Neurocrit Care DOI 10.1007/s12028-013-9891-5
ORIGINAL ARTICLE
Prolonged Low-Dose Thrombolysis in Posterior Circulation Stroke C. Hametner • L. Kellert • R. Veltkamp • L. Behrens S. Nagel • W. Hacke • P. Ringleb
•
Ó Springer Science+Business Media New York 2013
Abstract Background We aimed to investigate the feasibility, preliminary safety, and efficacy of prolonged low-dose intravenous thrombolysis in posterior circulation stroke patients with a thrombus lodged in the basilar artery who were ineligible for standard rtPA administration. Methods We retrospectively analyzed consecutively collected patients in our stroke database who suffered from a basilar artery thrombosis and were treated with prolonged (>1 h), intravenous, low-dose (B20 mg) rtPA between 01/2005 and 11/2012. Results Patients included in this study (n = 14) were 68.5 years (IQR 55.5; 72.75) of age and presented with a median NIHSS of 2 (1; 5.25). Median time from symptom onset to treatment was 63 h (33; 141). A median dose of 5.21 lg/kg h (4.46; 6.25) rtPA was administered over 24 h (min 10; max 48). No patient experienced symptomatic intracerebral hemorrhage, one patient developed a spinal epidural hematoma, and two elderly patients were switched
Electronic supplementary material The online version of this article (doi:10.1007/s12028-013-9891-5) contains supplementary material, which is available to authorized users. C. Hametner (&) L. Kellert R. Veltkamp S. Nagel W. Hacke P. Ringleb Department of Neurology, Heidelberg University, Im Neuenheimer Feld 400, 69120 Heidelberg, Germany e-mail: [email protected] L. Behrens Department of Neuroradiology, Heidelberg University, Im Neuenheimer Feld 400, 69120 Heidelberg, Germany
to comfort care and died. In eight patients (57 %) a decrease in thrombus size or no thrombus at all was detected on control imaging. Nine patients (64 %) had a favorable outcome (mRS 0–2) at day 90. Conclusions Prolonged low-dose thrombolysis with rtPA may be considered as individual treatment option in selected high-risk patients with basilar artery thrombosis. Presented data may lay the groundwork to further investigate safety and efficacy in a prospective trial. Keywords Low-dose thrombolysis rtPA Posterior circulation stroke Basilar artery thrombosis Brainstem Hemorrhagic transformation
Introduction Stroke due to basilar artery (BA) occlusion is associated with a high morbidity and mortality [1]. BA thrombosis may originate from arteriosclerotic vessels or the heart or result from in-stent thrombosis after interventional procedures. Patients with a thrombus lodged in the BA and relatively mild neurological symptoms pose a particular challenge, because they may present late after stroke symptom onset being ineligible for standard application of thrombolysis. Despite this mild clinical presentation, these patients are considered to be at high risk of developing severe ischemic stroke. After our first promising experience in an index patient with a basilar embolus [2], we began to treat highly selected patients suffering from BA thrombosis with prolonged low-dose recombinant tissue plasmin activator (ld-rtPA). The aim of the present study was to evaluate those patients who were treated with ld-rtPA, reporting feasibility, outcomes, and arising complications.
123
Neurocrit Care
Methods
Results
Study Design and Inclusion Criteria
Baseline characteristics are shown in Table 1. Of 1,417 patients identified in our stroke database between 01/2005 and 11/2012, 14 patients fulfilled the inclusion criteria. Nine men and five women (n = 14) were analyzed. NIHSS at admission in median was 2 (IQR 1; 5.25); premorbid median Rankin scale was 0.5 (0; 2).
We extracted data for consecutively documented patients treated with intravenous, prolonged (>1 h) recombinant tissue plasminogen activator at a low dose (10–20 mg) between 01/2005 and 11/2012 retrospectively from our local stroke database. This study was performed and our local stroke database managed according to the STROBE statement for reporting case–control studies [3]. Individual Selection of Patients Treated with ld-rtPA The consultant neurologist prescribed ld-rtPA treatment and treatment duration as off-label use. These individual decisions to administer ld-rtPA were made under consideration of several factors: (1) a thrombosis, diagnosed by CT angiography, MR angiography, or conventional angiography in the distal vertebral arteries (V4-segment) or in the proximal, middle, or distal part of the BA, persisted despite the administration of antiplatelet therapy; (2) stroke symptoms were fluctuating and thus clinical deterioration was feared; (3) possible benefits of the treatment outweighed potential risks; (4) the patient was awake, well aware of the precarious situation, and able to give his/her consent; and (5) in addition, a low lesion volume was preferred. However, factor 2 and 5 might have not been present in every patient, emphasizing the diversity of these decisions. All patients were informed in detail about the individual disease, potential risks of the treatment, and its off-label nature and gave their informed consent. Definitions Time-to-treatment (TTT) was defined as the time from onset of first stroke symptoms to the start of ld-rtPA. Neurological symptoms were measured according to the stroke scale score of the National Institute of Health (NIHSS), keeping in mind that this scale might not match the severity in vertebrobasilar strokes. The modified Rankin scale (mRS) was used to assess outcome at 90 days using a semi-structural interview conducted by an investigator who was not blinded to the initial treatment. Favorable neurological outcome was defined as mRS 0–2. Intracerebral hemorrhages were grouped according to the definition of morphological appearance as within the ECASS-2 trial [4]. A documented hemorrhage temporally related to any neurological deterioration (NIHSS decrease of C4 points) was defined as symptomatic intracerebral hemorrhage (sICH). As the treatment duration and dosage of ld-rtPA differed in the patients, we also present the dosages as lg/kg h. LB and CH reviewed imaging data independently.
123
Prolonged ld-rtPA Administration Median ld-rtPA dose was 5.21 lg/kg h (4.46; 6.25), which corresponds to a total median amount rt-PA of 10 mg (10; 20) over 24 h (min 10; max 48). The median TTT was 63 h (33; 141). One patient (#11) was treated within 24 h since onset of stroke symptoms. In one patient (#5) ld-rtPA was given twice. Data for each individual patient are given in Table 2. Additional Antiplatelet Drugs or Anticoagulation Ten patients received additional antiplatelet drugs, five of them dual antiplatelet therapy with aspirin and clopidogrel (patients #5, 10, 13, 14) or a glycoprotein-IIb/IIIa-inhibitor (patient #12). Weight-adapted heparin administration prior to ld-rtPA was identified in six patients (#3–6, 10, 13). No patient received a weight-adapted full dose of heparin during ld-rtPA treatment, whereas eight patients subsequently were given intravenous weight-adapted heparin.
Table 1 Baseline characteristics n
14
Age
65.6 (10.1)
Gender, female
5 (35.7 %)
TOAST 1
5 (35.7 %)
2
7 (50 %)
5
2 (14.3 %)
Diabetes
3 (21.4 %)
Hypertension
13 (92.9 %)
Hypercholesterolemia
12 (85.7 %)
Previous stroke
6 (42.9 %)
Coronary heart disease Current smoker
5 (35.7 %) 5 (35.7 %)
Body mass index >30 kg/m2
6 (42.9 %)
Alcohol intake (>40 g/d)
2 (14.3 %)
Continuous variables are given in mean and standard deviation, categorical variables as n (%) TOAST criteria 1 large-artery atherosclerosis, 2 cardioembolism, 3 small-vessel occlusion, 4 stroke of other determined etiology, 5 stroke of undetermined etiology
Vivo
Vivo
Vivo Vivo
8
9
10 11
BA
V4
V4
BA
BA BA
PCA
BA
V4
BA
V4
BA
BA
BA
BA
LOC
Mid
Distal
Distal
Mid
Distal Distal
Prox
Prox
Distal
Mid
Distal
Distal
Distal
Mid
Distal
BA
2
15
–
7
1 3
0
2
2
0
6
0
6
1
1
NIH
0
1
4
0
0 0
0
0
2
0
4
0
2
1
2
pRS
9
5
–
9
5 9
8
8
4
9
10
10
9
4
10
pc Aspects
3
21
–
7
18 3
0
0
3
2
6
0
10
1
1
NIH
Prior to ld-rtPA
A, C
A, C
A, C
GP
A, C NA
A
P
A
A
A, C
A
–
A
NA
ANC
0
1
1
0
1 0
0
0
0
1
0
1
1
0
0
HEP
0
0
0
0
0 0
28
192
823
144
57 12
34
130
1b 0
37
123
152
32
44
24
69
TTT (h)
0
0
0
0
0
0
0
HEP
5.34
5.21
4.84
6.94
12.63 23.81
5.56
4.53
4.39
4.39
4.84
4.25
11.11
3.26
5.21
rtPA (lg/kg h)
During ld-rtPA
10
10
10
10
10 20
10
10
10
20
20
10
10
20
20
rtPA dose (mg)
24
24
24
24
12 12
24
24
24
48
48
24
10
48
48
rtPA time (h)
1
1
0
1
1 0
0
1
0
1
0
1
1
1
1
HEP
No
HI2
No
No
No No
No
No
No
CT-A CT-A
; ?
Dyna Dyna
H ?
MR-A CT-A
Dyna
?
Yesc
CT-A
Angio Dyna
? ?
No
; H
MR-A
;
Yesd
;
CT-A
?
No
MR-A
CT-A
?
;
MR-A
H
No
No
Mod
Vessel
Complication
After ld-rtPA
2
17
e
5
8 2
0
0
0
2
e
2
25
0
2
NIH
3
5
6
4
4 3
0
0
1
2
6
4
5
2
2
mRS
Discharge
2
5
6
3
3 1
0
0
0
1
6
1
6
1
0
mRS
D90
e
d
c
b
a
Spinal epidural hematoma Death
Small bleeding in right cerebellum already present in baseline MRI (SWI) in slightly different configuration
Low-molecular-weight heparin 0.9 once, plus uptitration of phenprocumoun
Second treatment of patient (5)—this time after stent implantation with BA thrombus
LOC location, BA basilar artery, V4 vertebral artery V4 segment, PCA posterior cerebral artery, PC ASPECTS posterior circulation Alberta Stroke Program Early CT Score—modified using MRI, THR thrombus, ANC ancillary treatment, NA not available, A aspirin, C clopidogrel, P phenprocoumon, GP glycoprotein IIb/IIIa-inhibitor, HEP heparin, Vessel vessel status, ? stable condition, ; decline of thrombus, H (no thrombus), TTT time to treatment, Mod modality of vessel imaging, MR-A magnetic resonance imaging angiography, CT-A computed tomography angiography, Dyna Dyna-CT angiography, sICH symptomatic intracerebral hemorrhage, HT hemorrhagic transformation, HI2 subclassification of hemorrhagic transformation, mRS modified Rankin scale
Dilat
Vivo
7
Stent
Vivo
6
14
Vivo
5
13
Vivo
4
Stent
Vivo
3
Stent
Vivo
2
5a
Vivo
1
12
THR
ID
Admission
Table 2 Data for thrombus site, stroke severity, treatment with ld-rtPA and ancillary medication prior to, during, and after ld-rtPA and patient outcome are given
Neurocrit Care
123
Neurocrit Care Fig. 1 Thrombus formation in the basilar artery in patient 12 before (a) and after (b) administering ld-rtPA, suggesting successful thrombus dissolution. Vessel status of patient 9 before (c) and after (d) thrombolytic therapy is shown, indicating a persistent thrombus in the basilar artery
One patient (#8) was started on phenprocoumon during ldrtPA treatment. Vital parameters and laboratory measurements are shown in supplemental Table I.
Complications No sICH was observed during or after the administration of ld-rtPA. However, one female patient (#4) developed a spinal epidural hematoma >24 h after having undergone lumbar puncture of cerebral spinal fluid (performed to rule out subacute subarachnoid hemorrhage). She experienced pain in both legs and urinary retention 24 h after ld-rtPA treatment. After spinal decompressive surgery, she recovered without neurological sequelae. In 13 of the 14 patients, follow-up CT scans were available in which one of those patients (#13) showed new hemorrhagic transformation (HI2) (supplemental Fig. I). This patient was clinically stable without any signs of clinical worsening.
123
Clinical Outcome and Surrogate Outcome Parameters Follow-up data at day 90 were available for 12 of the 14 patients, as two elderly patients were switched to comfortfocused care and died later in the course of their disease. Nine patients (64 %) had a favorable outcome. In 8 patients (57 %), a decrease in thrombus size or no thrombus at all was detected on control imaging. This included all patients in whom the thrombus was located in the distal part of the BA and for whom control images were available (n = 4). Figure 1 shows two representative cases illustrating the resolution, but also persistence of thrombosis.
Discussion To our knowledge this is the first series (n = 14) of patients who were treated with prolonged thrombolysis by administering ld-rtPA, demonstrating that this is a justifiable treatment option for BA thrombosis in a late time window.
Neurocrit Care
A direct comparison of our patients with other stroke populations may not be expedient because (i) most of our patients had residual stenotic flow due to the BA thrombus and not occlusion, (ii) all patients presented late in the time window for treatment, and (iii) all patients were highly selected. Whether, TTT has a positive or a negative influence on outcome in posterior circulation stroke is still a matter of debate [5, 6]. Most recent prospective data claim that IVT benefits patients with low baseline ischemia (pcASPECTS C 8) even in a window of up to 48 h [7]. Notably, our patients were treated within a median TTT of 63 h, with the longest initial TTT being after 192 h. To the best of our knowledge this is the longest time to initiating rtPA treatment in stroke patients with BA thrombosis published to date. Our study has several limitations: the number of patients is small and the duration of treatment and the overall amount of rtPA administered were based on the individual decisions of the treating consultant neurologist. This produces differences in indication, in dosage of rtPA, in baseline and control imaging, and in ancillary medication. This single-center study also lacks randomization to compare ld-rtPA to placebo or to standard treatment. Because little is known about the natural course of patients suffering from BA thrombosis (not occlusion), interpreting the risk– benefit balance may be too early. The strength of our study is the unique treatmentapproach, which uses rtPA for posterior circulation stroke patients presenting in a substantial time window. Considering the low number of patients collected over a period of 7 years, our data may lay the groundwork for a future prospective trial.
circulation stroke patients, who are at high risk because of BA thrombosis—especially in cases of late presentation and less severe symptoms. The status of ld-rtPA compared to standard treatment is not established. To further investigate safety and efficacy in different dosage regimen a prospective trial is indicated. Conflict of interest CH, LK, SN, and RV report no conflicts and have nothing to disclose. WH and PR received speaker honoraria and travel expenses from Boehringer Ingelheim (manufacturer of AlteplaseÒ).
References 1. Mattle HP, Arnold M, Lindsberg PJ, Schonewille WJ, Schroth G. Basilar artery occlusion. Lancet Neurol. 2011;10:1002–14. 2. Veltkamp R, Jacobi C, Kress B, Hacke W. Prolonged low-dose intravenous thrombolysis in a stroke patient with distal basilar thrombus. Stroke. 2006;37:e9–11. 3. von Elm E, Altman DG, Egger M, et al. The strengthening the reporting of observational studies in epidemiology (STROBE) statement: guidelines for reporting observational studies. Lancet. 2007;370:1453–7. 4. Hacke W, Kaste M, Fieschi C, 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;352:1245–51. 5. Sairanen T, Strbian D, Soinne L, et al. Intravenous thrombolysis of basilar artery occlusion: predictors of recanalization and outcome. Stroke. 2011;42:2175–9. 6. Vergouwen MD, Algra A, Pfefferkorn T, et al. Time is brain (stem) in basilar artery occlusion. Stroke. 2012;43:3003–6. 7. Strbian D, Sairanen T, Silvennoinen H, Salonen O, Kaste M, Lindsberg PJ. Thrombolysis of basilar artery occlusion: impact of baseline ischemia and time. Ann Neurol. 2013;73(6):688–94.
Conclusion Prolonged low-dose thrombolysis with rtPA may be considered as individual treatment option in posterior
123
ORIGINAL ARTICLE
Prolonged Low-Dose Thrombolysis in Posterior Circulation Stroke C. Hametner • L. Kellert • R. Veltkamp • L. Behrens S. Nagel • W. Hacke • P. Ringleb
•
Ó Springer Science+Business Media New York 2013
Abstract Background We aimed to investigate the feasibility, preliminary safety, and efficacy of prolonged low-dose intravenous thrombolysis in posterior circulation stroke patients with a thrombus lodged in the basilar artery who were ineligible for standard rtPA administration. Methods We retrospectively analyzed consecutively collected patients in our stroke database who suffered from a basilar artery thrombosis and were treated with prolonged (>1 h), intravenous, low-dose (B20 mg) rtPA between 01/2005 and 11/2012. Results Patients included in this study (n = 14) were 68.5 years (IQR 55.5; 72.75) of age and presented with a median NIHSS of 2 (1; 5.25). Median time from symptom onset to treatment was 63 h (33; 141). A median dose of 5.21 lg/kg h (4.46; 6.25) rtPA was administered over 24 h (min 10; max 48). No patient experienced symptomatic intracerebral hemorrhage, one patient developed a spinal epidural hematoma, and two elderly patients were switched
Electronic supplementary material The online version of this article (doi:10.1007/s12028-013-9891-5) contains supplementary material, which is available to authorized users. C. Hametner (&) L. Kellert R. Veltkamp S. Nagel W. Hacke P. Ringleb Department of Neurology, Heidelberg University, Im Neuenheimer Feld 400, 69120 Heidelberg, Germany e-mail: [email protected] L. Behrens Department of Neuroradiology, Heidelberg University, Im Neuenheimer Feld 400, 69120 Heidelberg, Germany
to comfort care and died. In eight patients (57 %) a decrease in thrombus size or no thrombus at all was detected on control imaging. Nine patients (64 %) had a favorable outcome (mRS 0–2) at day 90. Conclusions Prolonged low-dose thrombolysis with rtPA may be considered as individual treatment option in selected high-risk patients with basilar artery thrombosis. Presented data may lay the groundwork to further investigate safety and efficacy in a prospective trial. Keywords Low-dose thrombolysis rtPA Posterior circulation stroke Basilar artery thrombosis Brainstem Hemorrhagic transformation
Introduction Stroke due to basilar artery (BA) occlusion is associated with a high morbidity and mortality [1]. BA thrombosis may originate from arteriosclerotic vessels or the heart or result from in-stent thrombosis after interventional procedures. Patients with a thrombus lodged in the BA and relatively mild neurological symptoms pose a particular challenge, because they may present late after stroke symptom onset being ineligible for standard application of thrombolysis. Despite this mild clinical presentation, these patients are considered to be at high risk of developing severe ischemic stroke. After our first promising experience in an index patient with a basilar embolus [2], we began to treat highly selected patients suffering from BA thrombosis with prolonged low-dose recombinant tissue plasmin activator (ld-rtPA). The aim of the present study was to evaluate those patients who were treated with ld-rtPA, reporting feasibility, outcomes, and arising complications.
123
Neurocrit Care
Methods
Results
Study Design and Inclusion Criteria
Baseline characteristics are shown in Table 1. Of 1,417 patients identified in our stroke database between 01/2005 and 11/2012, 14 patients fulfilled the inclusion criteria. Nine men and five women (n = 14) were analyzed. NIHSS at admission in median was 2 (IQR 1; 5.25); premorbid median Rankin scale was 0.5 (0; 2).
We extracted data for consecutively documented patients treated with intravenous, prolonged (>1 h) recombinant tissue plasminogen activator at a low dose (10–20 mg) between 01/2005 and 11/2012 retrospectively from our local stroke database. This study was performed and our local stroke database managed according to the STROBE statement for reporting case–control studies [3]. Individual Selection of Patients Treated with ld-rtPA The consultant neurologist prescribed ld-rtPA treatment and treatment duration as off-label use. These individual decisions to administer ld-rtPA were made under consideration of several factors: (1) a thrombosis, diagnosed by CT angiography, MR angiography, or conventional angiography in the distal vertebral arteries (V4-segment) or in the proximal, middle, or distal part of the BA, persisted despite the administration of antiplatelet therapy; (2) stroke symptoms were fluctuating and thus clinical deterioration was feared; (3) possible benefits of the treatment outweighed potential risks; (4) the patient was awake, well aware of the precarious situation, and able to give his/her consent; and (5) in addition, a low lesion volume was preferred. However, factor 2 and 5 might have not been present in every patient, emphasizing the diversity of these decisions. All patients were informed in detail about the individual disease, potential risks of the treatment, and its off-label nature and gave their informed consent. Definitions Time-to-treatment (TTT) was defined as the time from onset of first stroke symptoms to the start of ld-rtPA. Neurological symptoms were measured according to the stroke scale score of the National Institute of Health (NIHSS), keeping in mind that this scale might not match the severity in vertebrobasilar strokes. The modified Rankin scale (mRS) was used to assess outcome at 90 days using a semi-structural interview conducted by an investigator who was not blinded to the initial treatment. Favorable neurological outcome was defined as mRS 0–2. Intracerebral hemorrhages were grouped according to the definition of morphological appearance as within the ECASS-2 trial [4]. A documented hemorrhage temporally related to any neurological deterioration (NIHSS decrease of C4 points) was defined as symptomatic intracerebral hemorrhage (sICH). As the treatment duration and dosage of ld-rtPA differed in the patients, we also present the dosages as lg/kg h. LB and CH reviewed imaging data independently.
123
Prolonged ld-rtPA Administration Median ld-rtPA dose was 5.21 lg/kg h (4.46; 6.25), which corresponds to a total median amount rt-PA of 10 mg (10; 20) over 24 h (min 10; max 48). The median TTT was 63 h (33; 141). One patient (#11) was treated within 24 h since onset of stroke symptoms. In one patient (#5) ld-rtPA was given twice. Data for each individual patient are given in Table 2. Additional Antiplatelet Drugs or Anticoagulation Ten patients received additional antiplatelet drugs, five of them dual antiplatelet therapy with aspirin and clopidogrel (patients #5, 10, 13, 14) or a glycoprotein-IIb/IIIa-inhibitor (patient #12). Weight-adapted heparin administration prior to ld-rtPA was identified in six patients (#3–6, 10, 13). No patient received a weight-adapted full dose of heparin during ld-rtPA treatment, whereas eight patients subsequently were given intravenous weight-adapted heparin.
Table 1 Baseline characteristics n
14
Age
65.6 (10.1)
Gender, female
5 (35.7 %)
TOAST 1
5 (35.7 %)
2
7 (50 %)
5
2 (14.3 %)
Diabetes
3 (21.4 %)
Hypertension
13 (92.9 %)
Hypercholesterolemia
12 (85.7 %)
Previous stroke
6 (42.9 %)
Coronary heart disease Current smoker
5 (35.7 %) 5 (35.7 %)
Body mass index >30 kg/m2
6 (42.9 %)
Alcohol intake (>40 g/d)
2 (14.3 %)
Continuous variables are given in mean and standard deviation, categorical variables as n (%) TOAST criteria 1 large-artery atherosclerosis, 2 cardioembolism, 3 small-vessel occlusion, 4 stroke of other determined etiology, 5 stroke of undetermined etiology
Vivo
Vivo
Vivo Vivo
8
9
10 11
BA
V4
V4
BA
BA BA
PCA
BA
V4
BA
V4
BA
BA
BA
BA
LOC
Mid
Distal
Distal
Mid
Distal Distal
Prox
Prox
Distal
Mid
Distal
Distal
Distal
Mid
Distal
BA
2
15
–
7
1 3
0
2
2
0
6
0
6
1
1
NIH
0
1
4
0
0 0
0
0
2
0
4
0
2
1
2
pRS
9
5
–
9
5 9
8
8
4
9
10
10
9
4
10
pc Aspects
3
21
–
7
18 3
0
0
3
2
6
0
10
1
1
NIH
Prior to ld-rtPA
A, C
A, C
A, C
GP
A, C NA
A
P
A
A
A, C
A
–
A
NA
ANC
0
1
1
0
1 0
0
0
0
1
0
1
1
0
0
HEP
0
0
0
0
0 0
28
192
823
144
57 12
34
130
1b 0
37
123
152
32
44
24
69
TTT (h)
0
0
0
0
0
0
0
HEP
5.34
5.21
4.84
6.94
12.63 23.81
5.56
4.53
4.39
4.39
4.84
4.25
11.11
3.26
5.21
rtPA (lg/kg h)
During ld-rtPA
10
10
10
10
10 20
10
10
10
20
20
10
10
20
20
rtPA dose (mg)
24
24
24
24
12 12
24
24
24
48
48
24
10
48
48
rtPA time (h)
1
1
0
1
1 0
0
1
0
1
0
1
1
1
1
HEP
No
HI2
No
No
No No
No
No
No
CT-A CT-A
; ?
Dyna Dyna
H ?
MR-A CT-A
Dyna
?
Yesc
CT-A
Angio Dyna
? ?
No
; H
MR-A
;
Yesd
;
CT-A
?
No
MR-A
CT-A
?
;
MR-A
H
No
No
Mod
Vessel
Complication
After ld-rtPA
2
17
e
5
8 2
0
0
0
2
e
2
25
0
2
NIH
3
5
6
4
4 3
0
0
1
2
6
4
5
2
2
mRS
Discharge
2
5
6
3
3 1
0
0
0
1
6
1
6
1
0
mRS
D90
e
d
c
b
a
Spinal epidural hematoma Death
Small bleeding in right cerebellum already present in baseline MRI (SWI) in slightly different configuration
Low-molecular-weight heparin 0.9 once, plus uptitration of phenprocumoun
Second treatment of patient (5)—this time after stent implantation with BA thrombus
LOC location, BA basilar artery, V4 vertebral artery V4 segment, PCA posterior cerebral artery, PC ASPECTS posterior circulation Alberta Stroke Program Early CT Score—modified using MRI, THR thrombus, ANC ancillary treatment, NA not available, A aspirin, C clopidogrel, P phenprocoumon, GP glycoprotein IIb/IIIa-inhibitor, HEP heparin, Vessel vessel status, ? stable condition, ; decline of thrombus, H (no thrombus), TTT time to treatment, Mod modality of vessel imaging, MR-A magnetic resonance imaging angiography, CT-A computed tomography angiography, Dyna Dyna-CT angiography, sICH symptomatic intracerebral hemorrhage, HT hemorrhagic transformation, HI2 subclassification of hemorrhagic transformation, mRS modified Rankin scale
Dilat
Vivo
7
Stent
Vivo
6
14
Vivo
5
13
Vivo
4
Stent
Vivo
3
Stent
Vivo
2
5a
Vivo
1
12
THR
ID
Admission
Table 2 Data for thrombus site, stroke severity, treatment with ld-rtPA and ancillary medication prior to, during, and after ld-rtPA and patient outcome are given
Neurocrit Care
123
Neurocrit Care Fig. 1 Thrombus formation in the basilar artery in patient 12 before (a) and after (b) administering ld-rtPA, suggesting successful thrombus dissolution. Vessel status of patient 9 before (c) and after (d) thrombolytic therapy is shown, indicating a persistent thrombus in the basilar artery
One patient (#8) was started on phenprocoumon during ldrtPA treatment. Vital parameters and laboratory measurements are shown in supplemental Table I.
Complications No sICH was observed during or after the administration of ld-rtPA. However, one female patient (#4) developed a spinal epidural hematoma >24 h after having undergone lumbar puncture of cerebral spinal fluid (performed to rule out subacute subarachnoid hemorrhage). She experienced pain in both legs and urinary retention 24 h after ld-rtPA treatment. After spinal decompressive surgery, she recovered without neurological sequelae. In 13 of the 14 patients, follow-up CT scans were available in which one of those patients (#13) showed new hemorrhagic transformation (HI2) (supplemental Fig. I). This patient was clinically stable without any signs of clinical worsening.
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Clinical Outcome and Surrogate Outcome Parameters Follow-up data at day 90 were available for 12 of the 14 patients, as two elderly patients were switched to comfortfocused care and died later in the course of their disease. Nine patients (64 %) had a favorable outcome. In 8 patients (57 %), a decrease in thrombus size or no thrombus at all was detected on control imaging. This included all patients in whom the thrombus was located in the distal part of the BA and for whom control images were available (n = 4). Figure 1 shows two representative cases illustrating the resolution, but also persistence of thrombosis.
Discussion To our knowledge this is the first series (n = 14) of patients who were treated with prolonged thrombolysis by administering ld-rtPA, demonstrating that this is a justifiable treatment option for BA thrombosis in a late time window.
Neurocrit Care
A direct comparison of our patients with other stroke populations may not be expedient because (i) most of our patients had residual stenotic flow due to the BA thrombus and not occlusion, (ii) all patients presented late in the time window for treatment, and (iii) all patients were highly selected. Whether, TTT has a positive or a negative influence on outcome in posterior circulation stroke is still a matter of debate [5, 6]. Most recent prospective data claim that IVT benefits patients with low baseline ischemia (pcASPECTS C 8) even in a window of up to 48 h [7]. Notably, our patients were treated within a median TTT of 63 h, with the longest initial TTT being after 192 h. To the best of our knowledge this is the longest time to initiating rtPA treatment in stroke patients with BA thrombosis published to date. Our study has several limitations: the number of patients is small and the duration of treatment and the overall amount of rtPA administered were based on the individual decisions of the treating consultant neurologist. This produces differences in indication, in dosage of rtPA, in baseline and control imaging, and in ancillary medication. This single-center study also lacks randomization to compare ld-rtPA to placebo or to standard treatment. Because little is known about the natural course of patients suffering from BA thrombosis (not occlusion), interpreting the risk– benefit balance may be too early. The strength of our study is the unique treatmentapproach, which uses rtPA for posterior circulation stroke patients presenting in a substantial time window. Considering the low number of patients collected over a period of 7 years, our data may lay the groundwork for a future prospective trial.
circulation stroke patients, who are at high risk because of BA thrombosis—especially in cases of late presentation and less severe symptoms. The status of ld-rtPA compared to standard treatment is not established. To further investigate safety and efficacy in different dosage regimen a prospective trial is indicated. Conflict of interest CH, LK, SN, and RV report no conflicts and have nothing to disclose. WH and PR received speaker honoraria and travel expenses from Boehringer Ingelheim (manufacturer of AlteplaseÒ).
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Conclusion Prolonged low-dose thrombolysis with rtPA may be considered as individual treatment option in posterior
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