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Comparison of Partial (.6 mg/kg) versus Full-Dose (.9 mg/kg) Intravenous Recombinant Tissue Plasminogen Activator Followed by Endovascular Treatment for Acute Ischemic Stroke: A Meta-Analysis

Alexandros L. Georgiadis MD

From the Zeenat Qureshi Stroke Research Center, Department of Neurology, University of Minnesota, Minneapolis, Minnesota.

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Muhammad Zeeshan Memon MD,

Muhammad Zeeshan Memon MD

From the Zeenat Qureshi Stroke Research Center, Department of Neurology, University of Minnesota, Minneapolis, Minnesota.

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Qaisar A. Shah MD,

Qaisar A. Shah MD

From the Zeenat Qureshi Stroke Research Center, Department of Neurology, University of Minnesota, Minneapolis, Minnesota.

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Gabriela Vazquez PhD,

Gabriela Vazquez PhD

From the Zeenat Qureshi Stroke Research Center, Department of Neurology, University of Minnesota, Minneapolis, Minnesota.

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M. Fareed K. Suri MD,

M. Fareed K. Suri MD

From the Zeenat Qureshi Stroke Research Center, Department of Neurology, University of Minnesota, Minneapolis, Minnesota.

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Kamakshi Lakshminarayan MD, PhD,

Kamakshi Lakshminarayan MD, PhD

From the Zeenat Qureshi Stroke Research Center, Department of Neurology, University of Minnesota, Minneapolis, Minnesota.

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Adnan I. Qureshi MD,

Adnan I. Qureshi MD

From the Zeenat Qureshi Stroke Research Center, Department of Neurology, University of Minnesota, Minneapolis, Minnesota.

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Alexandros L. Georgiadis MD,

Alexandros L. Georgiadis MD

From the Zeenat Qureshi Stroke Research Center, Department of Neurology, University of Minnesota, Minneapolis, Minnesota.

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Muhammad Zeeshan Memon MD,

Muhammad Zeeshan Memon MD

From the Zeenat Qureshi Stroke Research Center, Department of Neurology, University of Minnesota, Minneapolis, Minnesota.

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Qaisar A. Shah MD,

Qaisar A. Shah MD

From the Zeenat Qureshi Stroke Research Center, Department of Neurology, University of Minnesota, Minneapolis, Minnesota.

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Gabriela Vazquez PhD,

Gabriela Vazquez PhD

From the Zeenat Qureshi Stroke Research Center, Department of Neurology, University of Minnesota, Minneapolis, Minnesota.

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M. Fareed K. Suri MD,

M. Fareed K. Suri MD

From the Zeenat Qureshi Stroke Research Center, Department of Neurology, University of Minnesota, Minneapolis, Minnesota.

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Kamakshi Lakshminarayan MD, PhD,

Kamakshi Lakshminarayan MD, PhD

From the Zeenat Qureshi Stroke Research Center, Department of Neurology, University of Minnesota, Minneapolis, Minnesota.

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Adnan I. Qureshi MD,

Adnan I. Qureshi MD

From the Zeenat Qureshi Stroke Research Center, Department of Neurology, University of Minnesota, Minneapolis, Minnesota.

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First published: 24 March 2011

https://doi.org/10.1111/j.1552-6569.2009.00441.x

Citations: 25

Correspondence: Address correspondence to Alexandros L. Georgiadis, MD, Zeenat Qureshi Stroke Research Center, Department of Neurology, University of Minnesota, 420 Delaware Street SE, Minneapolis, MN 55455. E-mail: [email protected].

J Neuroimaging 2011;21:113-120.

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Abstract

ABSTRACT

BACKGROUND

In the treatment of acute ischemic stroke, intravenous (IV) recombinant tissue plasminogen (rt-PA) and intraarterial (IA) interventions are often combined. However, the optimal dose of IV rt-PA preceding endovascular treatment has not been established.

METHODS

Studies that used combined IV and IA thrombolysis were identified from a search of the MEDLINE, PubMed, and Cochrane databases. We compared the rates of angiographic recanalization, symptomatic intracerebral hemorrhage (sICH), and favorable functional outcome between patients who had been treated with .6 mg/kg IV rt-PA and those who had received .9 mg/kg rt-PA.

RESULTS

Eleven studies met our criteria. In 7 studies, .6 mg/kg IV rt-PA had been administered to 317 patients, whereas 140 patients in 4 studies had received .9 mg/kg of IV rt-PA. The weighted mean of median National Institutes of Health Stroke Scale score at presentation was 18.3 in the .6 mg/kg group (median range 9-34), and 17.3 in the .9 mg/kg group (median range 4-39). Patients in the .9 mg/kg group had higher rates of favorable outcome [odds ratio (OR) = 1.60, 95% confidence interval (CI) = (1.07-2.40), P= .022] and similar rates of sICH [OR = .86 (95% CI .41-1.83), P= .70]. Depending on the statistics used, the higher angiographic recanalization rate among patients treated with .9 mg/kg was significant (P= .03, events/trial syntax logistic regression) or borderline significant (P= .07, random effects model).

CONCLUSION

Our analysis suggests that using .9 mg/kg IV rt-PA prior to IA thrombolysis is safe and may be associated with higher recanalization rates and better functional outcome at 3 months.

Introduction

Following the results of the National Institutes of Neurological Disorders (NINDS) stroke trial,¹ intravenous (IV) recombinant tissue plasminogen activator (rt-PA) has become the standard of care for the treatment of patients with acute ischemic stroke presenting within 3 hours of symptom onset. Adjunctive endovascular treatment is currently administered in most referral centers and includes pharmacological (administration of thrombolytic medication) and mechanical approaches (microwire manipulation, angioplasty, and/or stent placement) used in different combinations on a case-by-case basis (multimodal thrombolysis).

In order to not exceed the total dose of rt-PA assessed by NINDS trial (.9 mg/kg), initial studies used (“bridged”) .6 mg/kg IV rt-PA and administered the remaining dose of rt-PA or equipotent dose of a different agent via the intraarterial (IA) route.^2–4 More recent data^5–8 appear to suggest that endovascular treatment following full-dose IV thrombolysis may be safe. This approach offers the full benefit of IV thrombolysis and the potential added benefit of IA intervention. We performed a meta-analysis of the published data in order to compare the safety and efficacy of the 2 different doses of IV rt-PA used in the bridging approach.

Methods

Data Sources

We employed several strategies to identify studies that reported on ischemic stroke patients treated with combined IV thrombolysis and endovascular treatment. We searched the literature from 1995 to 2007 to identify individual studies, using the following computerized databases: PubMed (U.S. National Library of Medicine), Ovid (Wolters Kluwer), Cochrane Database of Systematic Reviews (Cochrane Collaboration resources), and the ClinicalTrials.gov website (U.S. National Institutes of Health). The key words used for search were “Intra-arterial therapy,”“Acute ischemic stroke,”“Combined intravenous and intra-arterial therapy,”“Bridging therapy,” and “Intra-arterial therapy for acute ischemic stroke.” Further, we searched by combining the above-mentioned keywords using PubMed's MeSH database service. Bibliographies of relevant review articles and text book chapters were reviewed to identify any pertinent studies. Web-based and manual searches of abstracts presented at scientific meetings were also performed. We contacted (when possible) authors when additional information was needed. Only studies published in English were used for this analysis.

Study Selection Criteria

Among the identified studies, we selected those that reported the use of combined IV thrombolysis and endovascular treatment for acute ischemic stroke. The studies included case series, nonrandomized controlled studies, and randomized controlled trials using either of the 2 IV t-PA dosages. We subsequently used the following inclusion criteria: (1) sample size exceeding 5 patients, (2) IV rt-PA dosing of .6 or .9 mg/kg, (3) availability of mean or median National Institutes of Health Stroke Scale (NIHSS) score at presentation, patient demographics (age, gender), and functional outcome assessed at discharge or later, (4) time interval between symptom onset and IV and endovascular treatment reported, (5) final recanalization following endovascular treatment reported, and (6) rate of symptomatic intracerebral hemorrhage (sICH) reported.

Studies were included regardless of the modality of endovascular treatment administered (pharmacological and/or mechanical). In the event of overlap of study populations, the smaller study was excluded.

Data Extraction

Using a predesigned data abstraction form, 2 reviewers (MZM and QAS) independently reviewed all manuscripts and abstracted the following information: (1) study characteristics (year of publication, design, recruitment period); (2) patient characteristics (number of patients, demographic characteristics, NIHSS score at presentation); (3) dose of IV rt-PA given and time from symptom onset to IV rt-PA administration; (4) time from symptom onset to angiography and/or IA treatment; (5) type of IA thrombolytic and mechanical devices used; (6) angiographic recanalization rates following endovascular treatment; (7) NIHSS score at 24-48 hours, when available; (8) rates of sICH; and (9) functional outcomes at discharge or later.

The primary endpoints assessed in the analysis were partial or complete recanalization, favorable functional outcome, and sICH. Studies sometimes used different definitions of those endpoints (see Table 1). We used a modified Rankin scale score of 0-1 at 1-3 months after treatment to define favorable outcome. In 2 of the 11 studies, we determined the favorable outcome rates by reviewing individual patient data presented in tables or by acquiring it directly from the authors. In 3 of the 11 studies, favorable outcome was defined by other measures acquired at discharge or last available follow-up. We repeated the analysis after excluding these 3 studies. Since we did not detect a difference in our results, we decided to include the studies and favorable outcome definitions used.

Table 1. Definitions of Outcome Measures and Types of Treatment in Different Studies

Studies	Number of Patients	Definitions				Types of Endovascular Treatment
		Angiographic Recanalization	Symptomatic Intracranial Hemorrhage	Favorable Functional Outcome	Early Neurologic Improvement	Mechanical^†	Pharmacological (Maximal Dose)
		Angiographic Recanalization	Symptomatic Intracranial Hemorrhage	Favorable Functional Outcome	Early Neurologic Improvement	Mechanical^†	rt-PA	RT	UK
.6 mg/kg IV rt-PA
EMS,² 1999	17	TIMI 2-3	≥4 p increase in NIHSSS	3 Mo mRS ≤ 1^‡	ND		20 mg
Ernst et al,¹⁷ 2000	20	ND*	ND	2-11 Mo mRS ≤1	ND		24 mg or .3 mg/kg
IMS,³ 2004	80	TIMI 2-3	Clinical deterioration, likely to result in disability or death	3 Mo mRS ≤ 1	NIHSSS ≤ 2		22 mg
Flaherty et al,¹⁸ 2005	62	ND*	ND	3 Mo mRS ≤ 1^‡	ND		22 mg
IMS II,¹⁹ 2007	81	TICI ≥ 2a* TIMI 2-3	Clinical deterioration, likely to result in disability or death	3 Mo mRS ≤ 1^‡	NIHSSS ≤ 2	US	22 mg
Wolfe et al,²⁰ 2008	41	TIMI 3, TIMI 1-3	≥4 p increase in NIHSSS	3 Mo mRS ≤ 2‡	≥4p improvement in NIHSSS		30 mg or .3 mg/kg
Sugiura et al,²¹ 2008	16	TIMI 2-3	Any clinical deterioration	3 Mo mRS ≤ 1	ND	Angioplasty	10 mg
.9 mg/kg IV rt-PA
Hill et al,⁵ 2002	8	ND*	ND	3 Mo mRS ≤3**	ND	Angioplasty	20 mg
Lee et al,⁶ 2004§	30	ND*	>0p increase in NIHSSS	3 Mo mRS ≤1	≥4p improvement in NIHSSS				1,000,000 U
Shaltoni et al,⁸ 2007	69	TICI ≥2a*	>2p increase in NIHSSS	d/c home or inpatient rehab	ND	Angioplasty, Stenting	24 mg	6 U	750,000 U
Burns et al,²² 2008	33	Qureshi 0-1*	≥4p increase in NIHSSS	NIHSSS 0-2** at time of d/c	ND	MERCI, Snare, Angioplasty, Stenting		2 mg

NIHSSS = National Institutes of Health Stroke Scale Score; IV = intravenous; IA = intraarterial; rt-PA = recombinant tissue plasminogen activator; RT = reteplase; UK = Urokinase; mRS = modified Rankin scale; d/c = discharge; TIMI = thrombolysis in myocardial infarction; TICI = thrombolysis in cerebral infarction; EMS = emergency management of stroke bridging trial; IMS = Interventional Management of Stroke Study; Mo = Month; n/a = not available; rehab = rehabilitation facility; ND = not defined; p = point(s); US = ultrasound; U = units
*By using information provided in tables or by contacting the authors we were able to obtain the number of patients who had TIMI 2-3. TICI ≥2a is equivalent to TIMI 2-3.
**By using information provided in tables or by contacting the authors we were able to obtain the number of patients who had mRS of 0-1.
^†Beyond microcatheter manipulation.
^‡Additional outcome measures recorded.
§Intravenous antiplatelets used in select cases.

When possible, we used a thrombolysis in myocardial infarction (TIMI) grade of 2-3 flow post-procedure to define partial or complete recanalization. For sICH, we used the definition provided by individual studies.

Any disagreements between the 2 data abstractors were reconciled with the mediation of a third investigator (ALG).

Statistical Methods

In order to compare the .6 mg/kg with the .9 mg/kg group, we pooled the demographic and clinical data from single studies: means of means or medians weighted by the sample size, and range of minimum and maximum individual patient data. When study range was not available it was approximated by the 95% confidence interval (CI). χ² test was not feasible to compare characteristics between the groups because individual patient data were not available and was therefore not performed.

Analysis endpoints were also pooled from individual studies. The endpoints of both groups were compared using a logistic regression model with event/trial syntax. In order to verify our results, we repeated the analysis using a more stringent random effects model based on the DerSimonian-Laird method.^9,10

The random effects model assumes that the selected studies constitute a random sample, whose total variance is a composite of the individual study variance inline image and the estimated variance between the studies. The resulting P-value associated with the Q-statistic of between group heterogeneity was used to determine statistical significance between groups.

In addition, the heterogeneity across studies for the 3 endpoints was estimated using the I² statistic.¹¹ I² statistic measures the percent variability of study estimates to the total variability observed. Publication bias for each dose regimens was assessed with trim and fill method.¹²

Angiographic recanalization and functional outcome of individual studies were also presented as forest plots. Analysis was performed using SAS 9.2 (SAS Institute Inc, Cary, NC, 2004) and R 2.6.2 (The R Foundation for Statistical Computing, 2008). The analyst (GV) was blinded to the dose used in both treatment groups. Significance was declared at P value < .05.

Results

A total of 125 studies were identified, of which 22 reported on the use of combined IV thrombolysis and endovascular treatment. A total of 11 studies were excluded (see Fig 1). Tables 1–3 present the characteristics and results of the 11 individual studies included in the analysis and Table 4 summarizes the pooled information for each group.

Details are in the caption following the image — **Figure 1**
Open in figure viewer PowerPoint

Selection diagram for the studies included in the meta-analysis.

Table 2. Sites of Arterial Occlusion and Time Intervals between Symptom Onset and Treatments

Studies	Occlusion Site									Time to IV in Hours		Time to IA Treatment in Hours
	Anterior Circulation						Posterior Circulation
	Cervical	Cervical and Intracranial	Intracranial Only				Posterior Circulation
	Cervical	Cervical and Intracranial	ICA terminus	M1	Distal MCA	ACA	ICVA	BA	PCA	Mean	Median	Mean	Median
.6 mg/kg IV rt-PA
EMS²	1		6	2	3						2.60		3.3†
Ernst et al.¹⁷	1	6	4	8	1						2.03		3.5
IMS³*	3	21	7	18^#	15	2^#	5**				2.33
Flaherty et al.¹⁸		8	7	21	6			2			2.15		3.77
IMS II¹⁹§											2.37		n/a
Wolfe et al.²⁰			11	27				5		2.52		n/a
Sugiura et al.²¹				9	7					1.83		2.5
.9 mg/kg IV rt-PA
Hill et al.⁵		2		2	3		1				1.70		5.17
Lee et al.⁶	2		5	10	1			3	1		2.25		3.83†
Shaltoni et al.⁸	2		16^‡	31	19			1			2.00		4.75
Burns et al.²²§										1.97		4.00†

ICVA = intracranial vertebral artery; BA = basilar artery; ICA = internal carotid artery; M1 = M-1 segment of the middle cerebral artery; ACA = anterior cerebral artery; PCA = posterior cerebral artery; IV = intravenous; IA = intraarterial; rt-PA = recombinant tissue plasminogen activator; n/a = not available.
†Time to angiography.
‡ In 11 cases, the proximal ACA and/or MCA were also involved.
§Sites of occlusion not available.
#Two patients had combined M1 and ACA lesions.
*Included are 18 cases of ICA stenosis, 15 of which had distal embolization into the MCA.
**Two cases had stenosis and not occlusion.

Table 3. Results from Individual Studies

Publication	Demographics		Baseline NIHSSS Median (Range) or Mean ± SD	Time to Treatment in Minutes Median (Range) or Mean ± SD			Rate of Endpoints
Publication	Age in Years Median (Range) or Mean ± SD	Men	Baseline NIHSSS Median (Range) or Mean ± SD	IV rt-PA	Femoral Puncture	Microcatheter Placement	Angiographic Recanalization	Favorable Functional Outcome	sICH	Early Neurological Improvement
.6 mg/kg IV rt-PA
EMS,² 1999	66 ± 11	53%	16 (9-21)¶	156 (138-168)¶	198 (180-228)¶	n/a	82%	35%	12%‡	n/a
Ernst et al,¹⁷ 2000	69 (36-89)	45%	21 (11-31)	122 (72-250)	n/a	210 (155-292)	69%	50%	5%	n/a
IMS,³ 2004	64 ± 13	50%	18 ± 5	136 ± 30	183 ± 45	217 ± 47	58%	30%	6%	14%
Flaherty et al,¹⁸ 2005	69* (20-89)	40%	18 (11-34)	129**	n/a	226**	59%	35%	8%	n/a
IMS II,¹⁹ 2007	64 ± 12	57%	19 ± 5	140 ± 31	n/a	n/a	58%	33%	10%	19%
Wolfe et al,²⁰ 2008	67 ± 14	39%	17 (11-20)	151 ± 31	n/a	n/a	66%	46%	12%	42%
Sugiura et al,²¹ 2008	70 ± 9	69%	19 ± 2	110 ± 22	n/a	150 ± 25	88%	63%	0%	n/a
.9 mg/kg IV rt-PA
Hill et al,⁵ 2002	49 (41-83)	88%	18 (10-24)	102 (65-129)	n/a	310 (190-375)	38%	25%	0%	38%
Lee et al,⁶ 2004	63 (47-82)	60%	18 (4-30)	135 (60-210)	230 (60—310)	n/a	71%	60%	7%	n/a
Shaltoni et al,⁸ 2007	60 ± 13	55%	18 (6-39)	124 ± 32	n/a	288 ± 57	73%	55%	6%	n/a
Burns et al,²² 2008	67 ± 12	33%	15 (13-19)	118 ± 27	n/a	240 ± 62	73%	30%	12%	n/a

EMS = Emergency Management of Stroke Bridging Trial; IMS = Interventional Management of Stroke Study; SD = standard deviation; NIHSSS = National Institutes of Health Stroke Scale Score; IV = intravenous; rt-PA = recombinant tissue plasminogen activator; n/a = not available; sICH = symptomatic intracranial hemorrhage.
*Mean age with range, **Median, no range available, ¶Median (25th-75th percentile), ‡Both hemorrhages occurred post 24 hours following treatment.

Table 4. A Summary of Study Characteristics According to Dose of Intravenous rt-PA Administered

	.6 mg/kg	.9 mg/kg
Number of studies (number of patients)	7 (n= 317)	4 (n= 140)
Mean age* (min–max), years	66.5 (18-93)**	62.1 (34-91)
Men (%)	156 (49%)	74 (53%)
Mean time to IV rt-PA* (min–max), minutes	138 (66-250)	122 (60-210)
Mean NIHSS score* (min–max)	18.3 (9-34)**	17.3 (4-39)
Clinical trials	2	1

P-values could not be assessed because individual patient data were not available.
*Weighted (by sample size) mean of study medians/means.
**Minimal and maximal individual patient values. If not available, the range was estimated using the 95% confidence upper and lower limits.

A dose of .6 mg/kg of IV rt-PA was administered in 7 studies that included 317 patients. Mean age was 66.5 years (range 18-93 years) and 51% were women. Mean time interval between onset of symptoms and IV rt-PA administration was 138 minutes (range 66-250 minutes). The mean (mean of median) NIHSS score at presentation was 18.3 (range 9-34) in the pooled data.

A dose of .9 mg/kg of IV rt-PA was administered in 4 studies that included 140 patients. Mean age was 62 years (range 34-91 years) and 47% were women. Mean time interval between onset of symptoms and administration of IV rt-PA was 122 minutes (range 60-210 minutes). The mean (mean of median) NIHSS score at presentation was 17.3 (range 4-39) in the pooled data.

sICH was seen in 26 (8%) patients in the .6 mg/kg group compared with 10 (7%) of patients in the .9 mg/kg group, odds ratio (OR) .86, 95% CI .41-1.83, P= .70) using a logistic regression model with events/trial syntax. This result was confirmed using a random effects model. No heterogeneity in rates of sICH was seen between series.

Favorable functional outcome was observed in 118 (37%) of patients in the .6 mg/kg group compared with 68 (49%) of patients in the .9 mg/kg group, OR 1.6 (95% CI 1.07-2.40, P= .022, events trial/syntax). The random effects model confirmed the presence of a significant difference between the 2 dose regimens, P= .023. The proportion of favorable functional outcome across studies were heterogeneous, I²: 60%, 95% CI: 22-80%. Rates of good functional outcome at study level are presented as a Forest plot in Fig 2. The direction of association did not change after excluding the 2 studies (one from each group) where the proportion of patients with mRS of 0 or 1 at last available follow-up was not provided. The magnitude of association decreased from 1.6 to 1.4 and significance could not be detected because of the small sample size. Assessment for publication bias for favorable outcome revealed no publication bias for .9 mg/kg and suggested 2 missing studies for .6 mg/kg yielding an estimate of 35%.

Partial or complete recanalization was observed in 179 (56%) of patients in the .6 mg/kg group compared with 94 (67%) of patients in the .9 mg/kg group, OR 1.57 (95% CI 1.03-2.37, P= .03). There was only borderline significance in the difference of the rates between the 2 treatment groups using the random effects model (P= .07). Heterogeneity across studies regarding angiographic recanalization rates was high I²: 72% (50-84%). Rates of angiographic recanalization in the studies included in the analysis are shown as a Forest plot in Fig 3. Clinical and angiographic outcomes are summarized in Table 5. Assessment for publication bias for partial or complete recanalization revealed no publication bias.

Table 5. Pooled Rates and Odds Ratios of Clinical and Angiographic Endpoints among Patients Receiving .6 mg/kg and Those Receiving .9 mg/kg of Intravenous rt-PA

	.6 mg/kg	.9 mg/kg	OR (95% CI)	P-Value
I. Using Logistic Regression with Events/Trial Syntax
Angiographic recanalization	179 (56%)	94 (67%)	1.57 (1.03-2.37)	0.03
Symptomatic ICH	26 (8%)	10 (7%)	0.86 (.41-1.83)	0.70
Favorable functional outcome at last available follow-up	118 (37%)	68 (49%)	1.60 (1.07-2.40)	0.02

	.6 mg/kg	.9 mg/kg	Diff	P-Value

II. Using Random Effects Model
Angiographic recanalization	59.3% (54.2- 64.5%)	67.9% (60.3-75.4%)	8.5% I²: 75.1% (55-86%)	0.07
Favorable functional outcome at last available follow-up	36.8% (31.5-42.0%)	47.5% (39.5-55.5%)	10.8% I²:60% (22-80%)	0.03
Symptomatic ICH	7.5% (4.6-10.4%)	6.9% (2.7-11.1%)	.62% I²: 0% (0-5.7%)	0.81

I² is a measure of heterogeneity (ranges from 0 to 1) and is the percent variation between study estimate and total variation.
rt-PA = recombinant tissue plasminogen activator; OR = odds ratio; CI = confidence interval; ICH = intracerebral hemorrhage.

Discussion

We found no significant difference in sICH rates between the .6 mg/kg (8%) and the .9 mg/kg (7%) groups. In the .9 mg/kg group, rates of angiographic recanalization and favorable functional outcome appeared to be higher (OR 1.60, 95% CI 1.07-2.40 and OR 1.57, CI 1.03-2.37, respectively) when compared using a logistic regression model with events/trial syntax. Using the more stringent random effects model, the results were similar with the exception of recanalization, which achieved only borderline significance.

The .9 mg/kg dose for IV rt-PA was established following the 2 NINDS dose-finding studies.^13,14 Escalating rt-PA doses were administered to patients, within 90 minutes from stroke onset in Part I¹³ and between 91 and 180 minutes from onset in Part II.¹⁴ No sICH was noted in the 58 patients who received .85 mg/kg of IV rt-PA or less in Part I versus 3/26 patients who had received a dose of .95 mg/kg or greater. Higher doses of rt-PA were significantly related to the risk of developing sICH (P= .045). There was no clear correlation between early neurological improvement and rt-PA dose administered. Based on these findings, an intermediate dose between .85 and .95 mg/kg was selected for the NINDS efficacy trial.¹ Subsequent studies combining IV thrombolysis and endovascular treatment were designed to avoid exceeding a total dose of .9 mg/kg rt-PA by administering a partial IV dose (.6 mg/kg) followed by IA administration of up to .3 mg/kg.

Our findings suggest that .9 mg/kg IV rt-PA prior to endovascular treatment is a safe alternative to .6 mg/kg. In our analysis, sICH rates were not higher in patients who were treated with full-dose IV rt-PA than in those treated with partial dose prior to endovascular therapy. The lack of difference in sICH rates could be related to the short half-life of IV rt-PA (3-5 minutes),¹⁵ which means that the thrombolytic effect would wane prior to the endovascular intervention. Moreover, in patients who have received full-dose IV rt-PA, smaller doses of IA thrombolytics are administered with greater emphasis on mechanical thrombectomy. It is also possible that the occurrence of sICH depends more on factors such as magnitude of ischemic injury and blood–brain barrier disruption rather than the dose of thrombolytics.¹⁶

Although we observed that the patients treated with .9 mg/kg IV rt-PA had a significantly higher rate of favorable outcomes, we believe that prospective studies ensuring randomization with uniform outcome ascertainment are required in order to confirm this finding.

Future studies should also address the optimal dosing of thrombolytic medications in IA procedures following .9 mg/kg IV rt-PA. The implication of our findings for current clinical practice is that patients who have been treated with full-dose IV rt-PA can be considered for endovascular treatment under well-defined protocols.

Our study has several limitations that must be considered prior to interpretation of the results. This was a meta-analysis combining the data of several case series with variable methodologies. The methodology and ascertainment of outcomes may have been more rigorous in the .6 mg/kg group (ascertainment bias) where 2 case series were derived from studies that were conducted as clinical trials. Outcome estimates were heterogeneous across studies that used the same treatment regimen. This was likely due to discrepancies in the definition of outcome measures and in the time points of data ascertainment. Furthermore, the variations in endovascular techniques and doses of IA thrombolytics induce additional heterogeneity in angiographic and clinical outcomes. While the numbers of patients in the studies were too small to perform subgroup analysis, we provided descriptive statistics in Tables 1 and 2 to facilitate interpretation. Because individual patient data were not available, we were unable to control for important prognostic factors such as patient age, time to treatment, NIHSS score at presentation, site of arterial occlusion, and technique of endovascular treatment (confounding bias). Meta-analyses are prone to publication bias. We therefore applied the trim and fill method which did not support the presence of substantial bias.

Conclusion

Our analysis suggests that using .9 mg/kg as opposed to .6 mg/kg of IV rt-PA prior to endovascular treatment is safe and associated with higher recanalization rates and functional outcome. Further controlled studies are needed to compare the angiographic and clinical outcomes associated with each of the 2 regimens of rt-PA used in the bridging approach.

References

1 Sacco RL, Kargman DE, Gu Q, et al. Race-ethnicity and determinants of intracranial atherosclerotic cerebral infarction. The northern Manhattan stroke study. Stroke 1995; 26: 14-20.
10.1161/01.STR.26.1.14
CAS PubMed Web of Science® Google Scholar
2 Lewandowski CA, Frankel M, Tomsick TA, et al. Combined intravenous and intra-arterial r-tpa versus intra-arterial therapy of acute ischemic stroke: emergency management of stroke (ems) bridging trial. Stroke 1999; 30: 2598-2605.
10.1161/01.STR.30.12.2598
CAS PubMed Web of Science® Google Scholar
3 Combined intravenous and intra-arterial recanalization for acute ischemic stroke. The interventional management of stroke study. Stroke 2004; 35: 904-911.
10.1161/01.STR.0000121641.77121.98
PubMed Web of Science® Google Scholar
4 Suarez JI, Zaidat OO, Sunshine JL, et al. Endovascular administration after intravenous infusion of thrombolytic agents for the treatment of patients with acute ischemic strokes. Neurosurgery 2002; 50: 251-259; discussion 259-260.
10.1097/00006123-200202000-00005
PubMed Web of Science® Google Scholar
5 Hill MD, Barber PA, Demchuk AM, et al. Acute intravenous–intra-arterial revascularization therapy for severe ischemic stroke. Stroke 2002; 33: 279-282.
10.1161/hs0102.101900
PubMed Web of Science® Google Scholar
6 Lee KY, Kim DI, Kim SH, et al. Sequential combination of intravenous recombinant tissue plasminogen activator and intra-arterial urokinase in acute ischemic stroke. AJNR Am J Neuroradiol 2004; 25: 1470-1475.
PubMed Web of Science® Google Scholar
7 Noser EA, Shaltoni HM, Hall CE, et al. Aggressive mechanical clot disruption: a safe adjunct to thrombolytic therapy in acute ischemic stroke? Stroke 2005; 36: 292-296.
10.1161/01.STR.0000152331.93770.18
PubMed Web of Science® Google Scholar
8 Shaltoni HM, Albright KC, Gonzales NR, et al. Is intra-arterial thrombolysis safe after full-dose intravenous recombinant tissue plasminogen activator for acute ischemic stroke? Stroke 2007; 38: 80-84.
10.1161/01.STR.0000251720.25337.b0
PubMed Google Scholar
9 Normand SL. Meta-analysis: formulating, evaluating, combining, and reporting. Stat Med 1999; 18: 321-359.
10.1002/(SICI)1097-0258(19990215)18:3<321::AID-SIM28>3.0.CO;2-P
CAS PubMed Web of Science® Google Scholar
10 Schmid JE, Koch GG, LaVange LM. An overview of statistical issues and methods of meta-analysis. J Biopharm Stat 1991; 1: 103-120.
10.1080/10543409108835008
PubMed Google Scholar
11 Higgins JP, Thompson SG. Quantifying heterogeneity in a meta-analysis. Stat Med 2002; 21: 1539-1558.
10.1002/sim.1186
PubMed Web of Science® Google Scholar
12 Duval S, Tweedie R. Trim and fill: a simple funnel-plot-based method of testing and adjusting for publication bias in meta-analysis. Biometrics 2000; 56: 455-463.
10.1111/j.0006-341X.2000.00455.x
CAS PubMed Web of Science® Google Scholar
13 Brott TG, Haley EC Jr, Levy DE, et al. Urgent therapy for stroke. Part I. Pilot study of tissue plasminogen activator administered within 90 minutes. Stroke 1992; 23: 632-640.
10.1161/01.STR.23.5.632
CAS PubMed Web of Science® Google Scholar
14 Haley EC Jr, Levy DE, Brott TG, et al. Urgent therapy for stroke. Part II. Pilot study of tissue plasminogen activator administered 91–180 minutes from onset. Stroke 1992; 23: 641-645.
10.1161/01.STR.23.5.641
PubMed Web of Science® Google Scholar
15 Qureshi AI, Pande RU, Kim SH, et al. Third generation thrombolytics for the treatment of ischemic stroke. Curr Opin Investig Drugs 2002; 3: 1729-1732.
CAS PubMed Google Scholar
16 Albers GW, Thijs VN, Wechsler L, et al. Magnetic resonance imaging profiles predict clinical response to early reperfusion: the diffusion and perfusion imaging evaluation for understanding stroke evolution (defuse) study. [see comment] Ann Neurol 2006; 60: 508-517.
10.1002/ana.20976
PubMed Web of Science® Google Scholar
17 Ernst R, Pancioli A, Tomsick T, et al. Combined intravenous and intra-arterial recombinant tissue plasminogen activator in acute ischemic stroke. Stroke 2000; 31: 2552-2557.
10.1161/01.STR.31.11.2552
CAS PubMed Web of Science® Google Scholar
18 Flaherty ML, Woo D, Kissela B, et al. Combined IV and intra-arterial thrombolysis for acute ischemic stroke. Neurology 2005; 64: 386-388.
10.1212/01.WNL.0000149529.78396.B0
CAS PubMed Web of Science® Google Scholar
19 The interventional management of stroke (IMS) II study. Stroke 2007; 38: 2127-2135.
10.1161/STROKEAHA.107.483131
PubMed Web of Science® Google Scholar
20 Wolfe T, Suarez JI, Tarr RW, et al. Comparison of combined venous and arterial thrombolysis with primary arterial therapy using recombinant tissue plasminogen activator in acute ischemic stroke. J Stroke Cerebrovasc Dis 2008; 17: 121-128.
10.1016/j.jstrokecerebrovasdis.2007.12.004
PubMed Google Scholar
21 Sugiura S, Iwaisako K, Toyota S, et al. Simultaneous treatment with intravenous recombinant tissue plasminogen activator and endovascular therapy for acute ischemic stroke within 3 hours of onset. AJNR Am J Neuroradiol 2008; 29: 1061-1066.
10.3174/ajnr.A1012
CAS PubMed Web of Science® Google Scholar
22 Burns TC, Rodriguez GJ, Patel S, et al. Endovascular interventions following intravenous thrombolysis may improve survival and recovery in patients with acute ischemic stroke: a case-control study. AJNR Am J Neuroradiol 2008; 29: 1918-1924.
10.3174/ajnr.A1236
CAS PubMed Google Scholar

Citing Literature

Volume21, Issue2

April 2011

Pages 113-120

Comparison of Partial (.6 mg/kg) versus Full-Dose (.9 mg/kg) Intravenous Recombinant Tissue Plasminogen Activator Followed by Endovascular Treatment for Acute Ischemic Stroke: A Meta-Analysis