Ankle-Brachial Index as a Predictor of Acute Ischemic Cerebrovascular Event After Central Retinal Artery Occlusion

Introduction

Central retinal artery occlusion (CRAO) involves the sudden blockage of the central retinal artery, constituting an ophthalmic emergency that frequently results in severe visual impairment [1]. According to data from the Korean National Health Insurance System, the standardized incidence rate is 2.00 per 100 000 individuals per year [2], while in Japan, which has a severely aging population, the incidence rate has risen to 16.05 per 100 000 per year [3]. CRAO is considered an important clinical indicator of stroke, given that it shares many risk factors with ischemic cerebrovascular diseases [4], and the incidence of stroke after CRAO has been increasing [5]. However, whether all individuals who have had CRAO should undergo comprehensive neurological and cardiovascular assessment for risk of subsequent ischemic vascular events is controversial [6–8], and performing such assessment is costly. Therefore, identifying those at higher risk of ischemic vascular events following CRAO may help ensure that at least they receive such assessment and potentially more aggressive secondary stroke prevention measures.

The ratio of systolic blood pressure measured at the ankle to that at the brachial artery, known as the ankle-brachial index, has proven to be a useful non-invasive criterion for diagnosing peripheral arterial disease in the legs [9–11], and lower values of the index have been linked to higher risk of recurrent stroke after acute cerebral ischemia [12–14]. This led us to wonder whether the index might help predict those at higher risk of acute ischemic cerebrovascular event (AICE), which was defined as ischemic stroke or transient ischemic attack, after CRAO. Therefore, this study aimed to evaluate the association between the ankle-brachial index and AICE following CRAO in 335 patients at a single center between 2019 and 2023.

Material and Methods

ETHICS STATEMENT:

This study was approved by the Ethics Committee of Henan Provincial People’s Hospital [(2018) Lunshen No. 38], and patients or their legal guardians provided written informed consent at enrollment.

STUDY DESIGN, SETTING, AND PATIENTS:

We prospectively analyzed patients at least 18 years old who were (1) admitted between February 2019 and March 2023 to the Henan Provincial People’s Hospital because of acute painless vision loss, and (2) received a diagnosis of CRAO at our center (Table 1) [15], due to embolism, thrombosis, or unknown causes [16]. Embolism was defined as ≥70% occlusion of the ipsilateral internal carotid artery on imaging or as the detection of a mobile or ulcerated atheroma or thrombus in the left heart or distal areas, as detection of atrial fibrillation, or as detection of an embolus during fundus examination. Thrombosis was defined as the presence of neoplasia, genetic predisposition to clotting, an acquired clotting disorder or other prothrombotic condition [16].

We excluded patients whose CRAO could be attributed to surgical complications, arteritis, or central retinal vein occlusion; whose ankle-brachial index was higher than 1.40 or unknown; or who were pregnant. We also excluded patients for whom a comprehensive medical examination was contraindicated.

DETERMINATION OF THE ANKLE-BRACHIAL INDEX:

After admission, systolic blood pressures in the ankle and at the brachial artery were measured using an automatic blood pressure monitor (Omron, Japan), an oscillometric device, while patients were supine (Figure 1). Certified technicians automatically measured the blood pressure of the patient’s bilateral ankles and bilateral brachial arteries twice, with a 5-min interval between each measurement [17].The ankle-brachial index was calculated by dividing the lower of the 2 ankle systolic blood pressures by the higher of the 2 brachial systolic blood pressures [17]. Patients were classified into those with an index ≤0.90, defined as “low”, and those with an index between 0.91 and 1.40, defined as “normal” [9].

OTHER ASSESSMENTS:

Demographic data and medical history were collected at baseline during a standardized interview involving the patients and family members. The following vascular risk factors were assessed: hypertension, defined as a previous diagnosis of hypertension, blood pressure ≥140/90 mmHg, or current antihypertensive therapy; diabetes mellitus, defined as a previous diagnosis of diabetes, fasting glucose ≥7.0 mmol/L, non-fasting glucose ≥11.1 mmol/L, or current hypoglycemic therapy; hyperlipidemia, defined as fasting total cholesterol >5.17 mmol/L, fasting triglycerides >1.7 mmol/L, or current lipid-lowering drugs; and smoking status, whether current, past, or never. History of stroke, coronary heart disease, atrial fibrillation, or peripheral arterial disease was determined by consulting medical records or performing appropriate examinations. Degree of stenosis in the cervical or intracranial artery was evaluated using magnetic resonance angiography or computed tomography angiography.

OUTCOME AND FOLLOW-UP:

The outcome of interest was the occurrence of at least one AICE within 12 months after CRAO. Such events included ischemic stroke, defined as neurological deficits that could be attributed to restricted diffusion on magnetic resonance imaging; and transient ischemic attack, defined as neurological symptoms lasting shorter than 24 h and neurological deficits in the absence of restricted diffusion on magnetic resonance imaging (Table 2) [16].

The outcome was assessed at 1, 3, 6, and 12 months after discharge through routine follow-up visits in our outpatient clinic or through phone interviews. All cases were independently assessed by the same neurologist specializing in stroke, who was unaware of ankle-brachial index data.

Patients who were followed up for more than 6 months but fewer than 12 months and who did not experience AICE during that time were assigned to the group who did not experience AICE during the study. Patients who were followed up for fewer than 6 months were considered lost to follow-up and exited from the study.

STATISTICAL ANALYSIS:

All data were analyzed using SPSS 21.0 for Windows (IBM, Armonk, NY, USA), and statistical significance was defined as P<0.05 unless otherwise noted. All variables were categorical and therefore reported as n (%). The significance of differences in categorical variables between patients with a low index and those with a normal index was assessed using the chi-squared test or Fisher’s exact test. The ankle-brachial index and variables that were associated with it in univariate analysis with P<0.1 were entered into multivariable logistic regression in order to explore a potential relationship between the index and AICE.

Results

BASELINE AND CLINICAL CHARACTERISTICS:

Of the 370 patients who met the inclusion criteria, 32 were excluded because they met the exclusion criteria. Another 3 patients completed baseline assessments but were lost to follow-up. Clinical parameters and laboratory characteristics procedural presentations are shown in Table 3. The remaining 335 patients (42.7% women), 56.1% of whom were at least 65 years old, were included in the final analysis. Most patients were followed up through outpatient visits, while 7.8% (26/335) of patients were followed up via telephone. Notably, none of those followed up by telephone experienced AICE. Additionally, 32.8% of patients (110/335) had low ankle-brachial index values, while the remaining 67.2% (225/335) had normal index values. A history of peripheral arterial disease was significantly more prevalent among patients with a low index than among those with a normal index (P=0.023; Table 3).

INCIDENCE OF AICE IN THE OVERALL POPULATION DURING 12-MONTH FOLLOW-UP:

Within 12 months after CRAO, 26.6% (89/335) of all patients experienced AICE, comprising 17.31% ischemic strokes and 9.25% transient ischemic attacks (Table 4). Patients with a low index exhibited an AICE incidence of 36.4%, which was significantly higher than the 21.8% incidence among those with a normal index (P<0.01; Table 3).

FACTORS ASSOCIATED WITH LOW ANKLE-BRACHIAL INDEX IN UNIVARIATE ANALYSIS:

Univariate analysis linked the following characteristics to low values of the ankle-brachial index at a significance level of P<0.05: hypertension, previous stroke, history of peripheral arterial disease, LDL cholesterol >3.12 mmol/L, and cervical or intracranial stenosis ≥50% (Table 3).

FACTORS ASSOCIATED WITH AICE IN MULTIVARIABLE ANALYSIS:

The 5 variables mentioned above, together with hyperlipidemia, which was associated with the ankle-brachial index at a significance level of P<0.1, were included in a multivariable model, which identified 4 characteristics as independent predictors of AICE (all P<0.05): hypertension, history of peripheral arterial disease, LDL cholesterol >3.12 mmol/L, and cervical or intracranial stenosis ≥50% (Table 5). The multivariable model that accounted for these 4 variables identified low ankle-brachial index as an independent predictor of AICE (OR 1.864, 95% CI 1.095–3.174, P=0.022; Table 5).

Discussion

LIMITATIONS:

Our data should be interpreted with caution given that our sample was relatively small and we likely failed to control for certain clinically relevant variables. We defined acute ischemic stroke as symptomatic; therefore, we may have missed cerebral infarction that was asymptomatic but detectable by magnetic resonance imaging. The fact that we followed up 7.8% of study participants over the phone rather than in person might have led us to miss some acute ischemic cerebrovascular events.

Conclusions

Despite these limitations, our study provides solid evidence that the ankle-brachial index independently predicts risk of AICE within 1 year after CRAO. Thus, this index can serve as a non-invasive, straightforward basis for screening patients, to identify those who may require intensified secondary stroke prevention.