THE STUDY OF RISK FACTOR AND STRATEGIES FOR PREVENTION OF RECURRENT ISCHEMIC STROKE :A COMPREHENSIVE SYSTEMATIC REVIEW

Background: Studies show that the majority of strokes are caused by modifiable risk factors, such as high-fat diets, sleep apnea, diabetes, heart disorders, and other diseases. Recurrence rates are higher in sub-Saharan Africa (SSA), where strokes occur in the fourth or fifth decades of life. To reduce the risk of stroke recurrence and death, individuals who have survived their first stroke must undergo regular medical follow-up. Understanding the risk factors for stroke recurrence can help create plans and treatments to lessen the burden of strokes. Regular medical follow-up and understanding these risk factors can help create effective treatments and plans to reduce stroke recurrence. Methods: This systematic review focused on full-text English literature published between 2014 and 2024, adhering to PRISMA 2020 principles. Without a DOI, editorials and review papers that were published in the same journal as the submission were not accepted. ScienceDirect, PubMed, and SagePub were among the many web resources used to compile the literature. Result: Using reliable resources including Science Direct, SagePub, and PubMed, the study examined over 7,000 publications. Following the determination that seven publications warranted a further inquiry, a more thorough examination of the full corpus was conducted. Conclusion: Risk factors such as hypertension, alcohol consumption, diabetes, female gender, non-adherence to treatment, and cardiac causes contribute to high stroke recurrence rates in sub-Saharan Africa. Treatment effectiveness varies among ethnic groups, with DAPT being effective in patients with ICAD. Statin-based therapies reduce recurrent stroke risk but increase hemorrhagic stroke risk. Vitamin D plays a crucial role in brain development


INTRODUCTION
A stroke is characterized as a neurological deficit related to a vascular etiology that results from an immediate focal lesion of the central nervous system, extending to the brain, retina, or spinal cord. 1 According to epidemiological data, strokes are extremely serious and frequent events that account for the second-largest cause of mortality worldwide and the thirdlargest source of disability.In all, roughly 100 million and 12 million stroke incidents were reported globally in 2019the total number of prevalent and incident cases.Over 6.5 million fatalities in 2019 were directly related to strokes. 2 As the second most frequent disease globally in 2019, stroke continued to be a major cause of mortality. 3The majority of strokes are caused by modifiable risk factors, according to the majority of the literature.These include high-fat diets, sleep apnea, diabetes, heart disorders, sickle cell disease, oral contraceptive use, migraines, smoking, migraines, hypertension, dyslipidemia, diabetes, and excessive exercise. 4,5A worldwide meta-analysis predicted that 11% of people may experience another stroke within a year after their initial one and 26% within five.Antithrombotic, statin, and antihypertensive medications, for example, can lower the risk of secondary vascular events by 20% to 30%, hence preventing secondary strokes. 6cording to recent studies, approximately 30% of strokes are repeated episodes, and these strokes have a higher chance of leaving a victim disabled or dead. 7Frequently occurring strokes are linked to not only early death but also substantial social and financial consequences, as well as cognitive and physical impairment.Patients with lacunar infarcts, in particular, have a 4-12 times higher diagnosis rate than the general population for dementia.Subcortical dementia is caused by recurrent lacunar strokes, and the most significant predictor of mortality is a cardioembolic stroke. 3Individuals who survive their first stroke are at high risk of having another one.A Stoke recurrence is defined as a new focal neurological deficit of vascular origin lasting more than twenty-four hours, at least twenty-eight days following the incident event, or as an abrupt functional decline in neurological status with a drop of four points or more on the National Institute of Health Stroke Scale (NIHSS). 8Mohan et al. performed a meta-analysis based on 13 studies published before to 2009 with 9115 stroke survivors.The results indicate a progressive increase in the pooled cumulative risk of stroke recurrence, from 3.1% at 30 days to 39.2% at 10 years after the initial stroke. 9 Most people are aware of the major and predicted risk factors for stroke. 4,10On the other hand, less is known about the risk factors for stroke recurrence especially in some areas. 11According to studies, sub-Saharan Africa (SSA) has higher stroke burden indices than the rest of the globe. 12,13Estimates of up to 316 cases per 100,000 annually, 1,460 cases per 100,000 annually, and a 3-year fatality rate above 80% have been made in SSA within the last ten years. 12,14Most of these strokes happen in the fourth or fifth decades of life, which has a significant negative impact on the socioeconomic output of people in SSA and has serious ramifications for families and society. 3A subsequent, more current meta-analysis by Lin and colleagues, which examined 37 research with over a million participants and was published between 2009 and 2019, provided strong confirmation of these data. 15Recurrence of a stroke also raises the chance of death from stroke and all other cardiovascular causes.In light of the aforementioned, it is crucial in these situations to avoid a stroke from happening again.Therefore, to lower the risk of stroke recurrence and death, people who have survived a first stroke must undergo regular medical follow-up.Both new and ancient blood indicators have made this possible. 16Knowing the pertinent risk factors for stroke recurrence in a given person may be useful in creating plans and treatments to lessen this burden.The purpose of this systematic literature review was to identify stroke recurrence rates and risk variables for recurrent strokes that were discovered in studies conducted over the previous ten years.

METHODS Protocol
Preferred Reporting Items for Systematic Review and Meta-Analysis (PRISMA) 2020 guidelines were scrupulously followed by the work's author.This was done to make sure the study complied with all rules.The method of choice was carefully created to guarantee the precision and coherence of the research outcomes.

CRITERIA FOR ELIGIBILITY
This study offers a thorough analysis of research conducted in the last ten years on risk factors and preventive measures for recurrent ischemic stroke.Through in-depth data analysis, this project aims to explain and enhance patient care procedures.This thesis' main goal is to highlight the importance of important topics that may be found in a range of literary works.
To guarantee the accuracy of the data used in this study, stringent inclusion and exclusion criteria were implemented.A piece cannot be considered for inclusion unless it was published in English between 2014 and 2024.Published reviews, editorials, submissions without a DOI, and duplicate journal entries are some of the exclusion criteria..

DATA RETRIEVAL
Before beginning this lengthy examination, the writers carefully read the title and abstract of each article to ascertain its significance.Only studies that satisfied the inclusion criteria and supported the article's objectives were given more weight.A series of searches led to a conclusive result: a recurrent pattern.The only language in which full-text entries were accepted was English.The most stringent screening process resulted in content that met all predefined inclusion criteria and had a direct bearing on the subject matter of the study.Research that didn't follow these patterns were usually ignored, and their findings weren't given much weight.Numerous pieces of information were found and examined during the assessment, including factors, titles, authors, dates of publication, locations, and study methodologies..

QUALITY ASSESSMENT AND DATA SYNTHESIS
The research referenced in the titles and abstracts of every article was assessed independently by the writers to determine which articles require additional investigation.The following step involved going over each document that was prequalified for review inclusion in advance.The evaluation findings serve as a guide for selecting the review papers.By speeding up the selection of publications for additional investigation, this criterion allowed for a more comprehensive evaluation of previous work and the circumstances that qualified it for review.

RESULT
Initially, our research team gathered nearly three thousand publications from reputable databases such as Science Direct, PubMed, and SagePub.Seven papers were identified through a thorough three-tier screening process as being immediately relevant to our ongoing systematic investigation.. Subsequently, certain areas were chosen for further investigation and a detailed examination of the complete manuscript.For simplicity of viewing, Table 1 provides a summary of the content that was evaluated for this analysis.According to Shah et al.'s review, SAPT is linked to a lower risk of recurrent ischemic stroke in patients who have had a transient ischemic attack or non-cardioembolic ischemic stroke.For high-risk TIA or small acute noncardioembolic ischemic stroke, dual-antiplatelet treatment (DAPT) including aspirin and clopidogrel or ticagrelor is more beneficial than salvage autopsy.For secondary stroke prevention in non-cardioembolic ischemic stroke or transient ischemic attack (TIA), SAPT is advised, whereas DAPT with aspirin and clopidogrel or ticagrelor is advised. 18ory's study revealed that Intracranial atherosclerotic disease (ICAD) is the most common cause of ischemic stroke worldwide, causing up to 50% of strokes in Asia and disproportionately affecting minorities in the United States.ICAD is the stroke subtype with a high risk of recurrence, with silent infarcts being significantly higher. 19e study by Lee et al. found that more intensive LDL-C-lowering statin-based therapies were associated with a reduced risk of MACE, recurrent ischemic stroke, and myocardial infarction.The benefit was not statistically different among the LDL-C-lowering strategies, and the risk was not significantly different among the LDL-C-lowering strategies. 20e enormous health burden of ischemic stroke, is a significant public health concern, as highlighted by Bangad's study.
Reducing the chance of another stroke is the goal of secondary stroke prevention techniques, which include medication and surgical procedures.These approaches take into account the cause of the initial stroke, cardiovascular risk factors, accessibility to therapy, expense, patient burden, and lifestyle modifications. 21rgatti et al. reported that ischemic and hemorrhagic strokes, with higher 25(OH)D levels at the first stroke event associated with a significantly lower risk of stroke recurrence.The study found a non-linear association between 25(OH)D levels and the risk of recurrent stroke, with 25(OH)D levels ≥ 9.3 ng/mL associated with a significantly lower risk.The study also found significant heterogeneity among studies, indicating a potential publication bias. 16alinda's studies reveal that recurrent strokes are associated with various risk factors in SSA.Hypertension, alcohol consumption, female sex, non-compliance with therapy, right-handedness, congestive heart disease, gout, facial palsy, dysarthria, and dyslipidemia are the most common vascular risk factors for recurrent strokes.Other risk factors include female sex, non-compliance with therapy, right-handedness, congestive heart disease, gout, and older age. 3

DISCUSSION
The recurrence rate of stroke that occurs again has not changed in the last two decades despite new and more effective acute treatments being developed. 17The known risk factors are the primary factors linked to stroke recurrence, and these factors are prevalent in sub-Saharan Africa.Recurrent strokes have a higher death rate than original strokes.The following are independent risk factors for recurrent stroke: female gender, diabetes mellitus, hypertension, alcohol consumption in the past, non-adherence to post-stroke treatment, and cardiac causes. 3The highest recurrence rate was observed in LAA and CE strokes, often following an LAA-LAA or CE-CE recurrence pattern.SVO stroke had a lower recurrence rate of clinical stroke compared to other TOAST subtypes, and SVO stroke was often followed by another stroke subtype. 17Smoking, HT, DM, AF, prior cerebrovascular events, and increased severity of stroke are independent risk factors of recurrent stroke. 4In sub-Saharan Africa, hypertension is a significant modifiable risk factor for stroke burden and recurrent strokes.Recurrence of stroke can be decreased with medication adherence and consistent attendance at follow-up clinics. 22n the other hand, it has been noted that a lack of awareness among stroke survivors causes delays in prompting medical attention and medication compliance.Three studies have found a correlation between alcohol consumption and the risk of stroke recurrence among stroke survivors. 23Diabetes mellitus has also been associated with recurrent stroke, consistent with previous studies. 3The small progress within non-AF secondary prevention and the increasing age and load of cardiovascular risk factors in the general population may balance out the effect of advances in stroke diagnostics and acute interventions on the stroke recurrence rate. 17The risk of stroke recurrence is high in ICAD, a stroke subtype with a high risk.The WASID study found a 19% risk of recurrent ischemic stroke at 2 years, with 75% occurring in the stenotic artery.Clinical features, including women and the early period after index events, are associated with greater risk. 19Imaging biomarkers, multiple infarcts, and border zone patterns are associated with higher risk. 24The study reveals that poor cholesterol control, low-density lipoprotein, elevated blood pressure, and inadequate physical activity are associated with greater stroke and major cardiovascular event recurrence, suggesting the need for early post-stroke management strategies. 19tiplatelet therapy is an important treatment for stroke prevention, especially in Asian populations.However, the effectiveness of this therapy varies among different ethnic groups.It is important to determine the optimal dosage, combination, and duration of antiplatelet medications for patients with multiple risk factors, high BMI, and genetic mutations such as the CYP2C19 loss-of-function gene. 18Individuals who carry the CYP2C19 loss-of-function gene are at greater risk of stroke.Therefore, further research is needed to evaluate the use of CYP2C19 gene testing-based antiplatelet therapy for stroke prevention. 25For patients with aortic arch and intracranial atherosclerotic disease, ticagrelor may be more effective than aspirin.However, it is important to consider the patient's bleeding risk before prescribing this medication.Studies have shown that increasing the dose of aspirin or switching to another antiplatelet agent after recurrent TIA or AIS is not effective. 18,26DAPT (dual antiplatelet therapy) is effective in preventing stroke in patients with intracranial arterial disease (ICAD). 19The SAMMPRIS trial found that DAPT for 90 days was superior to aspirin in preventing the recurrence of stroke in the initial period after an index event.The THALES trial also found that DAPT reduces the risk of recurrent stroke in patients with ICAD. 26However, the CHANCE trial did not find a difference between aspirin and clopidogrel versus aspirin alone in stroke recurrence at 90 days. 27Studies have not found an increase in hemorrhagic complications with DAPT in ICAD patients.Researchers are also investigating other drugs, such as cilostazol and oral factor XIa inhibitors, for secondary stroke prevention.However, a recent study failed to show a benefit for these agents. 28New lipid-lowering agents like bempedoic acid, monoclonal antibodies, and RNA knockdown strategies are also being studied.However, before widespread adoption, the cost, side effects, and effectiveness of these drugs must be evaluated. 21cording to a recent analysis of 11 randomized clinical trials involving over 20,000 individuals with a history of stroke, more intensive LDL-C-lowering statin-based therapies were found to be linked to a 12% lower risk of recurrent stroke and a 17% reduced risk of MACE.However, there was also a 46% increased risk of hemorrhagic stroke and a higher risk for new-onset diabetes associated with these therapies. 20The antithrombotic properties of statins may be the cause of the increased risk of hemorrhagic stroke, rather than LDL-C levels or the extent of LDL-C-lowering therapies. 29The effectiveness of statin-based therapies in reducing LDL-C levels varies depending on the cause of the stroke, and there are concerns that this approach may not benefit all patients with ischemic stroke. 20The recently issued 2021 AHA/American Stroke Association guideline for recurrent stroke prevention recommends atorvastatin, 80 mg daily, for patients with non-cardioembolic ischemic stroke and an LDL-C level greater than 100 mg/dL to reduce the risk of recurrent stroke. 30However, high-intensity statins should only be used when there is evidence of atherosclerosis.While it may be reasonable to lower LDL-C levels below 70 mg/dL with statin-based therapies for patients with ischemic stroke and evidence of atherosclerosis, the lowest level beyond which LDL-C should not be lowered is not yet clear based on current evidence. 20e neuroprotective effect of vitamin D against age-related brain degeneration underscores the critical role that the vitamin D system plays in brain development, function, and maintenance.The risk of a subsequent stroke in patients who have had their first hemorrhagic or ischemic event is positively correlated with 25(OH)D levels, according to a recent metaanalysis.. 16 Vitamin D is responsible for regulating calcium-phosphate homeostasis, renin secretion, insulin sensitivity, and vascular calcifications.Furthermore, low 25(OH)D levels are associated with dyslipidemia, atherosclerosis, and atherosclerosis plaque formation.Vitamin D also plays a role in modulating the immune response and cytokine biosynthesis, which can help reduce inflammatory and autoimmunity responses. 16The cardiovascular system now recognizes vitamin D as a non-canonical target, as it regulates calcium cell influx, endothelial cell survival, and inflammatory response. 31The fact that vitamin D deficiency is thought to be a substantial risk factor for stroke and other chronic degenerative and cardiometabolic disorders is crucial to remember.A non-linear relationship between 25(OH)D levels and stroke recurrence was discovered in a recent dose-response analysis, with low levels of 25(OH)D being negatively correlated with the risk of recurrent events in patients who have already survived a first stroke. 16

CONCLUSION
Stroke recurrence rates remain high in sub-Saharan Africa, with risk factors such as hypertension, alcohol consumption, diabetes mellitus, female gender, non-adherence to treatment, and cardiac causes being the main risk factors.Antiplatelet therapy is an important treatment for stroke prevention, but its effectiveness varies among different ethnic groups.
Triticagrelor may be more effective than aspirin for patients with aortic arch and intracranial atherosclerotic disease, but it is important to consider the patient's bleeding risk before prescribing this medication.DAPT (dual antiplatelet therapy) is effective in preventing stroke in patients with intracranial arterial disease (ICAD), but further research is needed to evaluate its effectiveness.Statin-based therapies have been linked to a 12% lower risk of recurrent stroke and a 17% reduced risk of MACE, but there is a 46% increased risk of hemorrhagic stroke and a higher risk for new-onset diabetes.
Vitamin D plays a crucial role in brain development, function, and maintenance, providing a neuroprotective effect against age-related brain degeneration.

Figure 1 .
Figure 1.Article search flow chart

Table 1 . The literature included in this study
A study byKolmos et al.has reported risk factors associated with stroke recurrence, including a history of hypertension, diabetes mellitus, atrial fibrillation, angina, ischemic heart disease, and cardiomyopathy.Lifestyle factors, prior IS or TIA, increased stroke severity, a high NIHSS score, and a modified Rankin Scale at discharge were also identified as independent predictors.A meta-analysis of proportions comparing stroke recurrence reported in each study found high heterogeneity and a sub-analysis of recurrent stroke by subtype. 17