Burden and Outcome of Prevalent Ischemic Brain Disease in a National Acute Stroke Registry

The National Acute Stroke Israeli is a prospective hospital-based registry, including all patients with consecutive acute stroke hospitalized during February to March 2004, March to April 2007, and April to May 2010. The registry was approved by the ethical committees of the participating medical centers. Details on the registry’s methods have been published.^11–13 Overall, 6279 patients with acute stroke were included in National Acute Stroke Israeli; 4452 of them diagnosed with ischemic stroke. The present observational study included 3757 patients with ischemic stroke with information on prior overt stroke per history and subclinical stroke, based on brain computed tomography (CT) or MRI. A subsample, including all patients with ischemic stroke hospitalized during the National Acute Stroke Israeli 2007 and 2010 periods in 8 hospitals, was followed up at 3 months. These hospitals were chosen to include various geographical areas, managing agents (government and the largest health fund), and hospital size. In total, 850 patients with ischemic stroke hospitalized at baseline in these 8 hospitals survived for the first 3 months after stroke, 787 of them (92.6%) were included in the follow-up.

A structured form was used for collection of data on patients’ characteristics, clinical diagnoses, stroke management, in-hospital complications, and outcome at discharge.

To assure completeness of data, a coordinating physician at each medical center was assigned who was responsible for data collection in all the hospital wards. Data checks for completeness and consistency were performed at a central coordinating center, on the basis of discharge medical reports and through computerized data queries. The occurrence of stroke before the present event was reported on the form. Old brain infarcts were identified with head CT/MRI on admission. Severity of stroke was categorized into 3 categories according to the National Institutes of Health Stroke Scale score; stroke subtype was defined with the Trial of Org 10172 in Acute Stroke Treatment (TOAST) classification, and the Oxfordshire classification was used for the clinical classification of stroke. Follow-up data were collected from survivors at 3 months through a telephone interview conducted using a form specially designed for this purpose.

At discharge, we assessed in-hospital death, complications, discharge to a nursing home, and disability defined as modified Rankin Scale ≥2 at discharge. Three months after stroke, disability (Barthel Index≤60) and dependency (by 2-simple questions) were assessed in patients who survived the hospitalization period, and total mortality during the first 3 months was reported.

Characteristics of patients, risk factors, and comorbidities on admission were presented for patients with no prior infarction, prior overt stroke, and subclinical stroke. Differences in age between the groups were studied with ANOVA, and χ² test was used for the comparison of the distribution of sex, vascular risk factors, comorbidities, as well as stroke severity, causes, clinical classification, medications at discharge, and outcomes.

Logistic regression models were computed for outcome variables, and odds ratios (ORs; 95% confidence interval [CI]) were presented for patients with prior overt stroke and patients with prior subclinical stroke, compared with patients with no prior infarction. Three models were studied: model 1, adjusting for age and sex; model 2, further adjusting for National Institutes of Health Stroke Scale, hypertension, ischemic heart disease, diabetes mellitus, atrial fibrillation, chronic kidney disease, prior disability (modified Rankin Scale, ≥2), peripheral artery disease, dementia; and model 3, adjusting also for Oxfordshire classiffication of stroke. Analyses were performed with SAS 9.2 (SAS; SAS Institute, Cary, NC).

In our national registry, prevalence of ischemic brain disease posed a significant health burden: approximately two thirds of patients with ischemic stroke had a prior overt stroke or subclinical stroke. The proportions of prior overt stroke and subclinical stroke were similar. The distribution of patients’ characteristics by group is shown in Table 1. Patients with prior ischemic brain damage were aged >4 years than those with no prior infarction. The distribution of sex was similar in all groups. Atrial fibrillation, dyslipidemia, ischemic heart disease, and chronic kidney disease were more common in patients with prior ischemic brain damage, both subclinical stroke and overt stroke, compared with those with no prior infarction. Significant differences in rates of hypertension, diabetes mellitus, dementia, prior disability (P<0.001 for all), and peripheral artery disease (P=0.001) were present, with rates lowest in patients with first stroke, higher in patients with prior subclinical stroke, and highest for patients with prior overt stroke. Minor neurological deficits (National Institutes of Health Stroke Scale, 0–5) were less common in patients with prior stroke (Table 2). Management of stroke differed by group: patients with prior ischemic brain damage underwent less vascular imaging while statins and blood pressure control treatment were more often recommended to them at discharge (Table 2).

Two-hundred fourteen patients (5.7%) died during hospitalization. Similar death rates were observed for patients with first stroke, prior subclinical stroke, and prior overt stroke (P=0.1). However, after adjustment for age and sex, death risk estimates were decreased for patients with prior overt stroke (OR, 0.65; 95% CI, 0.47–0.90) and prior subclinical stroke (OR, 0.54; 95% CI, 0.38–0.78) compared with those with first stroke. Findings were consistent after further adjustment (Table 3). Proportions of in-hospital complications were also similar for all study groups (≈28%; P=0.90), and no significant increase in risk of complications was found after adjustment for risk factors (Table 3). Unadjusted rates of discharge to a nursing home and disability at discharge were lowest in patients with first stroke, higher in patients with prior subclinical stroke, and highest for patients with prior overt stroke (P<0.001). Adjusted ORs for discharge to a nursing home were significantly increased for patients with prior overt stroke but not for those with prior subclinical stroke (Table 3). Adjusted estimates for disability were increased for patients with prior overt stroke (OR, 1.31; 95% CI, 1.03–1.66) and prior subclinical stroke (OR, 1.45; 95% CI, 1.16–1.82) compared with those with first stroke (Table 3).

Adjusted ORs (95% CIs) for poor outcomes at 3-month follow-up are presented in Table 4. No significant differences in rates of death at 3 months were found between the groups, and adjusted risk estimates were not significantly increased for patients with prior overt stroke (OR, 0.70; 95% CI, 0.41–1.19) and with prior subclinical stroke (OR, 0.70; 95% CI, 0.41–1.22). The groups differed in rates of functional outcomes at 3 months: rates of disability and dependency were higher for patients with prior ischemic brain damage than for those without. Among patients with prior ischemic brain damage, those with prior overt stroke showed higher rates of poor functional outcomes than those with prior subclinical stroke. The estimated risk of Barthel Index ≤60 for patients with both prior overt stroke (OR, 2.04; 95% CI, 1.14–3.68) and prior subclinical stroke (OR, 2.04; 95% CI, 1.15–3.64) were twice higher than for patients with a first stroke. Adjusted ORs (95% CI) for dependency were significantly increased for patients with prior overt stroke (OR, 1.95; 95% CI, 1.19–3.20) but not for those after subclinical stroke (OR, 1.36; 95% CI, 0.84–2.19; Table 4).

The reported prevalence of silent infarctions varies according to the definition of infarction and to the population studied. Previous studies based on CT reported 11% to 38% prevalence of silent stroke in patients with stroke⁸; our study supports these previous findings. Subclinical infarcts are not necessarily silent. They could be present in those that were clinically diagnosed, but the patient failed to report the prior stroke, and in those with subtle symptoms that were not reported or diagnosed by the physician. They have been associated with physical functional decline,¹⁵ frailty,¹⁶ impaired cognition, and visual field deficits.¹⁷ Furthermore, in population-based studies, patients with silent infarcts have a significantly increased risk of stroke^9,10 and of dementia,¹⁸ independent of other risk factors. Taking in account the potential impact of silent infarction, its prevalence should be taken into account when estimating the overall burden of stroke.

Regarding the significance of prevalent silent infarctions for patients with acute stroke, previous studies have not reported in associations with stroke outcome.^19,20 Our findings differ from those reports: we found that risks of short- and long-term disability for patients with ischemic stroke with prior subclinical stroke are similar to those with prior overt stroke. On the basis of our national data, we found that subclinical stroke should be considered an important cause of functional disability in the adult population, similar to overt strokes. The effect of subclinical stroke on the global burden of stroke is expected to increase with the increase in the proportion of elderly populations. It has been suggested previously to consider clinically diagnosed stroke as the tip of the iceberg of cerebrovascular disease.²¹ Subclinical stroke, transient ischemic attack, and overt strokes are all forms of atherothombotic vascular disease²² and should all be taken in account in the implementation of preventive strategies aimed at reducing the burden of stroke.

Our study is based on national data on unselected patients hospitalized with acute ischemic stroke throughout all hospitals nationwide. A coordinating physician at each medical center was assigned who was responsible for complete data collection. Patients not admitted were not included and it is possible that some minor strokes were misdiagnosed or missed, but selection bias because of exclusion of hospitalized patients is not reasonable in our study. Experienced physicians defined prior infarctions on the basis of CT/MRI on admission. However, only 1.8% of patients underwent MRI, thus categorization of subclinical infarction was based mostly on CT. Because the sensitivity to detect infarcts is lower for CT than for MRI,⁸ the reported frequency of subclinical infarctions likely underestimates their true prevalence in patients with acute stroke. Follow-up data on stroke survivors were not available for the entire cohort; however, hospitals selected for collection of follow-up data were chosen to include various geographical areas, managing agents, and hospital size; 92.6% of the survivors in these hospitals consented to be followed up. Finally, because no information is collected in our registry on patients not hospitalized, it is important to assess the generalizability of our findings for patients not admitted because of acute ischemic stroke.

In an unselected national cohort of patients with acute ischemic stroke, nearly two thirds had a prior overt stroke or subclinical stroke by CT. Poor functional outcomes were more common in patients with prior stroke, both overt and subclinical. These findings are of particular importance, given the updated definition of stroke for the 21st century.²³ Preventive strategies should be similar for patients with prior ischemic brain damage irrespective of the reported presence of stroke symptoms.