WHAT DETERMINES BETTER OUTCOME IN ACUTE ISCHEMIC STROKE PATIENTS TREATED WITH THROMBOLYSIS? -
University Medical Centre Ljubljana, Division of Neurology, Department of Vascular Neurology and Intensive Care, Neurocritical Care Unit, Zaloška 2, SI-
Aim of the work: Ischaemic stroke is one of the leading causes of death and disability worldwide. Intravenous alteplase is, despite the recent promising results in mechanical revascularisation, the only proven effective and possible treatment option in many centres. The aim of our retrospective study was to analyse whether time to treatment, severity or territory of stroke, gender and age matter in acute ischemic stroke patients, treated with iv alteplase.
Materials and Methods: In retrospective study we analysed data of all patients from 2 university and 3 general hospitals treated with iv alteplase due to acute ischemic stroke between January 2003 and December 2015. Data were collected in Safe Implementation of Treatment in Stroke register. Results on onset-
Results: Between January 1st, 2003 and December 31st, 2015 1228 acute ischemic stroke patients were treated with iv alteplase in 5 centres. However, due to lack of majority of important data (gender, age, NIHSS, time logistics, etc.), we analysed data from 1117 patients (91.0 %). Average age was 68.9 ± 12.5 years. There were more male than female patients (55.4 % vs. 44.6 %, respectively; p = 0.013), female patients were significantly older (71.3 ± 12.4 years; p < 0.001), had worse clinical presentation on stroke onset (NIHSS 13.8; p = 0.001) and worse outcome (p<0.0001). The average NIHSS score in 1117 patients was 13.2 ± 6.7. Patients, older than 80 years (N=156), had statistically worse clinical picture on admission than younger group (N= 961) (13.8 ± 6.4; 13.0 ± 6.5, respectively; p = 0.003) and had worse outcome after 3 months (p < 0.0001). “Golden hour” patients were otherwise rare (N=24), however they have statistically worse clinical picture at presentation (NIHSS 13.7 ± 7.8), comparing to “classical” (N=893; NIHSS 13.6 ± 6.3) or “late” group (N= 200; NIHSS 11.1 ± 6.8)(p < 0.0001), but better outcome after 3 months (p < 0.0001). Patients with total anterior circulation infarct had worse NIHSS than patients with partial anterior circulation or lacunar infarct (p < 0.0001; p < 0.0001, respectively), as well as worse outcome (p < 0.0001).
Conclusion: Advances are being made in acute ischemic stroke reperfusion therapy, such as shortening of the exclusion criteria (e.g. elderly or severe stroke patients) or implementation of the ultra-
Key words: stroke, ultra-
Ischaemic stroke is one of the leading causes of death and disability worldwide and intravenous alteplase is the only proven effective treatment in the acute setting worldwide [1, 2]. Recently, mechanical revascularisation showed promising results and as a method of an emergency stroke treatment, it is included in the guidelines . Epidemiological data showed that stroke in the USA moved from its third position as a leading cause of death to the fifth . This results are encouraging in developed countries, however, in most countries death rate due to stroke remains very high , and stroke is still the main cause of long-
The effectiveness of intravenous thrombolysis in acute ischemic stroke is time dependent and the effect is highest if the time from symptom onset to treatment is as short as possible. A new concept, otherwise very well known in trauma and out-
MATERIALS AND METHODS
The incidence of cerebrovascular diseases in Slovenia is around 200 patients/100.000 population, 85 % having ischemic stroke. We analysed all patients (2 university and 3 general hospitals; only University Medical Centre Ljubljana entered data regularly) included in SITS register, treated with i.v. thrombolysis with alteplase between January 1st, 2003 and December 31st, 2015. We presented results on onset-
We calculated and analysed some numerical results as the mean values, median and standard deviations. For statistical analysis, we used the Wilcoxon signed-
In 2003, Republic of Slovenia joined international register (SITS register) in order to compare results between centres in the country and worldwide. At the begging, all data where entered immediately, since alteplase was not registered for treatment in acute ischemic stroke and as a rule for patient safety. Between January 1st, 2003 and December 31st, 2015 in 5 centres, entering data into SITS register, we treated with alteplase 1228 acute ischemic stroke patients. Due to lack of majority of important data (such as gender, age, NIHSS, time logistics, etc.), we analysed data from 1117 patients (91.0 %). Average age was 68.9 ± 12.5 years.
After better public awareness in 2010, when we implemented FAST (Face Arm Speech Time) system, called “GROM”, we admitted and treated with thrombolysis a higher number of patients (Figure 1).
As seen in Table 1, there were more male than female patients (55.4 % vs. 44.6 %, respectively; p = 0.013). Female patients were significantly older (71.3 ± 12.4 years; p <0.001), as was the case also in a group of patients, adhering to an official guidelines concerning age eligibility (68.0 vs. 65.0, respectively; p < 0.0001).
Figure 1. Number of patients recruited in Republic of Slovenia to Safe Implementation of Treatment in Stroke register between 2003 and 2015. Note higher recruitment number (year 2010), probably due to better public awareness.
Table 1. Some demographic data, showing age and gender statistics in patients adhering to guidelines and those, older than 80 years at stroke onset.
N – number/broj; P -
Patients, older than 80 years are according to the guidelines [1, 2, 6] not eligible for thrombolytic treatment, except in experienced centres and with informed consent, if necessary, according to national rules. In Slovenia we treat such patients, when we have written consent (patients signed themselves or consent signed by the relatives). As seen from Table 1, we treated 156 (14.0 %) patients older than 80 years with alteplase (average age 85.0 ± 3.4 years).
In Table 2, we present NIHSS score in patients, adhering to guidelines  and in those, older than 80 years at stroke onset, as well as, according to time logistics (prehospital delay, in-
Table 2. Stroke severity at admission according to National Institute of Health Stroke Scale in patients adhering to guidelines and those, older than 80 years at stroke onset and according to time logistics (prehospital delay, hospital delay).
N – number/broj; P -
Patients, treated within first 60 minutes after stroke symptoms and signs onset, were otherwise rare (n=24; 2.1 %). Among them, 3 (12.5 %) patients were older than 80 years. The average NIHSS score was 13.7 ± 7.8. There was no significant difference between male and female patients. Patients, arriving according to the original study (n=893; 79.9 %) , within 60 to 180 minutes, had an average NIHSS before treatment of 13.6 ± 6.3. Between men and women we found statistically significant worse clinical picture on admission in woman (p = 0.001). As seen in Table 2, when we introduced new guidelines into a routine clinical practice, extending the time window up to 4.5 hours in 2009, we treated 200 patients with alteplase. The average NIHSS before treatment in this group (onset to needle time within 181 -
We also compared NIHSS results before treatment in all three groups (“golden hour” group, “classical” group and “late” group). We found that “late” group had statistically better clinical picture than “classical” group (p < 0.0001) on admission; however, we did not find any differences between late and golden or classical and “golden hour” group. The reason was a low statistical power due to a low number of stroke patients in the “golden hour” group.
Table 3. Stroke severity at admission (National Institute of Health Stroke Scale) in our cohort of patients according to stroke territory and time logistics.
Highest NIHSS score usually have patients with stroke in the posterior territory (mostly basilar artery occlusion). According to original study, published in 1995 , patients with NIHSS 4 or less and 25 or more, should not be treated with alteplase. All eligibility criteria from the National Institute of Neurological Disorders and Stroke recombinant tPA Stroke Study  were adopted within the alteplase package insert as contraindications/warnings. We, clinicians have expressed the need for clarification and better definition of these treatment criteria. One of the exclusion criteria chosen was also rapidly improving stroke symptoms. None of our patients was treated with alteplase if has had rapidly improving symptoms, and this is not true for patients, that probably have had minor stroke, such as lacunar stroke. However, excluding patients with rapid improvement to non-
So, if patients or their relatives signed informed consent, than we treated these patients with alteplase (as an off-
In our cohort of patients, according to SITS registry data, posterior circulation infarct (POCI) was a rare final diagnosis (only in 8 patients). As seen in Table 3, most of the patients had stroke in either anterior circulation or lacunar stroke. In 142 patients (12.7 %), there was no final diagnosis
As expected, there was significantly worse clinical picture according to NIHSS on admission in patients with total anterior circulation infarct (TACI) than in partial anterior circulation infarct (PACI) (p < 0.0001) or lacunar infarct (LACI) (p < 0.0001) or when compared to a group with no final diagnosis (p< 0.0001).
We evaluated outcome after 3 months with mRs in all three groups as far as time logistic was concerned (Figure 2) and in groups younger and older than 80 years on admission (Figure 3). In Figure 4 we can see the outcome results (mRs) corresponding to the stroke territory.
(Kliknite na sliku da uvećate grafikon/Click on picture to enlage graphic)
Figure 2. Outcome results in our cohort of patients, treated with alteplase, according to time logistic.
Graf 2. Ishod lečenja u našoj kohorti pacijenata, lečenim alteplazom, prema vremenskoj logistici.
As seen from Figure 2, the best outcome (mRs 0 -
their clinical picture was also worse than in the younger group(Table 2).
Table 4 shows that women had statistically worse outcome than men (p < 0.0001), as well as patients with acute ischemic stroke in TACI territory (p < 0.0001), and, as expected, the best outcome was in patients with lacunar infarction (Figure 4).
Figure 3. Outcome results in our cohort of patients, treated with alteplase, according to age on stroke onset.
Table 4. Stroke outcome after 3 months, evaluated with modified Rankin scale, according to gender, time logistic, age and stroke territory in our cohort of patients, treated with alteplase between 2003 and 2015.
N – number/broj;
“golden hour” group/ Grupa "Zlatni sat" -
“classical” group/"klasična" grupa -
“late” group/"kasna" grupa -
Figure 4. Outcome results in our cohort of patients according to the stroke territory.
It is also important to analyse mortality rate and reason for death as a safety precaution. Between 2003 and 2015 180 (16.2 %) of all treated patients died, mostly due to stroke (52.2 %), stroke related therapy or hemorrhagic transformation (any intracranial haemorrhage) (24.4 %). Almost one quarter of patients died due to stroke complications, such as pneumonia, pulmonary embolism or due to concomitant myocardial infarction, or the reason was not declared or unknown. Detailed results are in Table 5.
Despite the fact, that time window is extended in eligible patients from 3 to 4.5 hours, it is important to shorten time from onset to the treatment as much as possible. This could be dome with “GROM” notification or any campaign for public awareness that stroke is a devastating disease. However, in the chain of survival, any lay public as well as medical professionals are equally important. In Figure 5 we show time delay in stroke management in our country, divided into pre and hospital delay.
Table 5. Mortality rate, reason for death and intracerebral hemorrhage due to alteplase treatment, according to gender, time logistic, age and stroke territory in our cohort of patients, treated with alteplase between 2003 and 2015.
*patients with unknown outcome were excluded
Figure 5. Time delay in stroke management in patients, treated with alteplase in Republic of Slovenia between 2003 and 2015.
Our study showed that iv alteplase delivered within the first 60 minutes after stroke symptoms and signs onset guarantee better outcome, when compared to the so called “classical” group, as well as to the “late” group. However, only 2.1 % of patients were treated within the “golden hour” (Table 2). This percentage is, however, higher than in the report from the Get With The Guidelines -
Considering age, NIHSS pre-
As seen from the literature, authors concluded, that women are more likely to have a worse outcome after an acute stroke than men, some others suggested that women benefit more from intravenous thrombolysis after an acute ischemic stroke and some found no sex differences in safety and efficacy [17-
Classification of ischemic stroke, using the TOAST criteria, helps us to determine the pathophysiologic mechanism and stroke aetiology. According to literature data, patients with lacunar infarcts have higher probability of favourable outcome than patients with cardioembolism or large vessel disease [22, 23]. As seen in Figure 4, similar presentation was also seen in our cohort of patients.
Intracerebral haemorrhage still represents the most feared complication of thrombolysis. It is a complex and heterogeneous phenomenon, which involves multiple demographic, clinical, biological and hemodynamic parameters. The importance of a strict protocol for the control of elevated blood pressure is needed during the first 24 h following thrombolysis, as well as strict adherence to the eligibility for thrombolytic treatment. However, inclusion criteria, as were originally implemented with the first studies are probably obsolete, since we have now multimodal neuroradiological techniques . However, since it was not the aim of our study to analyse and statistically evaluate in detail the mortality rate in our group of patients, we presented just some data on this topic. In our group of patients the mortality rate was relatively high (16.2 %) and most of the patients died due to ischemic stroke (52.2 %) or intracerebral haemorrhage (24.4 %).
Despite better organisation in late years, implementing a telestroke project, we did not shorten much the pre-
Despite the increase in the global burden of stroke, advances are being made. Outcome in patients with acute ischaemic stroke, as shown in many studies, is significantly better in those who undergo thrombolysis compared with those who do not. It is also clearly evident that the levels of evidence supporting individual exclusion criteria for intravenous alteplase, such as treatment in elderly stroke patients or those with severe stroke vary widely.
Also, the term “golden hour” implies that morbidity and mortality are affected if care is not instituted within the first hour after insult. Earlier thrombolytic treatment of patients with acute ischemic stroke is associated with more frequent independent ambulation, reduced mortality and symptomatic intracranial haemorrhage. We were also able to show this in our study. However, we believe that this is still a challenge of reperfusion therapy for acute ischemic stroke in the near future. The findings in studies support intensive efforts to accelerate patient presentation and to streamline local system to shorten onset to treatment time. Finally, we did not discuss coexistence of multiple exclusion factors in a single patient, and the variation in practice among treating clinicians. Probably this should also be a challenge in the future studies to improve stroke patient care. We should continuously encourage trends, the public and healthcare professionals, to remain vigilant and committed to improving overall stroke care.
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Viktor ŠVIGELJ, MD, PhD
University Medical Centre Ljubljana, Division of Neurology, Department of Vascular Neurology and Intensive Care, Neurocritical Care Unit, Zaloška 2,
Phone: +386 1 522 4846
Fax: +386 1 522 1332
Rad primljen: 21.07.2016.
Rad prihvaćen 12.09.2016.
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