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Original Paper

Free Access

Preceding Intravenous Thrombolysis in Patients Receiving Endovascular Therapy

Park H.-K.a · Chung J.-W.b · Hong J.-H.c · Jang M.U.d · Noh H.-D.e · Park J.-M.f · Kang K.f · Lee S.J.g · Ko Y.g · Kim J.G.g · Cha J.-K.h · Kim D.-H.h · Nah H.-W.h · Han M.-K.a · Kim B.J.a · Park T.H.i · Park S.-S.i · Lee K.B.j · Lee J.k · Hong K.-S.l · Cho Y.-J.l · Lee B.-C.m · Yu K.-H.m · Oh M.S.m · Cho K.-H.n · Kim J.-T.n · Kim D.-E.o · Ryu W.-S.o · Choi J.C.p · Kim W.-J.q · Shin D.-I.r · Yeo M.-J.r · Sohn S.-I.c · Lee J.S.s · Lee J.t · Yoon B.-W.u · Bae H.-J.a

Author affiliations

aDepartment of Neurology, Cerebrovascular Center, Seoul National University Bundang Hospital, Seongnam, bDepartment of Neurology, Samsung Medical Center, Seoul, cDepartment of Neurology, Keimyung University Dongsan Medical Center, Daegu, dDepartment of Neurology, Hallym University Dongtan Sacred Heart Hospital, Hwaseong-si, eDepartment of Neurology, Yeungnam University Yeongcheon Hospital, Yeongcheon, fDepartment of Neurology, Eulji General Hospital, Eulji University, Seoul, gDepartment of Neurology, Eulji University Hospital, Eulji University, Daejeon, hDepartment of Neurology, Dong-A University Hospital, Busan, iDepartment of Neurology, Seoul Medical Center, and jDepartment of Neurology, Soonchunhyang University Hospital, Seoul, kDepartment of Neurology, Yeungnam University Hospital, Daegu, lDepartment of Neurology, Ilsan Paik Hospital, Inje University, Goyang, mDepartment of Neurology, Hallym University Sacred Heart Hospital, Anyang, nDepartment of Neurology, Chonnam National University Hospital, Gwangju, oDepartment of Neurology, Dongguk University Ilsan Hospital, Goyang, pDepartment of Neurology, Jeju National University Hospital, Jeju National University School of Medicine, Jeju, qDepartment of Neurology, Ulsan University College of Medicine, Ulsan, rDepartment of Neurology, Chungbuk National University Hospital, Cheongju, sClinical Research Center, ASAN Medical Center, tDepartment of Biostatistics, Korea University College of Medicine, and uDepartment of Neurology, Seoul National University Hospital, Seoul, Korea

Corresponding Author

Hee-Joon Bae, MD, PhD, FAHA

Department of Neurology, Seoul National University Bundang Hospital

Seoul National University College of Medicine, 82, Gumi-ro 173 Beon-gil

Bundang-gu, Seongnam-si, Gyeonggi-do 13620 (Korea)

E-Mail braindoc@snu.ac.kr

Related Articles for ""

Cerebrovasc Dis 2017;44:51-58

Abstract

Background: The beneficial effects of endovascular therapy (EVT) in acute ischemic stroke have been demonstrated in recent clinical trials using new-generation thrombectomy devices. However, the comparative effectiveness and safety of preceding intravenous thrombolysis (IVT) in this population has rarely been evaluated. Methods: From a prospective multicenter stroke registry database in Korea, we identified patients with acute ischemic stroke who were treated with EVT within 8 h of onset and admitted to 14 participating centers during 2008-2013. The primary outcome was a modified Rankin Scale (mRS) score at 3 months. Major secondary outcomes were successful recanalization defined as a modified Treatment in Cerebral Ischemia score of 2b-3, functional independence (mRS score 0-2), mortality at 3 months, and symptomatic hemorrhagic transformation (SHT) during hospitalization. Multivariable logistic regression analyses using generalized linear mixed models were performed to estimate the adjusted odds ratios (ORs) of preceding IVT. Results: Of the 639 patients (male, 61%; age 69 ± 12; National Institutes of Health Stroke Scale score of 15 [11-19]) who met the eligibility criteria, 458 received preceding IVT. These patients showed lower mRS scores (adjusted common OR, 1.38 [95% CI 0.98-1.96]). Preceding IVT was associated with successful recanalization (1.96 [1.23-3.11]) and reduced 3-month mortality (0.58 [0.35-0.97]) but not with SHT (0.96 [0.48-1.93]). Conclusion: In patients treated with EVT within 8 of acute ischemic stroke onset, preceding IVT may enhance survival and successful recanalization without additional risk of SHT, and mitigate disability at 3 months.

© 2017 S. Karger AG, Basel


Introduction

The results of recently released randomized clinical trials demonstrated the beneficial effect of endovascular therapy (EVT) on functional outcome in acute ischemic stroke patients [1,2,3,4,5]. However, heterogeneity exists regarding the use of preceding intravenous thrombolysis (IVT) among these trials. Despite its beneficial effect on functional outcome related to facilitating successful recanalization during EVT [6], the use of IVT ahead of EVT might be a double-edged sword because of the potential risk of hemorrhagic complications and possible intrahospital delay in administering EVT.

However, there has been no randomized trial to test the efficacy and safety of preceding IVT versus no IVT in patients receiving EVT. Only a few observational studies [6,7,8,9] have addressed this topic exclusively in non-Asian populations, and have several limitations: the use of first-generation thrombectomy devices [6,7,8,9], small sample size [6,7,9], single-centered study [6,7,10] and lack of adjustments for potential confounders [6,7,8]. Recently a subgroup analysis from a meta-analysis of 5 pivotal EVT trials published in 2015 showed that the effect of EVT did not differ according to preceding IVT [11]. There is still limited information related to preceding IVT in patients treated with EVT, especially in Asian population.

Using a multicenter prospective stroke registry database from South Korea [12], this study aimed at investigating the effectiveness and safety of preceding IVT versus no IVT in acute stroke patients receiving EVT.

Methods and Materials

Study Design and Subjects

This study was a retrospective analysis based on the Clinical Research Center for Stroke-5th division (CRCS-5) registry database, which is a prospective, nationwide, web-based multicenter acute stroke registry database of consecutive acute ischemic stroke patients admitted to 14 academic or regional stroke centers in Korea since 2008 [12,13].

Using the registry database, acute ischemic stroke patients, who were hospitalized at the participating centers between April 2008 and July 2013 and who received EVT within 8 h from their symptom onset, were identified. We excluded patients without primary outcome information at 3 months, with angiographic images unavailable or unacceptable in quality, or with no occlusion on conventional angiography.

EVT included all techniques used during endovascular procedure as follows: local use of thrombolytic agents such as urokinase or tirofiban at the site of arterial occlusion via intra-arterial approach, mechanical disruption via multiple passages of a microcatheter/microwire through the clot [14], use of mechanical thrombectomy devices, and stent placement.

Ethic Statements

Collection of clinical information for the purpose of monitoring and improving the quality and outcomes of stroke care was approved by the local institutional review boards (IRBs) of all participating centers of CRCS-5 with a waiver of informed consent because of study subject anonymity and minimal risk to participants. Use of the registry database and additional review of medical records for this study was approved further by the local IRBs.

Data Collection

From the CRCS-5 registry database, we obtained information regarding demographics; premorbid functional status; history of previous stroke or TIA; prior use of antiplatelet agents or anticoagulants; vascular risk factors such as hypertension, diabetes mellitus, dyslipidemia, habitual smoking, and atrial fibrillation; laboratory data including random glucose at presentation, hemoglobin, total cholesterol, and systolic and diastolic blood pressure; stroke characteristics such as initial stroke severity measured using the National Institute of Health Stroke Scale (NIHSS) score; ischemic stroke subtypes and location of occluded arteries; and acute treatment including the use and dose of intravenous tissue plasminogen activator, use of thrombolytic agents administrated intra-arterially, and type of endovascular devices used. For this study, we collected additionally the time interval from last-known well-being to hospital arrival (OtA) and to EVT start (OtEVT), and the time from hospital arrival to EVT start (AtEVT) through review of medical records.

We also gathered the cerebral digital subtraction angiographic images of all study subjects to assess the reperfusion state after EVT. In cases in which various endovascular techniques were used, we selected the final method as a representative of all the techniques. In cases with tandem occlusions, the target occlusion was defined as the most proximal occlusion.

Outcome Measurements

The primary outcome measure was the modified Rankin scale (mRS) score at 3 months. The mRS score after discharge was collected prospectively at the patients' routine clinic visit or through telephone interview with patients or their immediate caregivers at 3 months after stroke onset.

Secondary outcomes were successful recanalization, symptomatic hemorrhagic transformation (SHT), functional independence at discharge and 3 months, and 3-month mortality. Successful recanalization was achieving a modified treatment in cerebral ischemia (mTICI) grade of 2b or 3 in target occluded arteries [15]. The grade of mTICI was determined via independent assessment conducted by 2 stroke neurologists who were blinded to clinical outcomes. The discrepancies in mTICI grading were resolved by consensus (Kappa index: 0.900). SHT was defined according to the European Cooperative Acute Stroke Study III protocol [16]. A mRS score of ≤2 indicated functional independence.

Statistical Analyses

Categorical variables are presented as frequency (percentage), and continuous variables as mean ± SD or median (interquartile range), as appropriate. Baseline characteristics (Table 1) and outcome measures (Table 2) were compared between the no IVT group and the preceding IVT group.

Table 1

Baseline characteristics according to the use of preceding IVT (n = 639)

/WebMaterial/ShowPic/837854

Table 2

Clinical outcomes according to preceding IVT in patients with endovascular therapy

/WebMaterial/ShowPic/837853

For the primary outcome measure, we constructed multivariable ordinal logistic regression models to estimate adjusted common odds ratios (ORs) with 95% CIs for a shift in the direction of a better functional outcome on the mRS scores. Six levels were used after collapsing the mRS score of 5 and 6 into a single level since extremely severe disability might be considered worse, not better, than death [17].

For secondary outcomes, multivariable binary logistic regression models were applied to obtain adjusted ORs with 95% CIs. To account for possible within-hospital clustering, generalized linear mixed models were used in all regression analyses.

Two different sets of adjusting variables were used: (1) Model 1: variables with the p value <0.2 in comparisons according to the use of preceding IVT, and (2) Model 2: all variables in Model 1 plus the variables that were chosen according to their potential associations with outcome variables including age, initial stroke severity, location of occluded artery and EVT methods. In the analysis of SHT, initial random glucose was added to Model 2. Because of possible multi-collinearity problems among time interval variables (OtA, OtEVT, and AtEVT), we included an OtEVT alone as covariate in main multivariable analysis, and performed additional analyses entering other variables as covariates (OtA and OtEVT, and OtA and AtEVT instead of OtEVT alone). We also performed sensitivity analysis by excluding patients treated with EVT after 6 h from onset. We imputed missing values of baseline characteristics that were used for adjustments in multivariable models with a group median, as applicable, if missing frequencies were <5%. No outcome variables were imputed and each outcome variable was analyzed using available cases. Significance levels were set at a 2-tailed p-value of <0.05. Statistical analyses were performed using SAS 9.3 (SAS Institute, Cary, NC, USA).

Results

During the study period of the 17,207 acute stroke cases identified from the registry database between April 2008 and July 2013, 671 patients received EVT within 8 h from their symptom onset. Of this group, 639 met the eligibility criteria (Fig. 1).

Fig. 1

Enrollment of study subjects.

/WebMaterial/ShowPic/837851

Among the 639 included patients (mean age, 69 ± 12; male, 57% [n = 363]), preceding IVT was performed in 458 cases (72%). Compared to the patients without preceding IVT, those with preceding IVT were less likely to have a history of stroke or TIA and receive anticoagulants prior to the index stroke, and were more likely to arrive at hospitals and initiate EVT earlier (Table 1). There were no significant differences in the NIHSS score at presentation, location of target occluded arteries, and methods of EVT.

The patients with preceding IVT showed a significantly higher rate of successful recanalization (65 vs. 73%, p = 0.04) and lower rate of mortality at 3 months (24 vs. 15%, p = 0.01) compared to those without preceding IVT. Approximately 10% of patients in both groups experienced SHT. There were no significant differences in the proportion of functional independence, both at the time of discharge and at 3 months (Table 2).

In the multivariable analyses, there was a tendency of a shift in the distribution of the mRS scores in favor of the preceding IVT (Fig. 2 and Table 3). Preceding IVT increased the odds of successful recanalization about 1.8 times, and was not associated with SHT. Preceding IVT also significantly decreased the risk of death at 3 months. The overall pattern and direction of association with functional independence both at discharge and 3 months were favorable for the use of preceding IVT but were statistically insignificant after adjusting the possible confounders. In sensitivity analyses, preceding IVT increased the odds of better mRS score, successful recanalization, and 3-month survival (online suppl. Tables1, 2; for all online suppl. material, see www.karger.com/doi/10.1159/000471492). When limiting patients receiving EVT within 6 h from onset, the overall patterns in the effects of preceding IVT on various outcome variables maintained (online suppl. Table 3). In the subgroup analysis in patients with preceding IVT, the effectiveness and the safety of the low-dose alteplase therapy were not different from those of the standard-dose alteplase therapy (online suppl. Table 4).

Table 3

Prognostic impact of preceding IVT on clinical outcomes

/WebMaterial/ShowPic/837852

Fig. 2

Distribution of modified Rankin Scale scores at 3 months. IVT, intravenous thrombolysis.

/WebMaterial/ShowPic/837850

Discussion

From a retrospective nationwide multicenter registry database, we documented that preceding IVT in patients receiving EVT leads to a clinically significant increase in survival at 3 months, and successful recanalization of the occluded artery. The patients with preceding IVT also had a tendency toward better functional outcome, without an increase in SHT.

Regarding the effectiveness of preceding IVT, we demonstrated a significantly increased rate of successful recanalization, and a trend toward better functional outcomes at 3 months. Potential determinants of successful recanalization including time interval from stroke onset to treatment, stroke severity, EVT methods, and vascular risk factors [18,19] were evenly distributed between the 2 groups, or were included as covariates in multivariable analyses in our study. These results might be derived from the potential benefit of preceding IVT in patients receiving EVT because of (1) earlier initiation of reperfusion therapy, and (2) facilitation of recanalization during EVT [6]. The effect of treatment with intravenous alteplase may be maximized when early administration was achieved [16], and systemic thrombolytic agent might alter the texture and reduce the burden of clot. Therefore, the combination of the well-known advantages of the IVT with the higher recanalization rate of the EVT [2,3,4,5,7,20] might lead to better functional outcome in stroke patients due to large-vessel occlusion [21,22,23].

With respect to safety issues, preceding IVT reduced the 3-month mortality and was not associated with neurological deterioration related to hemorrhagic transformation. The 10.0% rate of SHT in the preceding IVT group is comparable to the 10.4% rate from the post-hoc analysis of the previous clinical trial [8]. Because of the concern about the risk of hemorrhagic complications and following poor functional outcome, low-dose alteplase had been used in several East-Asian countries [24,25]. The use of low-dose alteplase in more than 50% of the preceding IVT group might reduce the rate of SHT. The rate of 3-month mortality was 15% in the preceding IVT group, which is comparable with the findings of previous studies [1,2,3,4,5].

Despite potential benefits of preceding IVT including earlier initiation of reperfusion therapy and better accessibility to microvascular structure, a recently released matched-pairs analysis [10] may infer that preceding IVT might not improve the clinical outcomes in patients treated with a stent-retriever. Compared to the patients treated with first-generation thrombectomy devices, the beneficial effects of preceding IVT might be diminished when acute ischemic stroke patients were treated with a stent-retriever. In a new era of widespread use of stent-retriever, a randomized controlled trial examining the effect of preceding IVT in patients receiving EVT with stent-retriever might answer this question.

This study has limitations. First, insufficient sample size prevented us from performing propensity score or matching analysis. However, the information on the effectiveness and safety of preceding IVT in patients treated with EVT is insufficient, and comparison between preceding IVT and no IVT might not be performed in randomized clinical trials because of the ethical issues. Thus, further observational research with larger sample size is needed to clarify this issue. To our knowledge, however, our study is the largest to analyze the effect of preceding IVT in patients receiving EVT. Second, two thirds of EVT methods in this study consisted of intra-arterial lytics, mechanical disruption, and stent placement, which have not shown the benefit on clinical outcomes in previous studies. Thus, this study might be comparable to the antecedent studies including The Mechanical Retrieval and Recanalization of Stroke Clots Using Embolectomy [26] and the Interventional Management of Stroke III trial [27] rather than recently released randomized trials [1,2,3,4,5]. Third, although we collected as many variables as possible at the beginning of this study, and included the variables with p < 0.2 from bivariate analysis and clinically relevant variables in multivariable analysis, there might be unmeasured confounders that influence physicians not to use IVT in the no IVT group (other than time) such as more frequent comorbidities or poor general medical conditions, or distance from the place of stroke occurrence, which cannot be obtained in observational study. Fourth, since we excluded patients whose occluded arteries were recanalized with IVT and included patients with persistent occlusion despite IVT, the effect of IVT might be underestimated. Fifth, although the interval from onset to initiation of EVT was adjusted as a covariate in multivariable models, shorter time interval of the preceding IVT group might alone influence on the improved clinical outcome. Additionally, we cannot ignore the effect of earlier initiation of reperfusion therapy in the preceding IVT group that might lead to better outcomes in spite of making adjustments.

In this study, we documented that preceding IVT might enhance successful recanalization and survival at 3 months without additional risk of SHT in acute ischemic stroke patients, who had large cerebral artery occlusion, and were treated with EVT within 8 h of onset. A significant reduction in 3-month mortality and a trend, although not significant, toward a better outcome according to the mRS score may indicate the beneficial effect of preceding IVT in patients receiving EVT.

Source of Funding

This study was supported by a grant from the Korea Healthcare Technology R&D Project, Ministry for Health and Welfare, Republic of Korea (HI10C2020).

Disclosure Statement

The authors have no conflicts of interest to disclose.


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  25. Yamaguchi T, Mori E, Minematsu K, Nakagawara J, Hashi K, Saito I, Shinohara Y; Japan Alteplase Clinical Trial (J-ACT) Group: Alteplase at 0.6 mg/kg for acute ischemic stroke within 3 hours of onset: Japan alteplase clinical trial (J-ACT). Stroke 2006;37:1810-1815.
  26. Kidwell CS, Jahan R, Gornbein J, Alger JR, Nenov V, Ajani Z, Feng L, Meyer BC, Olson S, Schwamm LH, Yoo AJ, Marshall RS, Meyers PM, Yavagal DR, Wintermark M, Guzy J, Starkman S, Saver JL; MR RESCUE Investigators: A trial of imaging selection and endovascular treatment for ischemic stroke. N Engl J Med 2013;368:914-923.
  27. Broderick JP, Palesch YY, Demchuk AM, Yeatts SD, Khatri P, Hill MD, Jauch EC, Jovin TG, Yan B, Silver FL, von Kummer R, Molina CA, Demaerschalk BM, Budzik R, Clark WM, Zaidat OO, Malisch TW, Goyal M, Schonewille WJ, Mazighi M, Engelter ST, Anderson C, Spilker J, Carrozzella J, Ryckborst KJ, Janis LS, Martin RH, Foster LD, Tomsick TA; Interventional Management of Stroke (IMS) III Investigators: Endovascular therapy after intravenous t-PA versus t-PA alone for stroke. N Engl J Med 2013;368:893-903.

Author Contacts

Hee-Joon Bae, MD, PhD, FAHA

Department of Neurology, Seoul National University Bundang Hospital

Seoul National University College of Medicine, 82, Gumi-ro 173 Beon-gil

Bundang-gu, Seongnam-si, Gyeonggi-do 13620 (Korea)

E-Mail braindoc@snu.ac.kr


Article / Publication Details

First-Page Preview
Abstract of Original Paper

Received: June 08, 2016
Accepted: September 06, 2016
Published online: April 21, 2017
Issue release date: August 2017

Number of Print Pages: 8
Number of Figures: 2
Number of Tables: 3

ISSN: 1015-9770 (Print)
eISSN: 1421-9786 (Online)

For additional information: http://www.karger.com/CED


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