Factors Affecting the Delay of intravenous Thrombolysis in Hyperacute Ischemic Stroke Patients: A Single Centre Study

Abstract

Introduction
Intravenous thrombolysis with r-tPA is the gold standard procedure in managing acute ischemic stroke recommended by the World Stroke Association, which is performed by injecting the drug r-tPA (Alteplase) intravenously. Generally, the preparation time to achieve thrombolysis is divided into pre-hospital and in-hospital. If this time can be shortened, the efficacy of thrombolysis can be increased. This study aims to determine the factors that can affect the delay in thrombolysis.

Methods
This is an analytic observational study with a retrospective cohort design in ischemic stroke confirmed by a neurologist at the neurology emergency unit of Hasan Sadikin Hospital (RSHS) from January 2021 to December 2021 and divided into two groups, delay and non-delay thrombolysis. A logistic regression test was performed to determine the independent predictor of delayed thrombolysis.

Results
There were 141 patients with an ischemic stroke diagnosis confirmed by a neurologist at the neurological emergency unit at Hasan Sadikin Hospital (RSHS) from January 2021 to December 2021. A total of 118 (83.69%) patients were included in the “delay” category, while 23 (16.31%) patients were included in the “non-delay” category. Patients included in the “delay” category had an average age of 58.29+11.19 years with a male-to-female sex ratio of 57%, while patients included in the “non-delay” category had an average age of 55.57+15.55 years with a male-to-female sex ratio of 66%. The NIHSS admission score was a significant risk factor for delayed thrombolysis. Through multiple logistic regression, it was found that age, onset, female gender, NIHSS admission score, and NIHSS discharge score were independent predictors of delayed thrombolysis. However, all of them were not statistically significant.

Conclusion
Gender, risk factors for dyslipidemia, and arrival onset are independent predictors of delayed thrombolysis. Prehospital factors contribute relatively more to the delay in thrombolytic action.

Full text

ORIGINAL RESEARCH
Factors Affecting the Delay of intravenous
Thrombolysis in Hyperacute Ischemic Stroke
Patients: A Single Centre Study
Lisda Amalia
Department of Neurology, Faculty of Medicine, Universitas Padjadjaran/Dr. Hasan Sadikin General Hospital, Bandung, Indonesia
Correspondence: Lisda Amalia, Department of Neurology, Faculty of Medicine, Universitas Padjadjaran/Dr. Hasan Sadikin General Hospital, Jl. Pasteur
38, Bandung, 40161, Indonesia, Email dr.lisda@gmail.com
Introduction: Intravenous thrombolysis with r-tPA is the gold standard procedure in managing acute ischemic stroke recommended
by the World Stroke Association, which is performed by injecting the drug r-tPA (Alteplase) intravenously. Generally, the preparation
time to achieve thrombolysis is divided into pre-hospital and in-hospital. If this time can be shortened, the efcacy of thrombolysis can
be increased. This study aims to determine the factors that can affect the delay in thrombolysis.
Methods: This is an analytic observational study with a retrospective cohort design in ischemic stroke conrmed by a neurologist at the
neurology emergency unit of Hasan Sadikin Hospital (RSHS) from January 2021 to December 2021 and divided into two groups, delay and
non-delay thrombolysis. A logistic regression test was performed to determine the independent predictor of delayed thrombolysis.
Results: There were 141 patients with an ischemic stroke diagnosis conrmed by a neurologist at the neurological emergency unit at
Hasan Sadikin Hospital (RSHS) from January 2021 to December 2021. A total of 118 (83.69%) patients were included in the “delay”
category, while 23 (16.31%) patients were included in the “non-delay” category. Patients included in the “delay” category had an
average age of 58.29+11.19 years with a male-to-female sex ratio of 57%, while patients included in the “non-delay” category had an
average age of 55.57+15.55 years with a male-to-female sex ratio of 66%. The NIHSS admission score was a signicant risk factor for
delayed thrombolysis. Through multiple logistic regression, it was found that age, onset, female gender, NIHSS admission score, and
NIHSS discharge score were independent predictors of delayed thrombolysis. However, all of them were not statistically signicant.
Conclusion: Gender, risk factors for dyslipidemia, and arrival onset are independent predictors of delayed thrombolysis. Prehospital
factors contribute relatively more to the delay in thrombolytic action.
Keywords: factor, hyperacute, ischemic, stroke, thrombolysis
Introduction
According to the World Health Organization (WHO), stroke is a clinical sign that develops rapidly from focal or global
cerebral dysfunction, lasts more than 24 hours or causes death, and occurs without any apparent cause other than vascular
causes. A stroke occurs when blood ow to the brain is lost due to blockage or rupture of blood vessels, resulting in
a lack of oxygen and sudden death of some brain cells. Stroke is a neurological emergency that is the 3rd cause of death
and disability in the world. Stroke is generally divided into ischemic stroke (80%) and hemorrhagic (20%).
1,2
Ischemic stroke is a disease that begins with a series of changes in the brain which, if not treated immediately, can cause the
death of the affected part of the brain. Ischemic stroke is caused by obstruction or cessation of blood supply to the brain.
Failure to supply blood will cause impaired function of the brain or in which nerve cell death (necrosis) has occurred.
3,4
In the
early minutes to several hours after the onset of neurological dysfunction in stroke patients is the only time of opportunity to
prevent death or permanent disability so that it becomes a target for prompt and appropriate treatment for stroke patients in that
period so that acute stroke management becomes optimal. Most of the causes of stroke is a blood clot that clogs the arteries that
supply the brain, so the administration of clot-busting agents (thrombolytics) is considered an effort that can reduce the
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Open Access Full Text Article
Received: 21 March 2023
Accepted: 24 May 2023
Published: 31 May 2023

damage from ischemia by returning blood ow to normal. A high rate of clinical improvement is achieved when blood ow is
restored soon after the blockage occurs. The most widely used agent, approved for use, is a thrombolytic agent with
recombinant tissue plasminogen activator (r-tPA).
5,6
Intravenous thrombolysis with r-tPA is the gold standard procedure in managing acute ischemic stroke recommended
by the World Stroke Association, which is performed by injecting the drug r-tPA (Alteplase) intravenously. Patients who
are candidates for r-tPA recipients are screened according to inclusion and exclusion criteria based on standard operating
procedures and existing guidelines. In general, the preparation time to achieve thrombolysis is divided into two, namely
the time from onset to hospital admission (onset-to-door-time [ODT]) or pre-hospital and from the time the patient enters
the emergency room until the thrombolysis drug is administered (door-to-needle time [DNT]) or in-hospital. If this time
can be shortened, the efcacy of thrombolysis can increase.
6,7
However, in a study conducted in Wuhan, only 9.81% of
patients in 2020 and 8.12% of patients in 2019 met the criteria for thrombolysis.
3
From the onset to hospital admission (onset-to-door-time [ODT]) or pre-hospital, awareness and knowledge of patients and
families are needed to recognize the symptoms of a stroke. Awareness of symptoms and their severity, willingness to take them to
the hospital immediately without waiting for symptoms to improve, distance from home, availability of an ambulance or vehicle,
and referral system can affect during this time. Some patients and their families may not recognize a stroke’s early signs and
symptoms. In contrast, others may recognize the symptoms and signs of a stroke and realize the importance of rst treatment at
the hospital to immediately take the patient to the hospital. The behavior of patients or other families towards stroke with mild
symptoms tends to wait for symptom improvement rather than directly taking the patient to the hospital. Long distances and
limited transportation modalities can also extend the time to arrive at the hospital. A good referral system between hospitals can
speed up preparation time for thrombolysis.
8–13
The time from the emergency room door until the thrombolysis drug is given (door-to-needle time [DNT]) or in-
hospital is also inuenced by several internal factors in the hospital, namely triage efciency, efciency of multi-
disciplinary acute stroke services, and informed consent to patients or families regarding thrombolysis. Triage requires
varying times in carrying out emergency treatment screening so that appropriate screening for recognizing stroke and
acute stroke codes can be carried out immediately.
11–17
If this time can be shortened, then the efcacy of thrombolysis
can be increased. This study aims to determine the factors that can affect the delay in thrombolysis.
Methods
This is an analytic observational study with a retrospective cohort design in 141 patients with a diagnosis of ischemic stroke
enforced by a neurologist at the emergency department on admission of neurology at Hasan Sadikin Hospital (RSHS), during the
period from January 2021 to December 2021. Patients were categorized into two categories; namely, patients with the “delay”
category were dened as patients who experienced delayed thrombolysis (thrombolysis time > 60 minutes). In contrast, patients
with the “non-delay” category were dened as patients who do not experience delayed thrombolysis (thrombolysis time < 60
minutes).
Retrieval of medical record data will be carried out following the ethical provisions of Hasan Sadikin Hospital by
maintaining the condentiality of the patient. Demographic data, clinical characteristics, rt-PA screening, and ischemic
stroke outcomes will be recorded and further analyzed to determine the factors that affect thrombolysis delay. Risk
factors such as lipid prole and uric acid level were performed for study subjects. Factors that can be intervened will be
improved so that hyperacute ischemic stroke services can run optimally. Statistical analysis used univariate analysis and
a logistic regression test by estimating the Odds Ratio (OR) parameter.
The study was conducted after obtaining ethical approval from the research ethics committee of RSUP Dr. Hasan
Sadikin Bandung (LB.02.01/X.6.5/403/2022). This study complied with all relevant ethical regulations (including The
Declaration of Helsinki). All patients had obtained written informed consent.
Results
There were 141 patients diagnosed with ischemic stroke enforced by a neurologist at the neurology emergency unit of
Hasan Sadikin Hospital (RSHS) from January 2021 to December 2021. 118 (83.69%) patients were included in the
“delay” category. In comparison, 23 (16.31%) patients were included in the ‘non-delay’ patients category. Patients
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included in the “delay” category had an average age of 58.29 + 11.19 years with a male to a female sex ratio of 57%,
while patients included in the “non-delay” category had an average age of 55.57+15.55 years with a male to a female sex
ratio of 66% (Table 1). In patients with the “delay” category, hypertension was the most common risk factor, experienced
by 80 (67.8%) patients, followed by dyslipidemia in 51 (43.2%) patients. Whereas, in patients in the “non-delay”
category, hypertension was also the most common risk factor, experienced in 13 (56.5%) patients, followed by smoking
in 6 (26.1%) patients. Patient demographic characteristics are shown in Table 1 as follows. There was a signicant effect
on gender and risk factors for dyslipidemia and hyperuricemia on delayed thrombolysis (p<0.05). Both age and risk
factors such as hypertension, hypercoagulation, diabetes mellitus, smoking, rheumatic heart disease, previous stroke
episodes, atrial brillation, chronic kidney disease, and coronary heart disease did not have a statistically signicant
effect on thrombolysis delay. The average time from onset to hospital admission in the “delay” category of patients was
39.97+64.30 hours, while in patients with the “non-delay” category, it was 3.11+0.94 hours. In both “delay” and “non-
delay” patients, weak limbs were found to be the most common clinical manifestation in 113 (95.76%) patients and 22
(95.65%) patients, respectively. The mean score of the National Institutes of Health Stroke Scale (NIHSS) for admission
in patients with the “delay” category was 10.65 + 5.08, while in patients with the “non-delay” category, it was 11.96 +
5.00 hours. The mean score of the National Institutes of Health Stroke Scale (NIHSS) for discharge in patients in the
“delay” category was 4.82 + 4.55, while in patients in the “non-delay” category, it was 4.7 + 4.96 hours. Obtaining the
onset of arrival is a signicant factor for the delay in diagnosis (p <0.05). Both clinical manifestations, admission NIHSS
score, and discharge NIHSS score had no statistically signicant effect on thrombolysis delay. The clinical characteristics
of the patients are shown in Table 2.
For factors that have a p-value <0.05, multiple logistic regression tests were performed to determine the independent
predictor factors for delayed thrombolysis. It was found that male gender, risk factors for dyslipidemia, and arrival onset
were independent predictors of delayed thrombolysis (Table 3).
Discussion
In this study, it was found that the onset of the arrival of patients was signicantly related to delayed thrombolysis (p
<0.001), where the rapid onset of arrival tended not to delay thrombolysis. In contrast, the long onset of arrival managed
to delay thrombolysis. This is different from the research conducted by Erqing Chai et al. Thrombolysis time or onset-to-
door is an independent risk factor associated with delayed thrombolysis in patients undergoing rt-PA at the Department of
Cerebrovascular Disease Center of Gansu Provincial Hospital, in addition to NIHSS score and decision time. The study
Table 1 Demographic Characteristics of Ischemic Stroke Patients
Demographic Characteristic “Delay” (n=118) “Non-Delay” (n=23) P-value
Average age ± std (year) 58.29±11.19 55.57±15.55 0.112
Gender (n, %) 0.029*
Male 75 (64%) 9 (39%)
Female 43 (36%) 14 (61%)
Risk factors (n, %)
Hypertension 80 (67.8%) 13 (56.5%) 0.297
Dyslipidemia 51 (43.2%) 5 (21.7%) 0.047*
Hyperuricemia 6 (5.1%) 0 0.043*
Hypercoagulation 4 (3.4%) 1 (4.3%) 0.82
Diabetes Mellitus 26 (22%) 5 (21.7%) 0.96
Smoking 36 (30.5%) 6 (26.1%) 0.671
Rheumatic Heart Disease 3 (2.5%) 1 (4.3%) 0.633
Previous stroke 13 (11%) 1 (4.3%) 0.328
Atrial Fibrillation 14 (11.9%) 6 (26.1%) 0.074
Chronic Kidney Disease 2 (1.7%) 0 0.529
Coronary Heart Disease 9 (7.6%) 0 0.169
Note: *Statistically signicant.
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states that there is an inverse relationship between the onset of arrival and thrombolysis time, known as the “3-hour
effect”. The door-to-needle time between patients in the hospital with a beginning of arrival at the start of the window
period was longer than that of patients with a beginning of the arrival of almost 3 hours. In that study, the ‘3-hour effect’
could signicantly impair thrombolysis time, a decision related to the degree of emergency perceived by physicians.
Physicians pay more attention to critically ill patients with an onset close to the window period.
14,18
In this study, there was no signicant relationship between clinical manifestations and thrombolysis time, but clinical
manifestations tended to have a higher rate in patients with delayed thrombolysis. This is the same as a study by Chai
et al which stated that patients with a shorter symptom progression time had a longer thrombolysis time and were treated
with less urgency. It is known that the effect of intravenous thrombolysis decreases signicantly with increasing time
from onset to the needle. However, these results can be a wrong assumption because there were signicant population
differences between delayed and non-delay patients in this study.
14
The NIHSS score is also an independent risk factor associated with delayed thrombolysis.
14
The NIHSS score is
a relatively universal and concise stroke rating scale worldwide, especially for evaluating neurological decits in treating
acute ischemic stroke.
19
The NIHSS score level can more accurately reect the patient’s clinical situation intuitively.
20,21
In our study, patients with higher admission NIHSS scores had a lower risk of hospital delay although not statistically
signicantly related, which could be explained by the fact that clinical manifestations of severe signs and symptoms can
easily it is easy to convince family members and those closest to them to immediately take acute ischemic stroke patients
to the hospital to get further emergency treatment from a doctor. Patients with a higher NIHSS score undergo an
examination as soon as the patient arrives at the hospital, thereby reducing the risk of delayed thrombolysis.
14
In this study, hypertension was a risk factor experienced by most patients undergoing rt-PA. Patients who experience
delayed thrombolysis have a higher proportion of hypertension than those who do not share delayed thrombolysis. This is
the same as the study by Mowla et al, which stated that severe hypertension signicantly contributes to slowing
thrombolysis. Blood pressure above 185/110 mm Hg on arrival is a contraindication to thrombolysis. In that study,
investigators did not actively reduce hypertension >185/110 mmHg at triage when acute ischemic stroke was suspected.
Lowering blood pressure could signicantly decrease brain tissue perfusion, leading to further ischemic compromise.
Instead, the investigators monitored blood pressure closely until the thrombolysis. If there was no spontaneous fall below
Table 3 Regression Logistics of Delayed Intravenous Thrombolysis Patients
Variable Predictor Standard Error Odds Ratio 95% CI P-value
Gender (male) 0.477 2.592 1.04–1.17 0.046*
Dyslipidemia 0.613 0.293 1.12–1.30 0.045*
Hyperuricemia 0.844 2.779 1.10–1.23 0.226
Onset 0.001 2.521 −0.002–0.00 0.007*
Note: *Statistically signicant.
Table 2 Clinical Characteristics of Intravenous Thrombolysis Patients
Clinical Characteristic “Delay” (n=118) “Non-Delay” (n=23) P-value
Onset 39.97±64.30 3.11±0.94 <0.001*
Clinical manifestation (n, %)
Limb weakness 113 (95.76%) 22 (95.65%) 0.981
Speech disorder 67 (56.78%) 10 (43.48%) 0.241
Sensory disorder 29 (24.58%) 3 (13.04%) 0.227
Loss of consciousness 60 (50.85%) 14 (60.87%) 0.379
Seizure 8 (6.78%) 2 (8.7%) 0.743
Mean NIHSS on admission 10.65 ± 5.08 11.96 ± 5.00 0.264
Mean NIHSS on discharge 4.82 ± 4.55 4.7 ± 4.96 0.905
Note: *Statistically signicant.
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185/110 mm Hg, the rst dose of antihypertensives was administered in the ED before thrombolysis. This causes
hypertensive patients to experience delayed thrombolysis potentially.
22,23
Based on the results of multiple logistic regression tests, it was found that gender and dyslipidemia were independent
predictors of delayed thrombolysis with statistically signicant effects. In contrast, the onset of arrival and hyperuricemia
were independent predictors of delayed thrombolysis, with results that were not statistically signicant. The potential
causes of delayed thrombolytic therapy are numerous and can be divided into two categories, namely pre-hospital and in-
hospital factors, from symptom onset to treatment administration. Prehospital factors contribute relatively more to the
delay. Many delays are multifactorial, ranging from factors related to the patient, transportation, and referral systems to
delays in and out of the hospital. For example, delayed symptom recognition is more likely with increasing distance from
the care center and at lower priority triage which is more likely if the symptoms observed in the patient are atypical.
24
Delay in contacting emergency medical services has been found to contribute to more than half of cases of prehospital
delay,
25
which may result from the patient’s or family’s perception that the symptoms are not severe enough to warrant
a visit to the health care facility and medical treatment
26,27
or that the symptoms
28,29
More severe stroke symptoms were
correlated with an earlier presentation to the emergency department than those that resolved rapidly, or mild, symptoms
were associated with a delay in patient presentation to the emergency department (ED).
25
Female gender is thought to be associated with the late presentation of patients to the ED, which is inversely
proportional to the results of this study. However, relevant studies do not control for the age factor, namely female
patients who visit the emergency department due to acute ischemic stroke are older than male patients.
30,31
Living alone
is also an independent predictor factor associated with delay in patient presentation to the emergency room 30 which
shows results relatively similar to an older age.
32,33
Older people more often live alone and have strokes without realizing
it. Living alone makes seeking care difcult and also delays the process of referral and diagnosis.
30
In-hospital factors can be divided into delays in assessment, uncertainties associated with imaging, and delays related
to decision-making and administration of thrombolysis.
24
In this study, it was found that relatively younger patients
presenting to the ED with acute stroke were more likely to receive thrombolytic therapy compared to older patients.
However, younger patients are more likely to experience a delay in diagnosis because stroke presentation is less common
in a relatively younger age range, and the presence of atypical presentations is more likely to occur in a relatively
younger age group,
34
so treatment with thrombolysis may be delayed for done.
35
Several studies evaluate the usefulness of coordinated stroke warning systems and their effect on thrombolysis time.
A Swedish national survey of 49,907 patients admitted with acute stroke over two years found a decrease in delayed
thrombolysis time and an increase in the thrombolysis rate in cases of stroke alert when compared with cases in which
stroke alerts or stroke alerts were not activated.
36
One solution to improve the emergency room administration system to shorten Door-to-Needle (DNT) at RSHS is
to have a running “Code Stroke”. Code Stroke is a rapid response system to treat acute ischemic stroke patients by
getting immediate therapy so that the outcomes obtained are effective and maximum. Code Stroke aims to prioritize
and expedite services to diagnose and provide management of hyperacute stroke cases, specically hyperacute
ischemic stroke cases, which are candidates for intravenous thrombolysis and is expected to shorten administration
time in the emergency room.
Conclusion
Male gender, risk factors for dyslipidemia, and arrival onset are independent predictors of delayed thrombolysis.
Prehospital factors contribute relatively more to the delay in thrombolytic action. Further research needs to be done on
what factors inuence the delay in intravenous thrombolysis, whether awareness about stroke or access to hyper acute
stroke services.
Data Sharing Statement
No additional data is available.
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Funding
No funding research.
Disclosure
There is no competing interest.
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