Risk Factors for Hemorrhagic Transformation Following Acute Ischemic Stroke: Three Tertiary Hospitals Experience in Addis Ababa, Ethiopia

Background: Ischemic stroke is a major cause of morbidity and mortality globally, with a particularly heavy burden in low- and middle-income nations. Hemorrhagic transformation (HT) is a frequent and severe complication of acute ischemic stroke, developing in 3.2% to 43.3% of patients and leading to higher mortality. Determination of predictors of HT is very important for patient outcome improvement.

Objective: The objective of this study was to determine clinical and demographic predictors of hemorrhagic transformation in acute ischemic stroke patients admitted to three major hospitals in Addis Ababa, Ethiopia.

Methods: A retrospective case-control study was performed on 270 inpatient medical records of acute ischemic stroke patients in Saint Paul Hospital, Zewditu Memorial Hospital, and Tikur Anbessa Specialized Hospital between June 2019 and July 2022. Data were analyzed using SPSS version 26.0. Bivariate and multivariate logistic regression analyses were performed to determine associations of HT with potential predictors, and statistical significance was set at P < 0.05.

Results: The average age of the patients was 61.2 years, and most (37.8%) were between 61-70 years old. A history of diabetes mellitus carried a 5.4-fold risk of HT (AOR=5.4, P<0.05), and stress hyperglycemia 12.2 times (AOR=12.2, P<0.05). A history of stroke or transient ischemic attack increased the risk 3.7-fold (AOR=3.7, P<0.05). Warfarin therapy was associated with a 13.1 times greater risk (AOR=13.1, P<0.05), and concurrent use of anticoagulants raised the risk 3.8-fold (AOR=3.8, P<0.05).

Conclusion: Anticoagulant therapy, stress hyperglycemia, past history of stroke, and diabetes are important predictors of hemorrhagic transformation in acute ischemic stroke. Guideline-based management needs to be emphasized, and modifiable risk factors should be addressed with a view to decreasing the incidence of HT and improving outcomes.

Ischemic stroke is one of the major causes of morbidity and mortality worldwide as a result of decrease or cessation of blood flow to part or the entire brain, causing acute injury to tissue due to the finite energy reserves of the brain [1, 2]. Temporary decrease of blood flow can cause irreversible injury to neurons. Acute ischemic stroke subtypes are typically classified according to the TOAST criteria, taking into account underlying etiologies [1-3]. Stroke prevalence, incidence, and mortality have risen globally, with the majority of the burden falling on low- and middle-income countries [1]. The World Health Organization stated that stroke was the second cause of death from 2002 to 2012, and in Ethiopia, ischemic stroke is the sixth cause of death [1]. Stroke not only results in enormous mortality but also leaves as many as 50% of the survivors with lasting disabilities [4]. In the year 2004, stroke resulted in 5.7 million deaths (9.7% of total deaths), with more than 85% of these occurring in middle- and low-income countries [5]. In Sub-Saharan Africa, health-seeking behavior that is poor and very limited access to neurologic care are likely to further boost the future burden of stroke [5]. Acute ischemic stroke is also complicated by neurological and medical events that compromise outcome. The typical complications are pneumonia, urinary tract infection, gastrointestinal hemorrhage, myocardial infarction, deep vein thrombosis, and pulmonary embolism [6]. Early complications like pneumonia and increased intracranial pressure are independently associated with increased mortality and unfavorable functional outcome [6]. The majority of the complications happen in the initial three days, but certain ones, for instance, deep vein thrombosis and urinary tract infection, may occur later due to immobilization [6]. 

Hemorrhagic transformation (HT) represents an extremely unsafe complication of acute ischemic stroke, corresponding to secondary bleeding into the infarcted brain tissue. HT occurs in 3.2% to 43.3% of patients with ischemic stroke and is fatal in approximately 3% [7]. Onset time is typically variable but most commonly occurs in the first four days following infarction, with the majority of symptomatic events occurring within 36 hours [7]. HT encompasses both symptomatic hemorrhages, which are accompanied by clinical worsening, and asymptomatic instances that are only detectable on imaging [7]. The European Cooperative Acute Stroke Study (ECASS) classifies HT as hemorrhagic infarct and parenchymal hemorrhage, with subtypes based on imaging findings [4]. Pathogenesis of HT is multifactorial with primary factors being blood-brain barrier disruption and reperfusion injury [5]. Numerous risk factors are known to heighten the risk for HT, such as old age, stroke severity, atrial fibrillation, hypertension, hyperglycemia, diabetes mellitus, low cholesterol levels, low platelet count, renal failure, and early ischemic changes on imaging [8]. Anticoagulant or thrombolytic therapy also increases the risk [9]. Determination of these predictors is important to risk stratification and for guiding management in acute ischemic stroke, particularly in resource-poor nations like Ethiopia [10]. Thus, the present study aimed to evaluate the clinical presentation and predictors of hemorrhagic transformation among inpatients with acute ischemic stroke at three big hospitals in Addis Ababa, Ethiopia, from June 2019 to July 2022.

Study Design and Setting 

This retrospective case-control study was carried out in three of Addis Ababa's largest referral hospitals in Ethiopia: St. Paul's Hospital Millennium Medical College (SPHMMC), Zewditu Memorial Hospital (ZMH), and Tikur Anbessa Specialized Hospital (TASH). SPHMMC, which was founded in 1968, is one of the country's largest specialized referral hospitals with more than 700 inpatient beds and a catchment area of more than five million [11]. Both specialist inpatient and outpatient care are provided by neurology clinics managed by the Ministry of Health with 18 dedicated beds [12]. ZMH, which was originally set up by the Seventh-day Adventist Church and then nationalized in 1976, is now under the Ministry of Health and offers specialist neurologic and neurosurgical management with 10 ICU beds, 15 emergency beds, and 56 medical ward beds [13]. TASH, the teaching hospital of Addis Ababa University College of Health Sciences, is Ethiopia's largest referral hospital with over 700 beds and a multidisciplinary staff, and one of the primary training institutions for undergraduate and postgraduate medical students.

Study Period

Data was collected from June to August 2023, from patients hospitalized between June 2019 and July 2022.
Study Population 

The population source was all patients with ischemic stroke at SPHMMC, ZMH, and TASH. The study population was all adult patients admitted to inpatient care-including medical wards, intensive care units (ICU), and emergency departments-with documented acute ischemic stroke during the period of study.

Inclusion and Exclusion Criteria

Inclusion criteria were all adults who were inpatients with a clinical diagnosis of acute ischemic stroke verified by clinical evaluation and neuroimaging. Transient ischemic attack, traumatic intracerebral hemorrhage, or those with incomplete medical records that lacked laboratory results (serum creatinine, random blood sugar, lipid profile), ECG, physical examination, or brain imaging were excluded. Data Collection and Analysis Data were retrieved from medical records using a data abstraction tool in a systematic manner. The variables consisted of demographic data, clinical presentation, laboratory investigations, imaging reports, and treatment. Data were analyzed and entered using SPSS version 26.0. Bivariate and multivariate logistic regression analyses were conducted to determine predictors of hemorrhagic transformation, and statistical significance was established at P < 0>

Sample size determination

The sample size of this retrospective case-control study was calculated using the double population proportion formula to have adequate statistical power to observe differences in exposure between cases and controls. The following assumptions were used in the calculation:

Confidence level (1 - α) = 95% (Z = 1.96)

Power (1 - β) = 80% (ZB = 0.84)

Ratio of controls to cases (r) = 2:1

Two-sided test

The formula for the calculation of the number of cases is:

N cases = (Za/2 + ZB)2 p (1-p) (r +1)

                                            r (po-p1)2

Where:  =proportion of exposed among controls; =proportion of exposed among cases; =pooled proportion; r=ratio of controls to cases

Exposure Proportions Employed for Sample Size Calculation (Table 1).

Table 1: The frequencies of major exposures among cases and controls were as follows [14]:

Sample Size Estimates

According to the above requirements, sample size calculations have been done using different statistical methods (Kelsey, Fleiss, and Fleiss with continuity correction) to obtain the following sample size ranges.

Table 2: Sample Size calculation

Based on these estimates, the total sample size of 270 subjects (90 cases and 180 controls) was chosen to be large enough to have adequate power to identify clinically relevant associations of exposures with hemorrhagic transformation.

Sampling method

A total of 270 patients who were admitted to inpatient care at St. Paul's Hospital Millennium Medical College (SPHMMC), Zewditu Memorial Hospital (ZMH), and Tikur Anbessa Specialized Hospital (TASH) during the study period and met the inclusion criteria and did not meet exclusion criteria were enrolled in this study. Of these, 80 patients who developed hemorrhagic transformation (HT) and 190 patients who did not develop HT were selected by using a simple random sampling method to make the study representative and to reduce selection bias (Figure 1). Key variables have been studied in relation to hemorrhagic transformation after ischemic stroke, defining the dependent variable (hemorrhagic transformation) and various independent factors including patient demographics, medical history, laboratory results, treatment details, neurological status, and imaging findings (Table 3).

Table 3: List of Variables and Operational Definitions

Data Collection

The data were extracted from Hospital Management Information System (HMIS) and manual patients' registration books of those suffering from acute ischemic stroke. The charts of the patients were assessed systematically in order to confirm the presence or absence of hemorrhagic transformation. Data were collected by trained general practitioners, who were previously trained for consistency and accuracy. Details from the patients' records were collected by means of a self-prepared checklist containing all variables of interest. The gathered data were manually verified for completeness prior to further processing.

Data Analysis and Processing

The collected data were manually verified for completeness, coded, and analyzed using SPSS version 26.0. Categorical variables were summarized using frequencies and percentages and compared using the chi-square test. Bivariate logistic regression analysis was performed to test the association of each independent variable with the dependent variable individually. Variables with a p-value of less than 0.25 in bivariate analysis were included in a multivariable logistic regression model to identify independent predictors. Variables with a p-value of less than 0.05 in the multivariable model were considered statistically significant. Strength of association was expressed in terms of odds ratios (OR) with 95% confidence intervals (CI). Results were tabulated and presented in tables and text.

Ethical Issues

Ethical approval was obtained from St. Paul's Hospital Millennium Medical College's, Zewditu Memorial Hospital's, and Tikur Anbessa Specialized Hospital's Research Ethics Committees. Patient information confidentiality was maintained strictly in operation throughout the research.

Sociodemographic and clinical characteristics of the study participants

In this study 270 participants participated with 90 cases (HT) and 180 control (without HT) representing a response rate of 94.7%. In this study 37.8% of the study participants were of the age group of 61-70 years with mean and SD of 61.2±12.51 years respectively. Half of the study participants were male with 65.9% control and 34.1

Age was also recognized as a statistically significant risk factor for hemorrhagic transformation (HT) (p = 0.001), as in a Chinese study [15]. Although HT is not limited to any age, older patients are at greater risk for developing it due to multifactorial effects such as increased blood-brain barrier (BBB) permeability and systemic inflammation. Aged individuals also have a higher incidence of cerebrovascular disease and are more likely to be put on antithrombotic therapy, and common comorbidities include diabetes and hypertension. Both diabetes and hypertension enhance inflammation, which may contribute to the BBB disruption following stroke, and thus enhance HT risk.

Glasgow Coma Scale (GCS) status was also highly correlated with HT (p = 0.001), as in a Saudi Arabian study [16]. Reduced consciousness, as determined by lower GCS scores, patients can experience impaired cerebral autoregulation. Dysfunction of autoregulation can cause changes in cerebral perfusion pressure, increasing susceptibility to hemorrhagic transformation [17].

History of diabetes mellitus (DM) increased the risk 5.4 times greater than among those with no DM (AOR = 5.4, 95% CI: 2.35–12.31), as has also been observed in the Saudi Arabian study [16]. Diabetes carries microvascular complications that damage small blood vessels, leading to structural changes, increased permeability, and impaired autoregulation, all tending to increase patients toward HT. In addition to this, diabetes is also associated with low-grade chronic inflammation, which is characterized by higher plasma levels of TNF, interleukin-1β, interleukin-6, and interferon-gamma that can again contribute to increasing the risk of HT [18].

Stress hyperglycemia was associated with a 12.2 times increased risk for HT (AOR = 12.2, 95% CI: 2.30–65.12). Acute stress or critical illness-induced hyperglycemia is able to deteriorate BBB disruption, increasing permeability and susceptibility to rupture and hemorrhagic transformation of cerebral vessels.

Patients with a history of previous stroke were 3.7 times more likely to have HT (AOR = 3.7, 95% CI: 1.57–8.86), which is in agreement with findings from Saudi Arabia [16]. This increased risk is most likely due to pre-existing vascular injury from previous strokes that weakens vessel walls and makes them more fragile.

The use of heparin was linked with a 5.6-fold higher risk of HT (AOR = 5.6, 95% CI: 1.41–22.66), supported by data from Changi General Hospital in Singapore [19]. Similarly, warfarin exposure increased the risk of HT by 13.1-fold (AOR = 13.1, 95% CI: 16.91–131.62), as reported in the same study [19]. Patients on more than one anticoagulant were at 3.8-fold higher risk than those on a single anticoagulant, a previously undescribed observation in the literature. Anticoagulant therapy disrupts normal hemostasis, prolongs bleeding time, and increases hemorrhage risk. Increased doses and longer anticoagulant therapy, especially in patients with other risk factors, raise the risk of hemorrhagic complications like intracerebral hemorrhage and HT [18]. In summary, this investigation clarifies the multifactorial etiology of HT risk, highlighting the supreme significance of age, neurological condition, metabolic parameters, cerebrovascular event history, and anticoagulation therapy. These findings confirm the urgency of cautious risk stratification and patient-individualized management strategies to avoid HT in patients with acute ischemic stroke.

The study identified a significant association of hemorrhagic transformation in acute ischemic stroke patients. Advanced age, lower scores on the Glasgow Coma Scale, history of diabetes mellitus, stress-induced hyperglycemia, past history of stroke, and use of anticoagulant treatments-most notably heparin and warfarin-were found to be independent predictors of high risk for HT. These findings emphasize highly the importance of meticulous clinical assessment and vigilance in high-risk patients in order to reduce the risk of hemorrhagic complications. Individualized management plans that highly consider the benefits versus risks of anticoagulation, combined with the best control of metabolic and vascular comorbidities, are essential to maximize outcomes for this high-risk population.

Limitations

Incomplete or ambiguous information was common due to retrospective reliance on existing medical records and inconsistent documentation was common.