability or dependence in the
 daily activities of people who have suffered a stroke.

 The scale runs from 0-6, running from perfect health without symptoms to death.

 -  0 - No symptoms.

 -  1 - No significant disability. Able to carry out all usual activities, despite some
 symptoms.

 -  2 - Slight disability. Able to look after own affairs without assistance, but unable to
 carry out all previous activities.

 -  3 - Moderate disability. Requires some help, but able to walk unassisted.

 -  4 - Moderately severe disability. Unable to attend to own bodily needs without
 assistance, and unable to walk unassisted.

 -  5 - Severe disability. Requires constant nursing care and attention, bedridden,
 incontinent.

 -  6 - Dead. Treatment protocol

 Patients will be randomized to these two treatment:

 Group A: treatment with atorvastatin 80 mg (once-daily) from admission day until discharge
 Group B: No treatment with atorvastatin 80 mg until discharge, after discharge treatment with
 atorvastatin 80 mg will be started
Inclusion Criteria:

 -  Eligible patients were men and women over 18 years of age who had an acute ischemic
 stroke with a symptom time onset < 48 hours

 Exclusion Criteria:

 -  Patients with inflammatory or infectious diseases, cancer, hematological diseases and
 severe renal or liver failure, as well as those who were under treatment with
 anti-inflammatory were excluded