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Predictors of symptomatic intracranial haemorrhage after thrombolysis in basilar artery occlusion Reetta Ruuskanen, B.M. Department of Neurology, Helsinki University Central hospital Helsinki 18.10.2015 Thesis [email protected] Supervisors: Associate Professor Daniel Strbian, Associate Professor Tiina Sairanen, Prof Perttu J Lindsberg UNIVERSITY OF HELSINKI Faculty of medicine
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HELSINGIN YLIOPISTO -‐ HELSINGFORS UNIVERSITET Tiedekunta/Osasto -‐ Fakultet/Sektion – Faculty
Medicine Laitos -‐ Institution – Department
Neurology Tekijä -‐ Författare – Author
Reetta Ruuskanen Työn nimi -‐ Arbetets titel – Title
Predictors of symptomatic intracranial haemorrhage after thrombolysis in BAO Oppiaine -‐ Läroämne – Subject
Neurology Työn laji -‐ Arbetets art – Level
Thesis Aika -‐ Datum – Month and year
18.10.2015 Sivumäärä -‐Sidoantal -‐ Number of pages 21
Tiivistelmä -‐ Referat – Abstract
Background and purpose: To find out factors associated with development of
symptomatic intracranial haemorrhage (sICH) in patients with basilar artery occlusion.
Patients were treated with intravenous alteplase and full-‐dose anticoagulation with
heparin.
Methods: The data is from a consecutive cohort of 176 BAO patients treated at Helsinki
University Central Hospital during the period between 1995-‐2013. sICH was judged
according to European Cooperative Acute Stroke Study II. The extent of baseline
ischemia was evaluated with posterior circulation Acute Stroke Prognosis Early CT
score (pc-‐ASPECTS). Modified Rankin Scale (mRS) at three months was used to rate the
outcome. Favourable outcome was rated as 0 to 2 and unfavourable as 3 to 6.
Results: 13.6% of patients developed sICH. Pc-‐ASPECTS under 8 independently
increased the risk of sICH (p = 0.031). 70.3% of patients had 3-‐month mRS 3 to 6, among
whom were all sICH cases. High mean systolic blood pressure two hours after
thrombolysis was independently associated with development of sICH (p = 0.034).
Platelet count at baseline and 24 hours after tPA and heparin administration was lower
in patients with sICH than without sICH. Activated partial thromboplastin time (APTT)
values didn’t associate with developing sICH.
Interpretation: Low to normal platelet count, extensive baseline ischemic changes and
high systolic blood pressure at 2 hours after treatment increased the risk of developing
sICH. Avainsanat – Nyckelord – Keywords
Anticoagulation, basilar occlusion, heparin, intracranial bleeding, platelet, thrombolysis
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Contents 1 Introduction ............................................................................................................................................................. 1
2 Material ...................................................................................................................................................................... 4
3 Methods ...................................................................................................................................................................... 5
4 Results ........................................................................................................................................................................ 7
5 Discussion .............................................................................................................................................................. 17
6 Conclusions ............................................................................................................................................................ 19
7 References .............................................................................................................................................................. 20
8 Original article ...................................................................................................................................................... 22
1
1 Introduction
Basilar artery occlusion (BAO) is a rare but severe form of brain infarction. About one per cent
of all strokes is caused by BAO. Patients often have preceding non-‐specific symptoms such as
vertigo or headaches, which are followed by decreased consciousness, quadriparesis,
pupillary and oculomotor abnormalities, dysarthria and dysphagia. (1) The onset of
symptoms is slow in more than 60% of cases and instantaneous in 20% of cases. Most
patients, more than 99%, have two or more symptoms. (2) Differential diagnostic alternatives
are intracranial bleeding including subarachnoid haemorrhage (SAH), non-‐convulsive
epileptic seizures, hypoxic-‐ischemic encephalopathy and hypoglycaemia (3). The most
frequent causes of BAO are atherosclerotic occlusions resulting from local thrombosis at the
site of severe BA stenosis and embolic occlusions from cardiac and large artery sources (1).
Diagnosis can be made on the basis of a cranial computed tomography (CT) with CT-‐
angiography, magnetic resonance angiography (MRA) or digital subtraction angiography
(DSA) (3) .
Treatment aims to recanalization of occluded basilar artery. If recanalization does not occur,
85-‐95% of patients will die. (3) Treatment alternatives are antithrombotic agents,
intravenous thrombolysis (IVT), intra-‐arterial thrombolysis (IAT), and mechanical
endovascular treatment performed in an angio suite (1). Systematic analysis has shown that
there is “no significant difference in functional independence with endovascular therapy after
intravenous tissue plasminogen activator (tPA), as compared with intravenous tPA alone” in
BAO (4). With mechanical endovascular treatment there can even be a 90% recanalization
rate but there is no evidence of superiority of endovascular treatment over IVT concerning
clinical outcomes (1).
Since no controlled randomized trials have compared these acute treatment options with each
other, the choice of treatment is based on the local guidelines and accessibility. Further
research is needed to secure improvements in the treatment of BAO (1). A third of BAO
patients will become independent after thrombolysis. About half of patients with
recanalization will become independent. (3) The long-‐term quality of life of the survived BAO
patients have rarely been systemically analysed (5).
2
In Finland, primary treatment for BAO is IVT with alteplase and concomitant intravenous
heparin infusion. A requirement for IVT is that extensive ischemic changes in the brainstem or
other vertebro-‐basilar (VB) regions have not developed (6). Contraindications for
thrombolytic therapy are a duration of BAO exceeding 12 hours in the instantaneous onset
phenotype or 48 hours in the progressive (slow-‐onset) phenotype, absent brain stem reflexes
and/or a lack of spontaneous respiration, haemorrhage in brain imaging, detective
haemostasis and multiple comorbidities with a limited life expectancy (3).
Alteplase is a tissue plasminogen activator that converts plasminogen to plasmin, which
degrades fibrin clots (7). Alteplase is given 0.9 mg/kg, a maximum of 90 mg, first 10% by
bolus and the rest by intravenous infusion during an hour (6). Heparin inactivates clotting
factors such as thrombin, factor Xa and other proteases (7). Heparin-‐infusion is used to
prevent rethrombosis. Heparin is monitored using the activated partial thromboplastin time
(APTT). In the last years, patients with BAO have been treated with low-‐molecular-‐weight
heparin (LMWH) by bolus and subsequent subcutaneous enoxaparin 0.75 -‐ 1 mg/kg twice
daily. (6)
Some of the recognized outcome predictors include age, severity of stroke symptoms
evaluated by National Institutes of Health Stroke Scale (NIHSS), time to treatment, occlusion
length, thrombus volume, clot location, and possible collaterals (1). The absence of
hyperlipidaemia and presence of prodromal minor stroke were associated with a poor
outcome in a previous study (8).
If a patient develops symptomatic intracranial haemorrhage (sICH), mortality increases and
survivors have a worse prognosis (1). The known predictors of sICH after thrombolysis in
BAO are age, baseline NIHSS, and admission blood glucose. In ischemic anterior circulation
stroke patients, age > 75 years, NIHSS > 10 on admission and glucose > 8 mmol/l on
admission predict the development of sICH. Also, early infarct signs and a dense cerebral
artery sign in a CT head scan do increase the risk. (9)
3
Here, we tested whether routine heparin infusion with IVT is associated with intracranial
haemorrhage. The intention was to test demographic-‐, physiological-‐ and treatment-‐related
factors affecting the development of symptomatic intracranial haemorrhage. The results have
also been published as an original article, which is in the end of this thesis. (10).
4
2 Material
The data were from a consecutive cohort of BAO patients treated at Helsinki University
Central Hospital during the period between 1995-‐2013. The number of patients was 176.
Patients were treated with IV 0.9 mg/kg alteplase and immediately after or before
thrombolysis with full-‐dose anticoagulation with either intravenous unfractionated heparin
(UFH) or LMWH. Heparin was continued until the patient was mobilized. The APTT target was
between 75 and 100 seconds and it was monitored every 4 to 6 hours. If APTT values
exceeded 180 seconds they were recoded to 181 seconds.
We gathered the data from the electronic and paper patient charts manually and double-‐
checked a random sample. The data we gathered consisted of the age of patients; NIHSS on
admission, right after the treatment and 24 hours after the treatment; whether the patients
developed a symptomatic intracranial haemorrhage (sICH) or not and if they did, the delay
between the treatment and sICH; haemoglobin on admission; the leukocyte count on
admission; the thrombocyte count on admission and 24 hours after the treatment; proteinuria
on admission; the creatinine level on admission; the APTT level on admission and the first ten
APTT values registered; delays from heparin administration to each APTT value; maximal
APTT values after heparin administration in every 12 hours up to 120 hours; systolic and
diastolic blood pressure levels on admission and at 2/4/8/12/24/48 hours; blood glucose on
admission and the highest blood glucose levels at days one to seven after intervention.
Comparisons were made between the patients who developed sICH as a complication of
intervention and those who did not.
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3 Methods
Statistical analysis was carried out using SPSS statistical software 21.0. Distributions of the
continuous variables were tested for normality. Univariate analyses were performed with the
t-‐test or Mann–Whitney U test, as appropriate. We conducted a t-‐test for blood pressure
differences between sICH and non-‐sICH groups. Non-‐normal data were tested by
nonparametric tests between sICH and non-‐sICH groups. P-‐values lower than 0.05 were
considered significant.
The extent of baseline ischemia was evaluated with the posterior circulation Acute Stroke
Prognosis Early CT score (pc-‐ASPECTS) for CT (69% of patients) and magnetic resonance
imaging (MRI) (31% of patients). Post-‐treatment CT or MRI was obtained about 24 hours
after thrombolysis and additional CT if needed. sICH was judged according to European
Cooperative Acute Stroke Study II (ECASS-‐II) (11) . Recanalization was rated as partial to
complete and nil to minimal in post-‐treatment angiography. We used the modified Rankin
Scale (mRS) at three months to rate the outcome. A favourable outcome was rated as 0 to 2
and unfavourable as 3 to 6. MRS is explained in more detail in Table 1.
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Table 1. Modified ranking score from (12).
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4 Results
Out of 176 BAO patients who were treated with alteplase and full-‐dose heparin, 24 (13.6%)
developed sICH. One patient died before CT scan control. 90% of sICHs occurred within 48
hours from the treatment. Blood pressures at bleeding are estimates of the real pressures
since the values taken were the closest ones to the detection of sICH on head scan. Blood
pressure values were normally distributed.
In Table 2 we present baseline characters of sICH and non-‐sICH patients. Out of sICH-‐patients
there were 8 (33.3%) females and 16 (66.7%) males. The proportions didn’t differ compared
to non-‐SICH patients. Among the whole cohort, patients’ mean age was 65 years and standard
deviation 14 years. Diabetes mellitus type II was present in 13.1%, hypertension in 50.9%,
previous stroke in 23.4%, dyslipidaemia in 37.1% and congestive heart failure in 5.7% of
cases. These demographics did not differ between sICH and non-‐sICH patients. Medication
including statins, antihypertensives, antiplatelets, insulin, oral diabetes medication and
anticoagulation prophylaxis medication didn’t differ between sICH and non-‐sICH patients.
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Table 2. Baseline characters for patients with and without sICH.
Parameter, median (IQR, range) sICH -‐(n=151) sICH +(n=24) p-‐value
Age, years 64 (18, 27-‐92) 69 (18, 28-‐94) 0.354
Male 101 (66.9) 16 (66.7) 1.000
Baseline NIHSS 20 (19, 1-‐42) 25 (20, 3-‐39) 0.138
pc-‐ASPECTS<8 41 (27.2) 12 (50) 0.031
VB-‐leucoaraiosis 18 (15.9) 2 (10.5) 0.774
Baseline glucose, mmol/l 7.1 (3, 4.2-‐17.7)
7.8 (4.4, 5.2-‐18.5)‡ 0.324
Peak glucose<48 h
6.7 (2.3, 4.1-‐16.7)†
7.7 (2.7, 5.2-‐15)§ 0.062
Baseline systolic BP, mmHg 152 (23) 145 (22) 0.203||
Baseline diastolic BP 83 (17) 76 (18)
0.070||
Systolic BP (2 h) 147 (26) 160 (22)
0.034‡
Diastolic BP (2 h) 76 (17) 83 (24) 0.093‡
Baseline platelet count, E9/l 218 (81, 82-‐387) 183 (63, 107-‐312)
0.011‡
Baseline haemoglobin, g/l 142 (21, 89-‐186) 138 (28, 96-‐167)
0.474#
Baseline leucocytes, E9/l 9.1 (3.7, 2.7-‐22.8) 8.2 (3.7, 5.7-‐17.3)
0.404#
Baseline creatinine, μmol/l 78 (25, 38-‐272)** 80 (40, 50-‐180) 0.159
Diabetes 18 (11.9) 5 (20.8) 0.324
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*>85% data available; †76% availability; ‡>91% availability; §>66% availability; ||>98%
availability; #94% availability; **96% availability. Mean (SD) for BP values. NIHSS= National
institutes of health stroke scale; OTT=Onset to treatment time; VB=vertebro-‐basilar.
Prior antiplatelet 40 (26.5) 9 (37.5) 0.327
Prior warfarin 13 (10.1) 1 (4.8)
0.693*
OTT, min 447 (747, 48-‐
10910) 604 (1151, 85-‐3015) 0.256
Recanalization 80 (66.7) 5 (38.5)
0.066†
Hypertension 76 (50.3) 13 (54.2) 0.827
Dyslipidaemia 56 (37.1) 9 (37.5) 1.000
Atrial fibrillation 33 (21.9) 6 (25) 0.792
Congestive heart failure 10 (6.6) 0 0.361
10
Pc-‐ASPECTS less than 8 points was considered as extensive ischemic changes on the basis of
the original report (13). Patients with sICH more commonly had pc-‐ASPECTS <8 compared to
non-‐sICH patients (50% vs. 27%, p = 0.031). 123 (70.3%) patients had mRS 3 to 6 outcome
three months after thrombolysis and these included all sICH cases. The mean delay from the
treatment to sICH was 21 hours (SD 18 h, 2.3-‐73 h). Three months after thrombolysis 69
(39.4%) patients had died and out of them 22 were sICH patients. Only two sICH patients
survived (8,3%).
Mean systolic blood pressure two hours after thrombolysis associated with development of
sICH. The higher the pressure the greater the risk of sICH, mean 160 mmHg vs. non-‐sICH 147
mmHg (p = 0.034). Systolic blood pressure two hours after tPA administration was higher in
patients with sICH than without sICH. This is shown in Figure 1. The blue line represents
patients without sICH and the red line patients with sICH. Diastolic blood pressure values
didn’t differ.
11
Figure 1. Median systolic blood pressures within the two groups.
Blood glucose right after tPA administration and maximal values on the days 1 to 7 were
equal between the groups. Median blood glucose is shown in Figure 2.
12
Figure 2. Median blood glucose between the two groups.
Platelet count at baseline and 24 hours after tPA and heparin administration was lower in
patients with sICH than with non-‐sICH; 183 vs. 218 E9/l at baseline (p = 0.011) and 169 vs.
204 E9/l at 24 h (p = 0.035). Mean platelet count at baseline and at 24 hours is shown in
Figure 3. The blue lines represent patients without sICH and the red lines patients with sICH.
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Figure 3. Platelet count between the two groups.
Figure 4 shows median APTT values measured before heparin infusion and after that in
twelve-‐hour periods up to 120 hours.
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Figure 4. Median APTT values at different times between the two groups.
In Figure 5 there are median APTT values before heparin infusion and after that the first to
tenth measured APTT values. It is seen that APTT values didn’t differ with sICH and non-‐sICH
patients so they didn’t correlate with developing sICH.
15
Figure 5. Median APTT values in administration and the first to tenth measured APTT after the treatment.
In Figure 6 there are the APTT values obtained closest to sICH detection. Red dots represent
those five patients in whom the delay from APTT measurement to sICH detection was more
than three hours. The black dots represent patients in whom the delay was < 2 hours. The
blue x-‐axis represents the peak and the range of APTT values per 12-‐hour intervals.
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Figure 6. The APTT values of sICH patients.
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5 Discussion
The main intention of this research was to determine whether the heparin treatment
associates with the development of sICH. Heparin effect is measured by APTT values. We
found only three factors that differed between patients with sICH and without sICH, and these
were pc-‐ASPECTS <8 prior to treatment, the platelet count at baseline and 24 hours after
treatment and systolic blood pressure two hours after treatment. A low to normal
perithrombolytic platelet count was associated with sICH. The higher the systolic blood
pressure at two hours, the higher the risk of sICH development. The mean blood pressure of
sICH patients was 160 mmHg and that of non-‐sICH patients 147 mmHg at 2 h. Both these
were still below the acceptable 185 mmHg. Why is the two-‐hour point significant while the
other times are not? The blood content of actilyse (recombinant tissue plasminogen activator)
is highest close to the infusion and 2 h was the first registered time of blood pressure
measurements.
Earlier studies have shown association of blood pressure with sICH after IVT in BAO. In a
large study with 11 080 patients high systolic blood pressure 2 to 24 hours after thrombolysis
was associated with poor outcome and sICH. The optimal systolic blood pressure values were
141 to 150 mmHg and predicted the best outcome. If antihypertensives were given to the
newly recognized moderate hypertensive patients that predicted favourable outcome. (14)
In another smaller study there wasn’t association with high blood pressure and sICH but there
was poorer outcome with higher blood pressures (15).
Platelet count in association to sICH has not been studied extensively before in our best
knowledge. Nevertheless there have been studies that show that antiplatelet agents associate
with developing ICH after recombinant tPA. Also an association between sICH and atrial
fibrillation, leucoaraiosis, congestive heart failure, higher age and higher glucose has been
shown in a large meta-‐analysis with 65 264 acute ischemic stroke patients. (16) In our study
there wasn’t any association between congestive heart failure and sICH but there were very
few patients with this condition. We didn’t find any correlation with age and developing sICH
in accordance with a prior study (17), but there is also previous study with larger sample
showing age as a predictor of sICH (9).
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In the present study half of the patients with sICH had pc-‐ASPECTS <8 and all sICH patients
had unfavourable outcome (mRS 3-‐6). In a larger study with 619 BAO-‐patients extensive
ischemic changes on baseline were a predictor for poor outcome and in a meta-‐analysis of
acute ischemic stroke patients treated with recombinant tPA they were a predictor for IVT-‐
associated sICH(8,16). The APTT values didn’t differ in patients with or without sICH and,
indeed, over 50% of sICH patients had targeted APTT values (75-‐100).
Early hyperglycaemia can increase the risk of early-‐term death of spontaneous intracranial
haemorrhage patients when hyperglycaemia is defined to be more than 7.5 mmol/l (18). The
admission blood glucose over 8 mmol/l was a predictor for sICH in a larger patient cohort (9)
but in our study there wasn’t correlation between sICH and high admission blood sugar. Most
of our patients had their blood glucose under 10 mmol/l and that could partly explain our
results. The gender didn’t have association with developing sICH in our study and this is
similar to another study (19).
Our study may be biased by some factors. The cohort is from a single centre and the sample
size is quite small, yet BAO is a rare form of ischemic stroke and sICH is more rare a condition.
IVT treatment is the routine BAO treatment used in Helsinki, Finland. Missing data was
highest for blood glucose after the hyperacute period and proportion of missing data was
higher for patients with sICH than without sICH at later time points (34% vs. 24% < 48 h;
Table 2). This most probably correlates with the severe condition of the patients leading to
omitting the glucose measurements.
In further studies it would be interesting to analyse more intensively the long-‐term quality of
the lives of BAO patients. Another very important improvement would be to compare IVT and
IAT treatments in randomized controlled trial, but that is not likely to happen. Present
research should be continued with bigger sample size so the results would be more reliable
and there could be strategies to minimize the risk of sICH. Our patient’s APTT values didn’t
affect developing sICH but if they targeted lower would the results be different or would the
use of LMWH give more even anticoagulation?
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6 Conclusions
We found three factors that associated with the development of sICH. Extensive baseline
ischemic changes, i.e. pc-‐ASPECTS under 8, was the most significant factor which made sICH
more likely. Clinically significant factors also included a low to normal platelet count and high
systolic blood pressure at 2 hours after treatment. However, more studies are needed to
confirm these findings. APTT values didn’t have association with sICH. The results are in line
with previous studies showing association of blood pressure with sICH and maybe in the
future, we should more actively treat the blood pressure of BAO patients, even below the
present guidelines, to prevent symptomatic intracranial haemorrhage.
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(2) Savitz SI, Caplan LR. Vertebrobasilar disease. N Engl J Med 2005 Jun 23;352(25):2618-‐2626.
(3) Lindsberg PJ, Sairanen T, Strbian D, Kaste M. Current treatment of basilar artery occlusion. Ann N Y Acad Sci 2012 Sep;1268:35-‐44.
(4) Broderick JP, Palesch YY, Demchuk AM, Yeatts SD, Khatri P, Hill MD, et al. Endovascular therapy after intravenous t-‐PA versus t-‐PA alone for stroke. N Engl J Med 2013 Mar 7;368(10):893-‐903.
(5) Ottomeyer C, Zeller J, Fesl G, Holtmannspotter M, Opherk C, Bender A, et al. Multimodal recanalization therapy in acute basilar artery occlusion: long-‐term functional outcome and quality of life. Stroke 2012 Aug;43(8):2130-‐2135.
(6) Sairanen T, Strbian D, Lindsberg PJ. Basilar artery occlusion-‐-‐a diagnostic and therapeutic challenge. Duodecim 2013;129(9):950-‐958.
(7) Koulu M, Tuomisto J, et al. Farmakologia ja toksikologia. : Medicina; 2001.
(8) Greving JP, Schonewille WJ, Wijman CA, Michel P, Kappelle LJ, Algra A, et al. Predicting outcome after acute basilar artery occlusion based on admission characteristics. Neurology 2012 Apr 3;78(14):1058-‐1063.
(9) Strbian D, Engelter S, Michel P, Meretoja A, Sekoranja L, Ahlhelm FJ, et al. Symptomatic intracranial hemorrhage after stroke thrombolysis: the SEDAN score. Ann Neurol 2012 May;71(5):634-‐641.
(10) Sairanen T, Strbian D, Ruuskanen R, Silvennoinen H, Salonen O, Lindsberg PJ. Symptomatic intracranial haemorrhage after thrombolysis with adjuvant anticoagulation in basilar artery occlusion. European Journal of Neurology 2015;22(3):493-‐499.
(11) Hacke W, Kaste M, Fieschi C, von Kummer R, Davalos A, Meier D, et al. Randomised double-‐blind placebo-‐controlled trial of thrombolytic therapy with intravenous alteplase in acute ischaemic stroke (ECASS II). Second European-‐Australasian Acute Stroke Study Investigators. Lancet 1998 Oct 17;352(9136):1245-‐1251.
(12) Available at: http://www.neuroems.com/2014/06/17/stroke-‐the-‐survivor/.
(13) Puetz V, Sylaja PN, Coutts SB, Hill MD, Dzialowski I, Mueller P, et al. Extent of hypoattenuation on CT angiography source images predicts functional outcome in patients with basilar artery occlusion. Stroke 2008 Sep;39(9):2485-‐2490.
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(14) Ahmed N, Wahlgren N, Brainin M, Castillo J, Ford GA, Kaste M, et al. Relationship of blood pressure, antihypertensive therapy, and outcome in ischemic stroke treated with intravenous thrombolysis: retrospective analysis from Safe Implementation of Thrombolysis in Stroke-‐International Stroke Thrombolysis Register (SITS-‐ISTR). Stroke 2009 Jul;40(7):2442-‐2449.
(15) Kellert L, Sykora M, Gumbinger C, Herrmann O, Ringleb PA. Blood pressure variability after intravenous thrombolysis in acute stroke does not predict intracerebral hemorrhage but poor outcome. Cerebrovascular Diseases 2012;33(2):135-‐140.
(16) Whiteley WN, Slot KB, Fernandes P, Sandercock P, Wardlaw J. Risk factors for intracranial hemorrhage in acute ischemic stroke patients treated with recombinant tissue plasminogen activator: a systematic review and meta-‐analysis of 55 studies. Stroke 2012 Nov;43(11):2904-‐2909.
(17) Vergouwen MD, Compter A, Tanne D, Engelter ST, Audebert H, Thijs V, et al. Outcomes of basilar artery occlusion in patients aged 75 years or older in the Basilar Artery International Cooperation Study. J Neurol 2012 Nov;259(11):2341-‐2346.
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(19) Arnold M, Fischer U, Compter A, Gralla J, Findling O, Mattle HP, et al. Acute basilar artery occlusion in the Basilar Artery International Cooperation Study: does gender matter? Stroke 2010 Nov;41(11):2693-‐2696.
Symptomatic intracranial haemorrhage after thrombolysis withadjuvant anticoagulation in basilar artery occlusion
T. Sairanena, D. Strbiana, R. Ruuskanenb, H. Silvennoinenc, O. Salonenc and P. J. Lindsberga,d
aDepartment of Neurology, University of Helsinki, Helsinki; bFaculty of Medicine, University of Helsinki, Helsinki; cHelsinki MedicalImaging Center, Helsinki University Central Hospital, University of Helsinki, Helsinki; and dMolecular Neurology, Research Program
Unit, Biomedicum Helsinki, and Department of Clinical Neurosciences, University of Helsinki, Helsinki, Finland
Keywords:
cerebral hemorrhage,cerebrovascular disease,cohort study,computerizedtomography, stroke
Received 4 June 2014
Accepted 19 September 2014
European Journal of
Neurology 2015, 22: 493–499
doi:10.1111/ene.12597
Background and purpose: Our aim was to determine factors associated withsymptomatic intracranial haemorrhage (sICH) in basilar artery occlusionpatients treated with intravenous thrombolysis (IVT) and adjuvant anticoagu-lant therapy.Methods: A registry of 176 consecutive patients with angiography-proven bas-ilar artery occlusion who received IVT with alteplase and heparin between1995 to 2013 was assessed. Post-treatment sICH was evaluated with the Euro-pean Cooperative Acute Stroke Study II criteria. Unfavourable outcome wasdefined as a modified Rankin Scale score of 3–6 at 3 months.Results: Twenty-four patients developed sICH (13.6%, sICH+), all of whomhad unfavourable outcome and only two (8.3%) sICH+ patients survived. Onadmission, sICH+ patients more frequently had extensive ischaemic changesdefined as posterior circulation Acute Stroke Prognosis Early CT Score (PC-ASPECTS) < 8 (50% vs. 27% in sICH!, P = 0.031) and lower platelet counts(183 vs. 218 E9/l; P = 0.011). They also had higher systolic blood pressure(SBP) (median 160 vs. 147 mmHg, P = 0.034) immediately after IVT. In mul-tivariable regression analysis, lower platelet values [odds ratio (OR) 0.99, 95%confidence interval (CI) 0.97–0.996; P = 0.006], PC-ASPECTS < 8 on admis-sion (OR 3.6, 95% CI 1.3–10.3; P = 0.017) and higher SBP after treatment(OR 1.03, 95% CI 1.01–1.05; P = 0.017) were independently associated withsICH. Ninety per cent of the sICHs occurred within 48 h from IVT/anticoagu-lation treatment. No differences in activated partial thrompoplastin times priorto or after the treatment were observed between sICH+ and sICH! patients.Conclusions: The risk of sICH was largely determined by extension of ischae-mic changes on admission computed tomography. Clinically relevantly, alsohigher post-thrombolytic SBP as described earlier and lower perithrombolyticplatelet counts do increase the risk, a finding requiring confirmation in otherpatient series.
Introduction
In posterior circulation strokes and basilar artery occlu-sion (BAO), the occurrence of post-thrombolytic intra-cranial haemorrhage (ICH) has occasionally beenreported to be lower than in anterior circulation strokes
[1,2], although another registry reported a rate reason-ably in line with anterior circulation strokes [3]. Therates of symptomatic intracranial haemorrhage (sICH)in BAO have varied from 6% [3] even up to 30% withan endovascular multimodal approach [4], but the defi-nitions of (s)ICH were not uniform. The issue of sICH,however, is crucial in BAO since in addition to variablerecanalization therapies many centres apply anticoagu-lation [5] despite lack of formal guidelines (Table 1).Our long-standing in-house protocol also recommends
Correspondence: Dr T. Sairanen, Department of Neurology, Helsinki
University Central Hospital, Haartmaninkatu 4, 00290 Helsinki,
Finland (tel.: +358 9 4711; fax: +358 9 471 71796;
e-mail: [email protected]).
© 2014 EAN 493
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starting full anticoagulation at the time of thrombolysiswhenever a BAO diagnosis has been established andintracranial haemorrhage ruled out on admission headscan [6–8]. Incentives to this empirically evolvedapproach have been recurrent posterior circulationstrokes and re-occlusions, reported to occur at ratesfrom 10% up to 30% [9,10].
A recent meta-analysis on post-thrombolytic sICHconcluded that similar factors predict both ICH andpoor outcome [11]. In hemispheric stroke thromboly-sis, the SEDAN score including admission bloodsugar >8 mmol/l, early infarct and dense artery signson computed tomography (CT), age >75 years andNational Institutes of Health Stroke Scale (NIHSS)≥10 predicts development of sICH [12]. Age andstroke severity are strong predictors across all sICHrisk scores [13,14]. A reliable way is still being soughtto predict sICH after BAO recanalization therapies.
Since the development of sICH showed a strong corre-lation with poor outcome and death after BAO intrave-nous thrombolysis (IVT) in our previous analysis [7],this led us to analyse factors associated with post-throm-bolytic sICH in BAO thrombolysis with adjuvant anti-coagulation.
Methods
Patients
The cohort consisted of 176 consecutive BAO patientstreated with intravenous 0.9 mg/kg recombinant tissueplasminogen activator (rtPA) and concomitant unfrac-tionated heparin (UFH) in Helsinki University
Central Hospital from 1995 to April 2013. All patientswere registered prospectively and additional data wereretrieved from patient charts. All cardiovascular con-ditions refer to a diagnosis prior to BAO [6–8]. Noapproval by the ethical committee was required asdata were collected as part of routine care.
Physiological and laboratory variables
Systolic and diastolic blood pressures (BPs) were mea-sured prior to, during (between 15 min intervals up to2 h) and after (30 min intervals up to 8 h and 60 minup to 24 h). BP values on admission and at 2, 4, 8, 12,24 and 48 h after tPA administration were registered.Blood glucose on admission and maximal levels on days1!7 were registered. Laboratory data included admis-sion whole blood and platelet counts and creatinineconcentration. During anticoagulation with UFH, atarget activated partial thromboplastin time (APTT)was set between 75 and 100 s. The dynamics of APTTvalues from admission to the tenth consecutive value oruntil discontinuation of heparin treatment or until sus-picion/detection of sICH (when heparin was stopped)were analysed. All APTT values exceeding 180 s wererecoded to 181 s. Delays between heparin administra-tion and each consecutive APTT value were also regis-tered along with maximal APTT values for each 12 hinterval up to 120 h.
Imaging
The extent of baseline ischaemia was evaluated withthe posterior circulation Acute Stroke Prognosis Early
Table 1 Multimodal recanalization therapies and treatment associated intracranial bleeding complications (sICH) in BAO patient series with
adjunctive anticoagulation (AC)
Therapy modality Number of patients AC sICH n (%)
IVT or IVT + EMR [35] 16 ASA, IV heparin, or glycoprotein IIb/IIIa
inhibitor
1/16 (0.06)a
IAT [36] 16 IV unfractionated heparin for 24 h 2/16 (12.5)
IAT [1] 106 IV ASA/no heparin 1/106 (0.9)b
IVT/bridging + IAT or IVT/IAT + EMR [4] 91 Peritreatment heparin 22/74 (29) or 5/17 (30)
IVT + EMR [37] 53 Heparin bolus every hour after Tx (duration
not given)
8/53 (15)c
EMR [38] 28 On demand periprocedural AC 3/28 (11)d
EMR [39] 16 Periprocedural heparin 6/16 (38)e
EMR " IAT [40] 81 Periprocedural heparin 14/81 (23)f
EMR " IAT [41] 24 On demand periprocedural IV aspirin, heparin
or tirofiban
2/24 (8)g
IVT/present study 176 IV heparin infusion 24/176 (14)
Note that the definitions of sICH vary between studies.IVT, intravenous thrombolysis; IAT, intra-arterial thrombolysis; EMR, endovascular
mechanical recanalization; ASA, acetylsalicylic acid; Tx, treatment.aICH, lethal; bPROACT II criteria; cbleeding complications including subarachnoid haemorrhage, parenchymal haemorrhage and intraventric-
ular haemorrhage; dpost-procedure ICH (one lethal); ehaemorrhagic infarction; fdissections and subarachnoid haemorrhage; gincluding four
dissections.
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494 T. SAIRANEN ET AL.
CT Score (PC-ASPECTS) for either CT (n = 121/176,69%) or magnetic resonance imaging (MRI) (31% ofpatients). PC-ASPECTS <8 represented extensive is-chaemic changes [15]. Post-treatment CT or MRI wasobtained in all patients approximately 24 h afterthrombolysis and additional CT was obtained when-ever clinical deterioration occurred or ICH was sus-pected. sICH was judged according to EuropeanCooperative Acute Stroke Study II (ECASS II) crite-ria [16]. Thrombolysis in myocardial infarction (TIMI)was scored from post-treatment CT angiography(n = 53; 41%) and time-of-flight MR angiography(n = 78). Recanalization was dichotomized as partialto complete (TIMI 2–3) and nil to minimal (TIMI 0–1) in post-treatment angiography [17] available for131 of 176 patients (74%) with the preference of usingthe same modality as for pre-treatment angiogram.All radiological data were evaluated in a blindedfashion.
Clinical outcome
Unfavourable outcome was rated as modified RankinScale (mRS) 3–6, favourable outcome as mRS 0–2.mRS was assessed by video-trained, certified strokeneurologists either by appointment or by telephoneinterview of patients or caregivers.
Statistical analysis
Distributions of the continuous variables were tested fornormality. Univariate analyses were performed with thet test or the Mann–Whitney U test, as appropriate.Dichotomous variables were compared with the Fisherexact test. Data availability <99% is acknowledged inthe table footnotes. Finally, a model of backward binarylogistic regression was constructed studying factorsassociated with sICH. Parameters with P < 0.1 in uni-variate analysis and data availability >90% wereincluded in order to avoid selection bias and overfitting.Two-sided values of P < 0.05 were considered signifi-cant. SPSS 21.0 (IBM, Armonk, NY, USA) was used.
Results
Out of 176 BAO patients treated with IVT and full-dose heparin, 24 (13.6%) developed sICH. Onepatient died prior to control CT scan. All patientswith sICH scored mRS 3–6 at 3 months comparedwith 65.6% of patients without sICH (P < 0.0001).Twenty-two of 24 patients (91.7%) with sICH died.The mean delay from IVT start to sICH was 21 h(SD 18, 2.3–73 h). Demographics of patients with andwithout sICH, the admission parameters and theirfollow-up values are given in Table 2.
Table 2 Baseline characteristics for patients
with and without sICH. Post-thrombolytic
blood pressure (BP) and peak blood glu-
cose inside 48 h are also shown
Parameter, median (IQR) or n (%) sICH! (n = 151) sICH+ (n = 24) P
Age, years 64 (18, 27–92) 69 (18, 28–94) 0.354
Male 101 (66.9) 16 (66.7) 1.000
Diabetes 18 (11.9) 5 (20.8) 0.324
Hypertension 76 (50.3) 13 (54.2) 0.827
Dyslipidaemia 56 (37.1) 9 (37.5) 1.000
Atrial fibrillation 33 (21.9) 6 (25) 0.792
Congestive heart failure 10 (6.6) 0 0.361
Prior antiplatelet 40 (26.5) 9 (37.5) 0.327
Prior warfarin 13 (10.1) 1 (4.8) 0.693a
Baseline NIHSS 20 (19, 1–42) 25 (20, 3–39) 0.138
OTT, min 447 (747, 48–10 910) 604 (1151, 85–3015) 0.256
PC-ASPECTS < 8 41 (27.2) 12 (50) 0.031
VB-leucoaraiosis 18 (15.9) 2 (10.5) 0.774
Recanalization 80 (66.7) 5 (38.5) 0.066b
Baseline glucose, mmol/l 7.1 (3, 4.2–17.7) 7.8 (4.4, 5.2–18.5)c 0.324
Peak glucose < 48 h 6.7 (2.3, 4.1–16.7)b 7.7 (2.7, 5.2–15)d 0.062
Baseline systolic BP, mmHg 152 (23) 145 (22) 0.203e
Baseline diastolic BP 83 (17) 76 (18) 0.070e
Systolic BP (2 h) 147 (26) 160 (22) 0.034c
Diastolic BP (2 h) 76 (17) 83 (24) 0.093c
Baseline platelet count, E9/l 218 (81, 82–387) 183 (63, 107–312) 0.011c
Baseline haemoglobin, g/l 142 (21, 89–186) 138 (28, 96–167) 0.474f
Baseline leucocytes, E9/l 9.1 (3.7, 2.7–22.8) 8.2 (3.7, 5.7–17.3) 0.404f
Baseline creatinine, lmol/l 78 (25, 38–272)g 80 (40, 50–180) 0.159
Mean (SD) for BP values. OTT, onset to treatment time; VB, vertebro-basilar.a>85% data available; b76% availability; c>91% availability; d>66% availability; e>98% avail-
ability; f94% availability; g96% availability. Bold indicates significant value (P < 0.05).
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SYMPTOMATIC ICH IN BAO THROMBOLYSIS 495
Systolic BP was higher in patients with than with-out sICH 2 h after rtPA infusion, without significantchanges thereafter (Fig. 1a). Blood glucose levels didnot differ between patients with and without sICH(Fig. 1b).
The time until first follow-up APTT measurementwas similar for patients with and without sICH with amedian of 4 h (IQR 2.5; range 0.5–21.5) and 4.5 h(2.5; 2–16.5), respectively. Thereafter, the intervalswere 4–6 h in both groups and followed the institu-tional guideline. There were no differences in the max-imum or consequent APTT values on repeatedmeasurements between patients with and withoutsICH (Fig. 2a). Figure 2b shows the most relevantAPTT values, i.e. those that were obtained very closeto the detection of sICH. The admission platelet countwas significantly lower in patients with sICH andremained lower at 24 h after IVT (Fig. 3).
In multivariable regression analysis extensive base-line ischaemic changes, lower platelet count on admis-sion and higher systolic BP at 2 h were associatedwith sICH (Table 3).
Discussion
The detailed data from the present cohort allow us toestimate what affects the occurrence of sICH afterIVT with adjuvant anticoagulation in BAO patients.Half of the patients with PC-ASPECTS score <8 cor-responding to extensive ischaemic changes experiencedsICH. Randomized clinical trials have studied mostlyanterior circulation strokes, and early infarct signsexceeding one-third of the middle cerebral artery sup-ply area are considered a contraindication for IVT[18]. In BAO no such cut-off exists, naturally also dueto the lethal course of the disease if left untreated.Besides extensive baseline ischaemia, increased BPimmediately after IVT and low-normal perithromboly-sis platelet count are associated with sICH risk aswell. The latter modifiable factors could be amenableto future therapeutic strategies that aim at minimizingthe sICH risk besides the evident need for recanaliza-tion therapies.
The frequency of sICH per the ECASS II criteria inour protocol with full-dose heparin was 14% which iscomparable to or smaller than reported for intra-arte-rial thrombolysis, mechanical devices and the bridgingapproach (Table 1) but higher than the 6% reportedfrom the BASICS registry [19].
Systolic BP was higher in patients with sICH(160 mmHg) than without sICH (147 mmHg) 2 hafter starting rtPA (Fig. 1a), yet it was far below the185 mmHg considered acceptable after IVT [18]. Theinherent effect of high BP variability on sICH cannot
be captured by multivariate analysis due to the smallnumber of sICHs in our patient cohort, similar to aGerman IVT-treated cohort [20], but the effect is evi-dent in larger cohorts [21].
Extensive ischaemic changes on baseline scan havebeen found by us [7] and others [22] to predispose tosICH after BAO treatment and were also a strongpredictor for IVT-associated sICH in a meta-analysis
sICH+ 22 21 16 8 5 2 2 2sICH– 150 131 117 110 86 65 51 41
sICH+ 22 22 13 16 17 17 11
sICH– 148 142 116 127 132 141 127
(a)
(b)
Figure 1 Systolic blood pressure (SBP) and blood glucose prior
to and after treatment. (a) Mean (SD) SBP in patients with
sICH (red) and without sICH (blue) differed only at 2 h after
tPA administration (*P = 0.034). The number of patients with
documented with sICH for each time interval is shown. (b) Med-
ian (IQR) blood glucose did not differ between patients with
sICH (red) and without sICH (blue) at baseline or after treat-
ment. d, day(s).
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496 T. SAIRANEN ET AL.
on ischaemic stroke [11]. The predictive value of theNIHSS score for the presence of artery occlusion wassuggested to be poorer in the posterior circulation
than in the anterior circulation [23], and the cut-offvalue for baseline NIHSS for favourable outcome wasfound to be lower in posterior circulation than inanterior circulation strokes [24]. Last but not least, inline with the BASICS registry showing no effect ofage >75 years on the incidence of sICH age was notfound to be an independent risk factor either [25].
The possible effect of lower thrombocyte count onpost-thrombolytic sICH has been investigated in onlya few studies [11]. Prior observation of an associationbetween low platelet count and any post-thrombolyticICH [26] agrees with our finding that it predisposesalso to a sICH. However, our data do not show anyantiplatelet or warfarin use to be associated withsICH as suggested in a meta-analysis on stroke IVT[11], although such medications could intuitivelypotentiate the effect of lower platelet count to pro-mote sICH formation. Perhaps something could belearned from the prior stroke literature on plateletsand spontaneous ICH expansion, yet results are con-flicting [27]. Anyhow, a randomized study on platelettransfusion is under way in ICH patients [28]. Wis-dom should be adopted across stroke subtypes, sincein traumatic ICH the need for platelet transfusion issuggested to be guided by antiplatelet assay results[29].
Animal experiments have suggested that heparinenhances the thrombolytic effect of rtPA [30,31]. Hep-arin induced thrombocytopenia is an adverse event inpatients receiving UFH and usually occurs after aweek [32]. In none of our patients was the perihaem-orrhagic platelet count reduced by 50%, and in no
max 108-120 h
max 96-108 h
max 84-96 h
max 72-84 h
max 60-72 h
max 48-60 h
max 36-48 h
max 24-36 h
max 12-24 h
max pre-12 h
pre-heparin
Med
ian
APT
T (s
)
120
100
80
60
40
20
0
sICH+sICH-
sICH + 22 11 9 5 2 1 1 1 1 1
sICH - 142 140 130 116 98 91 76 73 63 53
APT
T (s
)
200
175
150
125
100
75
50
25
0
Time: heparin-to-sICH (hours)
84807672686460565248444036322824201612840
69 (50-108) 70 (57-86) 79 (64-103) 77 (63-95) 80 (62-93) 76 (60-94) 76 (60-94)
(a) (b)
Figure 2 Activated partial thrombin time (APTT) values and sICH. (a) There were no differences in peak APTT values between
patients with (red) and without (blue) sICH. The two drops in the peak APTT values are explained by the detection of almost 70% of
sICHs by 24 h and all sICHs by 73 h after tPA injection. (b) The most relevant APTT values obtained time-wise closest to sICH
detection. The red dots represent five patients in whom the delay between APTT measurement and sICH detection was >3 h; in all
other patients it was ≤2 h. For comparison, the peak (median, IQR) APTT values per 12-h intervals in patients without sICH are out-
lined in blue on the x axis.
Table 3 Logistic regression on parameters associated with sICH
development after treatment with IVT and full-dose heparin in BAO
patients
OR 95% CI P
Platelet count at baseline 0.99 0.97–0.996 0.006
PC-ASPECTS <8 at baseline 3.6 1.26–10.27 0.017
Post-thrombolytic systolic BP (2 h) 1.03 1.01–1.05 0.017
24 hBaseline
Mea
n th
rom
bocy
te c
ount
(E9/
l)
250
230
210
190
170
150
*
*
sICH+sICH-
Figure 3 Perithrombolytic platelet counts and sICH. The plate-
let counts were lower in patients with sICH (red) than without
sICH (blue) at baseline and 24 h after IVT and full-dose heparin
treatment. *P = 0.011 at baseline; *P = 0.035 at 24 h.
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SYMPTOMATIC ICH IN BAO THROMBOLYSIS 497
case was heparin induced thrombocytopenia clinicallyconfirmed. Since no correlation was found betweenAPTT and sICH, a full-dose anticoagulant regimenwas continued in BAO thrombolysis. However, ourcurrent protocol advises a target of 2.0!2.5-fold thebaseline APTT levels and heparin dosing is adjustedby weight [33]. At present, UFH has been replaced bylow-molecular-weight heparin in most acute cardiacindications including ST-elevation myocardial infarc-tion [34].
The shortcomings of our study are that the cohortis derived from a single centre and the partly retro-spective nature of the data collection. Yet the treat-ment protocol has remained stable for a long timeand access to original patient data was available. Therelatively low number of sICHs underpowers statisti-cal analysis. Our data on IVT and anticoagulationmay naturally not be transferable to centres whereBAO patients receive only IVT. In the absence of anon-anticoagulated reference group firm conclusionson the role of anticoagulation in development of sICHcannot be drawn.
In conclusion, these data encourage vigilance for aburden of multiple, concomitant sICH risk factors inBAO thrombolysis, especially in severely ill patientswith extensive baseline ischaemic changes in the verte-bro-basilar area. Intensive follow-up and treatment ofBP even below guidelines may be warranted if the riskof sICH is estimated as high due to multiple coexis-ting factors, possibly including also a low plateletcount.
Acknowledgements
TS and DS had full access to all the data and takeresponsibility for the integrity of the data and theaccuracy of the data analysis. The authors thank DrOlli S. Mattila for reviewing the literature on experi-mental anticoagulation data. Funds were receivedfrom Maire Taponen Foundation (TS), Finnish Acad-emy (PJL), Sigrid Jus!elius Foundation (PJL), PaavoNurmi Foundation (PJL) and Helsinki UniversityHospital District Government Subsidiary ResearchFunds (PJL).
Disclosure of conflicts of interest
DS, OS, HS, PJL: none. TS received a consultancy feefrom Boehringer Ingelheim.
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