MINISTRY OF EDUCATION AND TRAINING MINISTRY OF DEFENCE 108 INSTITUTE OF CLINICAL MEDICAL AND PHARMACEUTICAL SCIENCES NGUYEN THI THANH MAI STUDY ON EFFECTIVENESS TREATMENT AND PREVENTION OF RECURRENT I[.]
MINISTRY OF EDUCATION AND TRAINING MINISTRY OF DEFENCE 108 INSTITUTE OF CLINICAL MEDICAL AND PHARMACEUTICAL SCIENCES NGUYEN THI THANH MAI STUDY ON EFFECTIVENESS TREATMENT AND PREVENTION OF RECURRENT ISCHEMIC STROKE OF ASPIRIN COMBINED WITH CILOSTAZOL Speciality: Internal neurology Code: 62720147 ABSTRACT OF PHD THESIS Hanoi – 2022 The work has been completed at: 108 INSTITUTE OF CLINICAL MEDICAL AND PHARMACEUTICAL SCIENCES Science instructor: Prof Nguyen Van Thong, MD PhD Nguyen Hong Quan, MD PhD Reviewer: Assoc Prof Tran Van Tuan, MD PhD Assoc Prof Nguyen Quoc Dung, MD PhD Assoc Prof Nguyen Hoang Ngoc, MD PhD The thesis will be defended at the Institute level thesis judging committee meeting at 108 Institute Of Clinical Medical And Pharmaceutical Sciences At day month .2022 The thesis can be found at: National Library of Vietnam The library of 108 Institute Of Clinical Medical And Pharmaceutical Sciences INTRODUCTION Stroke is the third leading cause of death globally, accounting for 10% of all deaths and the leading cause of disability Therefore, prevention and specific treatment of stroke have been the focus of modern medicine Antiplatelet drugs such as aspirin, dipyridamole, clopidogel, etc have proven to be effective in reducing the risk of stroke recurrence, but there is still a certain recurrence rate New researches in recent years, especially in Asian patients, have shown that cilostazol has been shown to be as effective as aspirin in both the acute phase, the prevention of recurrence, and the risk of bleeding that tends to be lower than other antiplatelet agents Combining cilostazol with aspirin right from the acute stage of ischemic stroke has also shown to be safer and more effective for treatment - prevention than aspirin only However, there has not been a study to comprehensively evaluate this issue for Vietnamese people on the effects of drug combinations right from the acute stage as well as the imaging of cerebral artery stenosis, the change in carotid intima-media thickness Therefore, we conduct this study with the following two objectives: Evaluating the effectiveness of treatment, prevention of recurrent ischemic stroke and safety of cilostazol combined with aspirin Determining the changes in carotid intima-media thickness on both sides, degree of cerebral artery stenosis before and after treatment Chapter 1: OVERVIEW 1.1 Definition of stroke 1.2 The main features of the anatomy and physiology of cerebral circulation 1.2.1 The main features of the anatomy of the cerebral arteries 1.2.2 Some features of the physiology of cerebral circulation 1.3 Pathophysiology of ischemia 1.4 Atherosclerotic stenosis of the cerebral arteries 1.4.1 Structure of artery wall 1.4.2 Atherosclerosis Atherosclerosis is a complex degenerative condition that begins with endothelial dysfunction and lipid accumulation in the intima and media, followed by arterial wall thickening and external remodeling, and finally vascular invasion, thrombosis, and embolism 1.4.3 The definition of cerebral atherosclerotic stenosis Cerebral atherosclerotic stenosis is defined as a decrease in lumen diameter of a segment or over a long segment of the carotid or basilar vertebral arteries 1.4.4 Diagnostic methods of cerebral atherosclerotic stenosis 1.4.4.1 Doppler ultrasound of cerebral blood vessels * Doppler ultrasound of the extracranial arteries This is the simplest and easiest method to The main goal is to detect lesions that cause carotid artery occlusion due to atherosclerosis * Transcranial Doppler ultrasound This technique is commonly applied in the following cases: Detect narrowing of arteries in the brain, evaluate collateral circulation when there is occlusion or stenosis, evaluate and monitor vasospasm 1.4.4.2 Computed tomography of cerebral blood vessels This is a useful technique for cerebrovascular survey because it is minimally invasive, rapid, and readily available in more clinical settings than MRA and DSA, and it has high interoperability in the assessment of the stenosis of intracranial vessels 1.4.4.3 Magnetic resonance imaging of brain and cerebral vessels Non-Contrast MRA (MRA TOF): A method of imaging blood vessel flow by applying a repeated pulse of RF (radio frequency) per tissue volume, followed by a dephase gradient and phase reconstitution Static tissues are saturated by the action of repeated RF pulses, so there is a relatively low signal Contrast-enhanced MRA are performed with a gradient echo sequence with a short repetition time after intravenous bolus administration of gadolinium Gadolinium shortens T1 to less than 10 ms to increase signal intensity of injected vessels This is a reliable method for examining cerebral vessels 1.5 Treatment of ischemic stroke 1.5.1 The main theoretical foundations for the treatment of cerebral stroke 1.5.2 General and comprehensive treatment * Airway circulation and oxygen delivery * Circulation guarantee * Adjustment of other physiological constants 1.5.3 Specific treatment 1.5.3.1 Recirculation * Use of intravenous thrombolytics (tPA) * Collecting thrombus with mechanical instruments * Decompression craniotomy surgery 1.5.3.2 Platelets and antiplatelet agents * Platelets * Antiplatelet agents: Drugs affecting arachidonic acid metabolism Drugs increasing cyclic AMP of platelets: Cilostazol: Acts on many stages of the atherothrombotic process, both intravascular processes and those in vascular wall such as inhibition of platelet aggregation, vasodilation, endothelial protection, anti-inflammatory effects and inhibition of proliferation of vascular smooth muscle cells Also, it has protective effects against ischemic injury – reperfusion and neuroprotective effects 1.5.3.3 Anticoagulants Include oral vitamin K antagonists, new generation anticoagulants and heparin 1.5.3.4 Blood lipid control, the role of statins According to the recommendations of the American Heart Association and American Stroke Association 2021 for stroke prevention and TIA 2021, ischemic stroke patients with LDL-C > 100 mg/dL are prescribed atorvastatin 80mg/day to reduce the risk of stroke recurrence with IA recommendation 1.5.3.5 Nutritional and neuroprotective drugs Neuroprotective drugs such as cerebrolysin, citicolin are not only relatively safe in treatment but also effective, of which cerebrolysin has been recommended by the European Academy of Neurology to have functional rehabilitation effects in acute stroke 1.5.4 Treatment and prevention of complications 1.5.5 Care, nurture and practice for rehabilitation 1.5.6 Level II prophylactic treatment Controlling risk factors Antithrombotic treatment Anticoagulants Surgery and vascular interventions 1.6 Some studies on cilostazol in treatment 1.6.1 Studies on cilostazol in level II prophylactic treatment - CSPS-2 study by author Shinohara in 2010: The stroke rate was 2.76% in the cilostazol group compared with 3.71% in the aspirin group, the difference was statistically significant with p = 0.035 The bleeding rate in the cilostazol group was 0.77% compared with 1.78% in the aspirin group The difference was statistically significant with p = 0.0004 - CASISP study (2008): The results showed that the rate of recurrent ischemic stroke did not differ between the two groups, but the aspirin group had a higher bleeding rate - CATHARSIS study (2013): The results showed that the stroke rate in the combination treatment group was 2.5%/year compared with 5.2%/year in the aspirin alone group; The rate of new asymptomatic ischemic stroke was 4.8% in the combination treatment group and 10% in the aspirin alone group 1.6.2 Studies on treatment in the acute phase - CAIST study: There was no difference in the proportion of patients with mRS ≤ after months and the risk of bleeding or other vascular events - The study of cilostazol and aspirin combination therapy in acute phase (2012) by Nakamura et al: The percentage of patients with neurological deficits increasing in the first days in the aspirin-alone treatment group was higher than in combination treatment group - The ADS study of Aoki et al 2019: The study found no difference between the groups in stroke recurrence rates, no difference between the clinical outcomes in both groups 1.6.3 Some studies on atherosclerosis - The study of Hollander et al (2003): It has shown that carotid intima-media thickness is an independent risk factor for stroke - The study of Kwon et al (2005): In the cilostazol group, 6.7% progressed in intracranial stenosis, 24.4% decreased stenosis; the aspirin group alone had 28.8% progressed in intracranial stenosis and 15.4% reduction in intracranial artery stenosis, the difference was statistically significant - DAPC study (2010): Carotid intima-media thickness was significantly reduced in the cilostazol group compared with the aspirin group CHAPTER 2: SUBJECTS AND METHODS OF RESEARCH 2.1 SUBJECTS Including 102 patients with mild and moderate acute ischemic stroke, hospitalized in the first 72 hours from onset, receiving inpatient treatment at Phu Tho Provincial General Hospital from August 2015 to October 2018 2.1.1 Criteria for selecting patients * Being diagnosed with ischemic stroke * Being hospitalized 72 hours before onset * Mild and moderate severity (NIHSS score on admission ≤ 15 points) * 40 - 80 years old * Voluntary participation in the study 2.1.2 Exclusion criteria * Transient ischemic attack * Due to embolism from the heart * There is progressive heart failure * There is a history of cerebral stroke with sequelae according to the modified Rankin score greater than points * Have a history of bleeding in the brain or gastrointestinal bleeding * There are indications to use thrombolytic drugs, thrombus intervention * There are contraindications to antiplatelet drugs (gastroduodenal disease, bleeding disease, history of allergy to aspirin, cilostazol ) * Patients with serious medical diseases such as liver failure, kidney failure, cancer * Have a coagulation-bleeding disease *Patients with contraindications to cranial magnetic resonance imaging such as metal materials, pacemakers 2.1.3 Study sample size The following formula was used to calculate sample size for intervention studies (Taken from Nakamura's study in 2012: P1= 0,7, P2= 0,5 According to the formula for calculating n = 93 During the period from August 2015 to October 2018 we selected 102 patients in this study 2.2 Methods of the research Using a controlled, descriptive intervention study model, patients were randomly assigned to two groups 2.2.1 Conducting patient admissions * Patients were randomly divided into two groups: - Test group: The patient was treated on day with aspirin 300mg + cilostazol 200mg; the following days with aspirin 100 mg and cilostazol 200mg for months, then cilostazol 200mg/day monotherapy for up to months - Control group: The patient was treated on day with aspirin 300mg, then aspirin 100mg/day for months 2.2.2 Evaluation and monitoring criteria + Age, sex, pulse, blood pressure, height and weight on admission + Time from onset to initiation of treatment + High blood pressure + Blood glucose level test after admission + Addiction to tobacco when regularly smoking more than 10 cigarettes/day + Blood lipid index on admission + Assessment of the degree of cerebral stroke according to the NIHSS scale + Consciousness was assessed according to the Glasgow scale + Assessment of muscle strength according to the British Medical Research Council's muscle strength classification + Assessment of the degree of disability according to the modified Rankin scale 2.2.3 Evaluation of treatment effectiveness, stroke recurrence, 14 Muscle strength of legs Improved (muscle strength increased ≥ score) No improvement (no change in muscle strength) 32 31,4 14 33,3 18 30 p > 0,05 70 68,6 28 66,7 42 70 p > 0,05 In terms of muscle strength of hands, the group that did not improve accounted for the majority of 71.6% The difference between the groups (C + A) and the aspirin group was not statistically significant In terms of muscle strength of legs, the group that did not improve accounted for 68.6% The difference between the groups (C + A) and the aspirin group was not statistically significant Table 3.20 The improvement on muscle strength on admission and after months General (C+A) Aspirin Long-term Numb muscle strength Numbe Percentage Numbe Percentage er of Percentage r of r of improvement patients (%) patients (%) patient (%) p s Muscle strength in hands Improved (muscle strength 55 increased ≥ score) No improvement (no change in 46 muscle strenth) 54,5 30 71,4 25 42,4 p