Stroke Risk in Patients with Hypertensive Retinopathy: A Systematic Literature Review

Systemic arterial hypertension (SAH) is a major cardiovascular risk factor associated with target-organ damage, including cerebrovascular disease and hypertensive retinopathy. Because the retina and brain share similar microvascular features and mechanisms of vascular regulation, retinal vascular changes may serve as indicators of systemic microvascular damage. Hypertensive retinopathy can be detected through fundoscopic examination, which may reveal arteriolar narrowing, arteriovenous crossing changes, retinal hemorrhages, cotton-wool spots, hard exudates, and optic disc swelling. These findings have been associated with an increased risk of cerebrovascular events. Stroke, whether ischemic or hemorrhagic, remains a leading cause of mortality and long-term disability worldwide. Although previous studies have examined the association between hypertensive retinopathy and stroke risk, the available evidence remains inconclusive. A systematic synthesis of the literature is therefore needed to clarify this association and to assess the potential prognostic value of retinal findings in individuals with systemic arterial hypertension. This study aims to systematically review and synthesize the available scientific evidence on the association between hypertensive retinopathy and the risk of ischemic and/or hemorrhagic stroke in individuals with systemic arterial hypertension. A systematic review of observational studies will be conducted. The review protocol will be registered on the Open Science Framework (OSF), and the review will follow the recommendations of the Meta-analysis of Observational Studies in Epidemiology (MOOSE). Electronic researches will be performed in PubMed, Embase, Scopus, and Web of Science from database inception to the date of the final search. The search strategy will combine terms related to systemic arterial hypertension, hypertensive retinopathy, stroke, and their synonyms. No restrictions will be applied regarding publication date or language. In addition, the reference lists of included studies and other relevant publications will be screened to identify potentially eligible studies. Eligibility criteria will be structured according to the PECO framework. The population will include individuals aged 40 years or older, of any sex or ethnicity, diagnosed with systemic arterial hypertension. The exposure will be hypertensive retinopathy diagnosed or classified according to the Keith-Wagener-Barker classification system. Observational studies evaluating stroke outcomes in this population will be considered eligible. The primary outcome will be fatal or nonfatal ischemic and/or hemorrhagic stroke and/or transient ischemic attack, as specified in the study protocol. Secondary outcomes will include retinal microvascular ischemic changes and findings such as cotton-wool spots, microaneurysms, retinal hemorrhages, papillitis, and optic disc edema. Study selection will be conducted using Rayyan. Three reviewers will independently screen titles, abstracts, and full-text articles against the predefined eligibility criteria. Disagreements will be resolved through consensus, with a fourth reviewer available when necessary. Data will be independently extracted by three reviewers using a standardized form. Methodological quality and risk of bias will be assessed using the Newcastle-Ottawa Scale. The certainty of the evidence will be evaluated using the GRADE framework, according to the criteria described in the protocol. A narrative synthesis will summarize the characteristics and findings of the included studies. When clinical and methodological comparability is sufficient, meta-analyses will be performed using Review Manager (RevMan), applying random-effects models to account for anticipated between-study heterogeneity. Continuous outcomes will be expressed as mean differences or standardized mean differences, with 95% confidence intervals, as appropriate. Dichotomous outcomes will be expressed as risk ratios with 95% confidence intervals. Statistical heterogeneity will be assessed using the I² statistic. This review is expected to clarify the available evidence on the association between hypertensive retinopathy and stroke risk among individuals with systemic arterial hypertension. It will assess whether retinal vascular abnormalities and the severity of hypertensive retinopathy are associated with ischemic and/or hemorrhagic cerebrovascular outcomes, while considering the methodological quality and certainty of the available evidence. The findings may help identify potential retinal markers of cerebrovascular risk, support the clinical interpretation of fundoscopic findings, and inform future research on the prognostic value of hypertensive retinopathy. The review may also identify evidence gaps and methodological limitations to be addressed in future studies. The results will be interpreted according to the strength, consistency, and certainty of the available evidence. No direction or magnitude of association will be presumed before the review and analyses are completed.