Prior IV Thrombolysis Facilitates Mechanical Thrombectomy in Acute Ischemic Stroke Pierre Guedin, MD,*† Aurelie Larcher, MD,† Jean-Pierre Decroix, MD,† Julien Labreuche, BST,‡ Jean-Francois Dreyfus, MD, PhD,x Serge Evrard, MD,† Adrien Wang, MD,† Philippe Graveleau, MD,*† Philippe Tassan, MD,jj Fernando Pico, MD, PhD,{ Oguzhan Coskun, MD,* Georges Rodesch, MD, PhD,* Frederic Bourdain, MD,† and Bertrand Lapergue, MD, PhD†
Background: In acute ischemic stroke (AIS), bridging therapy, including intravenous thrombolysis (IVT) and mechanical thrombectomy (MET), appears to be very promising. However, data on the impact of IVT before the endovascular procedure are limited. Methods: To examine the impact of IVT on the MET procedure, we compared the duration of this procedure, number of passes, recanalization rate, safety issues, and outcome in consecutively recruited patients either eligible for MET alone (intravenous fibrinolysis contraindication) or receiving MET preceded by IVT for proximal middle cerebral artery (MCA) occlusion within 6 hours of stroke onset. Results: From January 2011 to June 2013, 68 cases with proximal MCA occlusion were available for analysis (MET alone, 40; IVT 1 MET, 28). The 2 groups did not differ significantly in baseline characteristics. The median National Institutes of Health Stroke Scale score at admission was 15 (10-20) for MET and 18 (13-19) for IVT 1 MET groups, respectively (P 5 .39). The median duration of the endovascular procedure (from groin puncture to recanalization) was significantly shorter in the IVT 1 MET group compared with that in MET alone (35 minutes [21-60] versus 60 minutes [25-91]; P 5 .043). The number of passes of the thrombectomy device per patient tended to be lower in the IVT 1 MET group than those in the MET group (P 5 .080). The IVT 1 MET group also had a higher rate of complete recanalization and a better outcome at 3 months. Conclusions: Prior IVT may facilitate the MET procedure. Further studies on MET in AIS should assess the direct impact of IVT on the
From the *Department of Diagnostic and Interventional Neuroradiology, Foch Hospital, University Versailles Saint-Quentin en Yvelines, Paris, France; †Division of Neurology, Stroke Center, Foch Hospital, University Versailles Saint-Quentin en Yvelines, Paris, France; ‡Department of Biostatistics, Lille University Medical Center, Lille, France; xDepartment of Clinical Research and Innovation and Laboratory of Pharmacology, UPRES EA220, Foch Hospital, University Versailles Saint-Quentin en Yvelines, Paris, France; jjDivision of Neurology, Stroke Center, Poissy Saint-Germain-En-Laye Hospital, Poissy, France; and {Department of Neurology and Stroke Center, Mignot Hospital, University Versailles Saint-Quentin en Yvelines, Le Chesnay, France. Received October 7, 2014; revision received December 8, 2014; accepted December 10, 2014. Presented at European Stroke Conference, Nice, 2014 (e-poster session). The authors report no disclosures.
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The authors received no grant support or sponsorship. P.G, A.L., J.-P.D., and B.L. participated in the conception and design of the study. P.G, B.L., A.L., J.-F.D., S.E., A.W., J.-P.D., P.G., F.B., O.C., and G.R. analyzed and interpreted the data. P.G, B.L., A.L., S.E., A.W., J.-P.D., P.G., F.B., O.C., G.R., P.T., and F.P. were responsible for the provision of study material or patients. P.G., B.L., J.-F.D., and J.-P.D. were responsible for collection, assembly, and possession of the raw data. J.L. and J.-F.D. were responsible for the statistical expertise. B.L., P.G., A.L., J.-F.D., J.L., and F.B. collectively wrote the article. Address correspondence to Bertrand Lapergue, MD, PhD, Division of Neurology, Stroke Center, Foch Hospital, University Versailles Saint-Quentin en Yvelines, Suresnes, France. E-mail: b.lapergue@ hopital-foch.org. 1052-3057/$ - see front matter Ó 2015 by National Stroke Association http://dx.doi.org/10.1016/j.jstrokecerebrovasdis.2014.12.015
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endovascular procedure. Key Words: Mechanical endovascular therapy— intravenous thrombolysis by rtPA—acute ischemic stroke - recanalization. Ó 2015 by National Stroke Association
Mechanical thrombectomy (MET) is an adjuvant or alternative therapy for acute ischemic stroke (AIS) when intravenous thrombolysis (IVT) is contraindicated or has failed. Recent studies have shown that MET by use of a stent retriever is successful in achieving a high rate of arterial recanalization with a low complication rate.1,2 The benefit (clinical end point and recanalization rate) of combining IVT with MET versus MET alone has been suggested recently.3,4 A study in 2012 on 49 patients with successful recanalization, reported that IVT before the MET procedure decreased the mean time of this latter procedure by 20 minutes.5 Our primary aim was to check whether our registry data replicate these findings, and to evaluate if the number of passes of the thrombectomy device was also reduced subsequent to IVT.
Methods Standard Protocol Approvals, Registration, and Patient Consents Locally competent ethics committees (DF8, Ambroise Pare Hospital, Paris) approved the use of the retrospective analyses of patients’ data. Informed consent was obtained from the patients or their representatives.
Patients and Treatments Patients were identified from a prospective clinical registry of patients with AIS treated at our Stroke Unit between January 2011 and June 2013 for endovascular MET. The following criteria were required for inclusion in this study: - Proximal middle cerebral artery (MCA) occlusion or intracranial internal carotid artery occlusion within 6 hours of stroke onset, without associated cervical internal carotid artery occlusion/critical stenosis. Patients referred for AIS with cervical internal carotid occlusion/critical stenosis and basilar occlusion were excluded from this study to decrease bias because of the heterogeneity of patients and endovascular approaches. - Stand alone thrombectomy or bridging therapy: in accordance with our institutional stroke protocol, patients presenting within 4.5 hours of AIS symptom onset with large proximal occlusion received a combined therapy associating intravenous fibrinolysis (recombinant tissue plasminogen activator
[rtPA], .9 mg/kg, in accordance with the European Cooperative Acute Stroke Study [ECASS] III trial)6 followed by adjunctive MET (bridging therapy). Stand alone thrombectomy was indicated in cases of contraindication of IV rtPA in accordance with ECASS III trial.6 - Most patients underwent brain magnetic resonance (MR) imaging and MR angiography in the acute phase. In cases of MR imaging contraindication, brain computed tomography (CT) scan and CT angiography were performed. Only patients with an Alberta Stroke Program Early Computed Tomography score superior to 5 were included. All MET procedures were performed using the Solitaire FR (ev3, Covidien, Dublin, Ireland) via the femoral artery approach and using general anesthesia with close blood pressure monitoring. Groin punctures were routinely closed with an Angio-Seal closure device (St. Jude Medical, Minnetonka, MN). Following the instructions for use of the Solitaire FR, the balloon catheter is positioned within the internal carotid artery to allow both flow arrest during thrombus retrieval and thromboaspiration through its sidearm. The Solitaire FR device is delivered and then deployed over the thrombus through a microcatheter, with inner diameter ranges between .0180 and .027 (inches). A control angiogram is performed to determine the immediate reperfusion status. The device is left deployed before recovery for a few minutes. Before recovery, the microcatheter is advanced to cover the proximal marker of the device. Then, the balloon guide catheter is inflated to induce proximal internal carotid occlusion and flow arrest during the recovery. Subsequently, the Solitaire device and microcatheter are slowly recovered as a unit under constant aspiration with a 60-mL syringe through the balloon guide catheter. A control angiogram is performed to confirm revascularization and reperfusion. This sequence is repeated until thrombolysis in cerebral infarction (TICI) 2b or 3 flow (defined as successful revascularization) is established with a maximal delay of 6 hours from symptom onset to maximal TICI.
Data Collection and Definitions Information on patients’ characteristics, medical history, laboratory and imaging findings, vital signs before treatment, severity of ischemic stroke, and clinical outcome was collected using the same structured
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questionnaire. The severity of the ischemic stroke was assessed using National Institutes of Health Stroke Scale (NIHSS) score at admission and 24 hours later. We defined early neurologic improvement as an NIHSS score of 0-1 at 24 hours or a decrease of at least 4 points in the NIHSS score. All patients had a CT or MR imaging scan 24 hours after treatment onset, to assess hemorrhagic complications. Symptomatic intracranial hemorrhage was defined as parenchymal hematoma type 2 according to imaging at 24 hours, associated with an increase of at least 4 NIHSS points within 24 hours, or resulting in death. Time from symptom onset (or from when the patient was last seen in a normal condition) to groin puncture was recorded. During the MET procedure, the number of passes of the thrombectomy device, the presence of erratic emboli (defined as an angiographic occlusion in a previously unaffected vascular territory observed on the angiogram after clot removal), the time of recanalization, and the TICI score were all monitored. The modified Rankin Scale at 90 days was assessed by senior vascular neurologists during face-to-face interviews or via telephone conversations. Favorable functional outcome was defined as a 90-day modified Rankin Scale of 2 or lower.
Statistical Analysis Quantitative variables are expressed as means (6standard deviation) in the case of normal distribution or medians (interquartile range) otherwise. Normality of distributions was checked graphically and using the Shapiro–Wilk test. Qualitative variables are expressed as numbers (percentages). Comparisons between the 2 study groups (MET alone versus IVT 1 MET) were made using the c2 test (Fisher exact test was used when the expected cell frequency was ,5) for categorical variables and Student t test (or Mann–Whitney U test) for quantitative variables. In view of the study sample size, no multivariable analysis was performed. Statistical testing was done at the 2-tailed a level of .05. Data were analyzed using the SAS software package, release 9.3 (SAS Institute, Cary, NC).
Results From January 2011 to June 2013, 68 cases with proximal MCA occlusion were treated by MET, of which 28 had received full-dose IV rtPA before MET (within a median [IQR] time from symptom onset of 148 [120-170] minutes). The median time from onset to groin puncture was 231 minutes (IQR, 180-280) with no significant difference between the 2 study groups (P 5 .62). Stand alone thrombectomy (n 5 40) was indicated in cases of contraindication of IV rtPA: wake-up stroke (n 5 12, 30%), current anticoagulant use (n 5 12, 30%), stroke onset-tofibrinolysis time between 4.5 and 6 hours (n 5 5,
12.5%), and other cases (major surgery, ischemic stroke with hemorrhagic transformation, etc, n 5 11, 27.5%). Baseline characteristics and main clinical outcomes are described in Table 1. The 2 study groups did not differ significantly in baseline characteristics, with a median NIHSS (IQR) at admission of 18 (13-19) in the IVT 1 MET group and 15 (10-20) in the MET group (P 5 .39). Successful recanalization was achieved in 82% of cases (46 [67.7%] with complete recanalization and 10 [14.7%] with partial recanalization). Patients treated by IVT 1 MET had a higher rate of recanalization than patients treated by MET alone (96% versus 73%, P 5 .011, Table 1). As shown in Figure 1, the number of passes of the thrombectomy device per patient tended to be lower in the IVT 1 MET group than those in the MET group (P 5 .080). Among the 56 patients with successful recanalization, the duration of endovascular procedure (from groin puncture to recanalization) was significantly shorter in the IVT 1 MET group compared with that of MET alone (median [IQR], 35 [21-60] versus 60 [25-91] minutes, P 5 .043, Fig 2). Regarding the complications, erratic emboli occurred in only 4 cases (6%); all cases were observed in the MET group. Overall, 4 patients (6%) had symptomatic intracranial hemorrhage (2 per study group) and death occurred in 10 cases (15%) at 90 days with no difference between the 2 groups. Regarding the clinical efficacy outcomes, significantly more patients treated by IVT 1 MET presented early neurologic improvement than patients treated by MET alone (75% versus 48%, P 5 .023). However, the between-group difference in rate of favorable outcome did not reach the significance level (Table 1), despite a significant impact of successful recanalization. The rate of favorable outcome was 70% (39 of 56) in patients with successful recanalization in comparison with 8% (1 of 12) in patients without (P , .001). Stand alone thrombectomy (n 5 40) was indicated in cases of contraindication of IV rtPA such as wake-up stroke (n 5 12, 30%). The benefit and risk of recanalization treatment of wake-up stroke patients are currently largely debated. Among these 12 patients, the median of estimated onset-to-groin puncture time was 235 minutes (180-262), favorable outcome was 50% (6 of 12), and 1 symptomatic Intracerebral Hemorrhage was reported. These data did not differ significantly from the overall population.
Discussion This study suggests that combined IVT 1 MET decreases the duration of the endovascular procedure versus MET alone, without increasing hemorrhagic or embolic complications. Shorter duration of MET procedure was associated with a lower number of passes
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Table 1. Baseline characteristics and clinical outcomes of patients treated by mechanical endovascular therapy with and without previous intravenous thrombolysis Bridging therapy
Number of patients Baseline characteristics Age, y, mean 6 SD Men Hypertension Diabetes Hypercholesterolemia Current smoking NIHSS, median (IQR) Systolic BP, mm Hg, mean 6 SD Diastolic BP, mm Hg, mean 6 SD Glucose, mmol/L, median (IQR) Onset-to-groin puncture time, min, median (IQR) Clinical outcomes Successful recanalization No Partial Complete Early NI Favorable outcome* Symptomatic ICH 90-Day mortality
All (N 5 68)
No (MET alone)
Yes (IVT 1 MET)
68
40
28
67.2 6 13.9 26 (38.2) 28 (41.1) 4 (5.9) 20 (29.4) 15 (23.8) 16 (10-20) 152 6 23 80 6 13 6.7 (5.6-7.8) 213 (180-280)
64.6 6 15.3 15 (37.5) 17 (42.5) 2 (5.0) 10 (25.0) 9 (25.0) 15 (10-20) 146 6 22 80 6 14 6.7 (5.5-8.2) 204 (175-290)
69.2 6 13.5 11 (39.3) 11 (39.3) 2 (7.1) 10 (35.7) 6 (22.2) 18 (13-19) 155 6 22 80 6 10 6.8 (5.8-7.5) 240 (187-275)
56 (82.4) 12 (17.7) 10 (14.7) 46 (67.7) 40 (58.8) 40 (58.8) 4 (5.9) 10 (14.7)
29 (72.5) 11 (27.5) 7 (17.5) 22 (55.0) 19 (47.5) 21 (52.5) 2 (5.0) 7 (17.5)
27 (96.4) 1 (3.6) 3 (10.7) 24 (85.7) 21 (75.0) 19 (67.9) 2 (7.1) 3 (10.7)
P
.24 .88 .79 1.00 .34 .80 .39 .24 .88 .96 .62 .011 .013
.023 .21 1.00 .51
Abbreviations: BP, blood pressure; ICH, intracerebral hemorrhage; IQR, interquarlite range; IVT, intravenous thrombolysis; MET, mechanical endovascular therapy; mRS, modified Rankin Scale; NI, neurologic improvement; NIHSS, National Institutes of Health Stroke Scale; SD, standard deviation. Values are number (%) unless otherwise indicated. *Favorable functional outcome was defined as a 90-day mRs of 2 or lower.
with the thrombectomy device in the IVT 1 MET group and a higher rate of recanalization. Time from groin puncture to maximal recanalization was 46 minutes (24.5-85) in our cohort. This was similar with the time from groin puncture to maximal recanalization of 40 minutes (30-54) reported in the stent retriever–based retrospective studies of Davalos et al3 with 141 patients treated by Solitaire, or 47.8 minutes
Figure 1. Number of passes of the thrombectomy device according to prior use of intravenous thrombolysis. *P value for the comparison in number of passes was calculated using the Mann–Whitney U test (before categorization done for the presentation). Abbreviations: IVT, intravenous thrombolysis; MET, mechanical endovascular therapy.
(Trevo group) and 47.3 minutes (Merci group) in the Trevo2 trial.1 This suggests that our technical results of MET procedures are reliable and comparable with those previously reported. A significantly shorter duration of the MET procedure after IVT versus stand alone thrombectomy was also reported in the study of Pfefferkorn et al.5 Among 49 patients with acute AIS and carotid artery/MCA occlusion
Figure 2. Time from groin puncture to maximal recanalization according to prior use of intravenous thrombolysis. *P value for the comparison in time from groin puncture to maximal recanalization was calculated using the Mann–Whitney U test. Bars indicate the median values. Abbreviations: IVT, intravenous thrombolysis; MET, mechanical endovascular therapy.
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(n 5 19), or basilar artery occlusion (n 5 30), and with successful recanalization, combined IVT 1 MET decreased endovascular procedure time (defined as the interval between the onset of thrombus manipulation by suction, retrieval or mechanical fragmentation, and recanalization) by 20 minutes (44.2 6 40.5 versus 24.8 6 22.8, P 5 .042). We replicate this finding among our stroke patient cohort. In contrast with the report by Pfefferkorn, only stroke patients with proximal MCA/Intracranial Internal Carotid Artery occlusion were included and treated uniquely by Solitaire (no heterogeneity in device use). Our primary outcome was the reduction in procedure duration (groin puncture to recanalization) and this reduction in time was around the same (20 minutes) as in study by Pfefferkorn. This suggests that the impact of IVT on procedure time was not dependant on difficulties related to thrombus access (arterial tortuosity). Moreover, to minimize bias due to nonrandomized design of our study, only MCA/intracranial carotid artery occlusions were included without ipsilateral carotid artery occlusion or critical stenosis. Taken together, these 2 studies underline the potential additional effect of IVT 1 MET. Indeed, we observed a lower number of passes in the IVT 1 MET versus MET alone (P for trend 5 .080). In the IVT 1 MET group, successful revascularization was achieved in 71.4% of procedures after 1 or 2 passes against 55.2% in the MET alone group. This was consistent with results reported in the retrospective cohort study using Solitaire for MET in AIS.3 The IVT 1 MET group also had a higher rate of successful recanalization (96.4% versus 72.5%; P 5 .011). Interestingly, Pfefferkorn et al did not report an effect of combined IVT 1 MET on recanalization rate (74% versus 77%). This may be explained by different stent retriever devices used in their study. Dorn et al7 also observed that the recanalization rate was higher when IVT was administered before MET. As previously reported by others, the failure of recanalization remains high (17.7%) in our cohort of proximal MCA occlusion. The composition and length of the clot may explain these results. Riedel et al8 reported that among 128 patients with acute MCA stroke, IVT has no potential to recanalize occluded vessels if thrombus length exceeds 8 mm. The length of the thrombus may also affect the rate of complete recanalization with thrombectomy in AIS. These data are scarce and future studies about recanalization treatment in acute stroke should be focused on the characteristics of clot (composition, length, and imaging features). Four cases (10%) of emboli in a previously unaffected vascular territory were noted in the MET alone group but none occurred in the IVT 1 MET group (P 5 .14). This is similar to the 12.5% (18 cases) reported by Gascou et al9 among 144 patients treated by Solitaire but the per-
centage of emboli in this study were not impacted by prior IVT (P 5 .35). Our study has the limitations of being retrospective and of nonrandomized design. Despite 3 negative randomized control trials about endovascular approach in AIS reported in 2013, our results confirm high rate of recanalization and additive effect with IVT 1 MET approach.10-12 However, the combined effect of IVT 1 MET now needs to be assessed in larger patient populations. Recruitment in randomized trials of endovascular therapy as compared with standard therapy is thus urgently required.
Conclusion Our study shows that prior IVT may facilitate the MET procedure (duration and recanalization rate). Our study also suggests that a lower risk of distal embolization exists when MET is performed after prior IVT. Further studies on MET in AIS should include its combination with IVT and assess the direct impact of IVT on the subsequent endovascular procedure. Acknowledgments: We thank Mary Osborne-Pellegrin for help in editing the final draft of the article.
References 1. Nogueira RG, Lutsep HL, Gupta R, et al. Trevo versus merci retrievers for thrombectomy revascularisation of large vessel occlusions in acute ischaemic stroke (trevo 2): a randomised trial. Lancet 2012;380:1231-1240. 2. Saver JL, Jahan R, Levy EI, et al. Solitaire flow restoration device versus the merci retriever in patients with acute ischaemic stroke (swift): a randomised, parallel-group, non-inferiority trial. Lancet 2012;380:1241-1249. 3. D avalos A, Pereira VM, Chapot R, et al. Retrospective multicenter study of solitaire FR for revascularization in the treatment of acute ischemic stroke. Stroke 2012; 43:2699-2705. 4. Rouchaud A, Mazighi M, Labreuche J, et al. Outcomes of mechanical endovascular therapy for acute ischemic stroke: a clinical registry study and systematic review. Stroke 2011;42:1289-1294. 5. Pfefferkorn T, Holtmannspotter M, Patzig M, et al. Preceding intravenous thrombolysis facilitates endovascular mechanical recanalization in large intracranial artery occlusion. Int J Stroke 2012;7:14-18. 6. Hacke W, Kaste M, Bluhmki E, et al. Thrombolysis with alteplase 3 to 4.5 hours after acute ischemic stroke. N Engl J Med 2008;359:1317-1329. 7. Dorn F, Stehle S, Lockau H, et al. Endovascular treatment of acute intracerebral artery occlusions with the solitaire stent: single-centre experience with 108 recanalization procedures. Cerebrovasc Dis 2012;34:70-77. 8. Riedel CH, Zimmermann P, Jensen-Kondering U, et al. The importance of size: successful recanalization by intravenous thrombolysis in acute anterior stroke depends on thrombus length. Stroke June 2011;42: 1775-1777. 9. Gascou G, Lobotesis K, Machi P, et al. Stent retrievers in acute ischemic stroke: complications and failures during
PRIOR IV THROMBOLYSIS AND THROMBECTOMY IN AIS the perioperative period. AJNR Am J Neuroradiol 2014; 35:734-740. 10. Broderick JP, Palesch YY, Demchuk AM, et al. Endovascular therapy after intravenous t-PA versus tPA alone for stroke. N Engl J Med 2013;368: 893-903.
957 11. Ciccone A, Valvassori L, Nichelatti M, et al. Endovascular treatment for acute ischemic stroke. N Engl J Med 2013; 368:904-913. 12. Kidwell CS, Jahan R, Gornbein J, et al. A trial of imaging selection and endovascular treatment for ischemic stroke. N Engl J Med 2013;368:914-923.
Background: In acute ischemic stroke (AIS), bridging therapy, including intravenous thrombolysis (IVT) and mechanical thrombectomy (MET), appears to be very promising. However, data on the impact of IVT before the endovascular procedure are limited. Methods: To examine the impact of IVT on the MET procedure, we compared the duration of this procedure, number of passes, recanalization rate, safety issues, and outcome in consecutively recruited patients either eligible for MET alone (intravenous fibrinolysis contraindication) or receiving MET preceded by IVT for proximal middle cerebral artery (MCA) occlusion within 6 hours of stroke onset. Results: From January 2011 to June 2013, 68 cases with proximal MCA occlusion were available for analysis (MET alone, 40; IVT 1 MET, 28). The 2 groups did not differ significantly in baseline characteristics. The median National Institutes of Health Stroke Scale score at admission was 15 (10-20) for MET and 18 (13-19) for IVT 1 MET groups, respectively (P 5 .39). The median duration of the endovascular procedure (from groin puncture to recanalization) was significantly shorter in the IVT 1 MET group compared with that in MET alone (35 minutes [21-60] versus 60 minutes [25-91]; P 5 .043). The number of passes of the thrombectomy device per patient tended to be lower in the IVT 1 MET group than those in the MET group (P 5 .080). The IVT 1 MET group also had a higher rate of complete recanalization and a better outcome at 3 months. Conclusions: Prior IVT may facilitate the MET procedure. Further studies on MET in AIS should assess the direct impact of IVT on the
From the *Department of Diagnostic and Interventional Neuroradiology, Foch Hospital, University Versailles Saint-Quentin en Yvelines, Paris, France; †Division of Neurology, Stroke Center, Foch Hospital, University Versailles Saint-Quentin en Yvelines, Paris, France; ‡Department of Biostatistics, Lille University Medical Center, Lille, France; xDepartment of Clinical Research and Innovation and Laboratory of Pharmacology, UPRES EA220, Foch Hospital, University Versailles Saint-Quentin en Yvelines, Paris, France; jjDivision of Neurology, Stroke Center, Poissy Saint-Germain-En-Laye Hospital, Poissy, France; and {Department of Neurology and Stroke Center, Mignot Hospital, University Versailles Saint-Quentin en Yvelines, Le Chesnay, France. Received October 7, 2014; revision received December 8, 2014; accepted December 10, 2014. Presented at European Stroke Conference, Nice, 2014 (e-poster session). The authors report no disclosures.
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The authors received no grant support or sponsorship. P.G, A.L., J.-P.D., and B.L. participated in the conception and design of the study. P.G, B.L., A.L., J.-F.D., S.E., A.W., J.-P.D., P.G., F.B., O.C., and G.R. analyzed and interpreted the data. P.G, B.L., A.L., S.E., A.W., J.-P.D., P.G., F.B., O.C., G.R., P.T., and F.P. were responsible for the provision of study material or patients. P.G., B.L., J.-F.D., and J.-P.D. were responsible for collection, assembly, and possession of the raw data. J.L. and J.-F.D. were responsible for the statistical expertise. B.L., P.G., A.L., J.-F.D., J.L., and F.B. collectively wrote the article. Address correspondence to Bertrand Lapergue, MD, PhD, Division of Neurology, Stroke Center, Foch Hospital, University Versailles Saint-Quentin en Yvelines, Suresnes, France. E-mail: b.lapergue@ hopital-foch.org. 1052-3057/$ - see front matter Ó 2015 by National Stroke Association http://dx.doi.org/10.1016/j.jstrokecerebrovasdis.2014.12.015
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endovascular procedure. Key Words: Mechanical endovascular therapy— intravenous thrombolysis by rtPA—acute ischemic stroke - recanalization. Ó 2015 by National Stroke Association
Mechanical thrombectomy (MET) is an adjuvant or alternative therapy for acute ischemic stroke (AIS) when intravenous thrombolysis (IVT) is contraindicated or has failed. Recent studies have shown that MET by use of a stent retriever is successful in achieving a high rate of arterial recanalization with a low complication rate.1,2 The benefit (clinical end point and recanalization rate) of combining IVT with MET versus MET alone has been suggested recently.3,4 A study in 2012 on 49 patients with successful recanalization, reported that IVT before the MET procedure decreased the mean time of this latter procedure by 20 minutes.5 Our primary aim was to check whether our registry data replicate these findings, and to evaluate if the number of passes of the thrombectomy device was also reduced subsequent to IVT.
Methods Standard Protocol Approvals, Registration, and Patient Consents Locally competent ethics committees (DF8, Ambroise Pare Hospital, Paris) approved the use of the retrospective analyses of patients’ data. Informed consent was obtained from the patients or their representatives.
Patients and Treatments Patients were identified from a prospective clinical registry of patients with AIS treated at our Stroke Unit between January 2011 and June 2013 for endovascular MET. The following criteria were required for inclusion in this study: - Proximal middle cerebral artery (MCA) occlusion or intracranial internal carotid artery occlusion within 6 hours of stroke onset, without associated cervical internal carotid artery occlusion/critical stenosis. Patients referred for AIS with cervical internal carotid occlusion/critical stenosis and basilar occlusion were excluded from this study to decrease bias because of the heterogeneity of patients and endovascular approaches. - Stand alone thrombectomy or bridging therapy: in accordance with our institutional stroke protocol, patients presenting within 4.5 hours of AIS symptom onset with large proximal occlusion received a combined therapy associating intravenous fibrinolysis (recombinant tissue plasminogen activator
[rtPA], .9 mg/kg, in accordance with the European Cooperative Acute Stroke Study [ECASS] III trial)6 followed by adjunctive MET (bridging therapy). Stand alone thrombectomy was indicated in cases of contraindication of IV rtPA in accordance with ECASS III trial.6 - Most patients underwent brain magnetic resonance (MR) imaging and MR angiography in the acute phase. In cases of MR imaging contraindication, brain computed tomography (CT) scan and CT angiography were performed. Only patients with an Alberta Stroke Program Early Computed Tomography score superior to 5 were included. All MET procedures were performed using the Solitaire FR (ev3, Covidien, Dublin, Ireland) via the femoral artery approach and using general anesthesia with close blood pressure monitoring. Groin punctures were routinely closed with an Angio-Seal closure device (St. Jude Medical, Minnetonka, MN). Following the instructions for use of the Solitaire FR, the balloon catheter is positioned within the internal carotid artery to allow both flow arrest during thrombus retrieval and thromboaspiration through its sidearm. The Solitaire FR device is delivered and then deployed over the thrombus through a microcatheter, with inner diameter ranges between .0180 and .027 (inches). A control angiogram is performed to determine the immediate reperfusion status. The device is left deployed before recovery for a few minutes. Before recovery, the microcatheter is advanced to cover the proximal marker of the device. Then, the balloon guide catheter is inflated to induce proximal internal carotid occlusion and flow arrest during the recovery. Subsequently, the Solitaire device and microcatheter are slowly recovered as a unit under constant aspiration with a 60-mL syringe through the balloon guide catheter. A control angiogram is performed to confirm revascularization and reperfusion. This sequence is repeated until thrombolysis in cerebral infarction (TICI) 2b or 3 flow (defined as successful revascularization) is established with a maximal delay of 6 hours from symptom onset to maximal TICI.
Data Collection and Definitions Information on patients’ characteristics, medical history, laboratory and imaging findings, vital signs before treatment, severity of ischemic stroke, and clinical outcome was collected using the same structured
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questionnaire. The severity of the ischemic stroke was assessed using National Institutes of Health Stroke Scale (NIHSS) score at admission and 24 hours later. We defined early neurologic improvement as an NIHSS score of 0-1 at 24 hours or a decrease of at least 4 points in the NIHSS score. All patients had a CT or MR imaging scan 24 hours after treatment onset, to assess hemorrhagic complications. Symptomatic intracranial hemorrhage was defined as parenchymal hematoma type 2 according to imaging at 24 hours, associated with an increase of at least 4 NIHSS points within 24 hours, or resulting in death. Time from symptom onset (or from when the patient was last seen in a normal condition) to groin puncture was recorded. During the MET procedure, the number of passes of the thrombectomy device, the presence of erratic emboli (defined as an angiographic occlusion in a previously unaffected vascular territory observed on the angiogram after clot removal), the time of recanalization, and the TICI score were all monitored. The modified Rankin Scale at 90 days was assessed by senior vascular neurologists during face-to-face interviews or via telephone conversations. Favorable functional outcome was defined as a 90-day modified Rankin Scale of 2 or lower.
Statistical Analysis Quantitative variables are expressed as means (6standard deviation) in the case of normal distribution or medians (interquartile range) otherwise. Normality of distributions was checked graphically and using the Shapiro–Wilk test. Qualitative variables are expressed as numbers (percentages). Comparisons between the 2 study groups (MET alone versus IVT 1 MET) were made using the c2 test (Fisher exact test was used when the expected cell frequency was ,5) for categorical variables and Student t test (or Mann–Whitney U test) for quantitative variables. In view of the study sample size, no multivariable analysis was performed. Statistical testing was done at the 2-tailed a level of .05. Data were analyzed using the SAS software package, release 9.3 (SAS Institute, Cary, NC).
Results From January 2011 to June 2013, 68 cases with proximal MCA occlusion were treated by MET, of which 28 had received full-dose IV rtPA before MET (within a median [IQR] time from symptom onset of 148 [120-170] minutes). The median time from onset to groin puncture was 231 minutes (IQR, 180-280) with no significant difference between the 2 study groups (P 5 .62). Stand alone thrombectomy (n 5 40) was indicated in cases of contraindication of IV rtPA: wake-up stroke (n 5 12, 30%), current anticoagulant use (n 5 12, 30%), stroke onset-tofibrinolysis time between 4.5 and 6 hours (n 5 5,
12.5%), and other cases (major surgery, ischemic stroke with hemorrhagic transformation, etc, n 5 11, 27.5%). Baseline characteristics and main clinical outcomes are described in Table 1. The 2 study groups did not differ significantly in baseline characteristics, with a median NIHSS (IQR) at admission of 18 (13-19) in the IVT 1 MET group and 15 (10-20) in the MET group (P 5 .39). Successful recanalization was achieved in 82% of cases (46 [67.7%] with complete recanalization and 10 [14.7%] with partial recanalization). Patients treated by IVT 1 MET had a higher rate of recanalization than patients treated by MET alone (96% versus 73%, P 5 .011, Table 1). As shown in Figure 1, the number of passes of the thrombectomy device per patient tended to be lower in the IVT 1 MET group than those in the MET group (P 5 .080). Among the 56 patients with successful recanalization, the duration of endovascular procedure (from groin puncture to recanalization) was significantly shorter in the IVT 1 MET group compared with that of MET alone (median [IQR], 35 [21-60] versus 60 [25-91] minutes, P 5 .043, Fig 2). Regarding the complications, erratic emboli occurred in only 4 cases (6%); all cases were observed in the MET group. Overall, 4 patients (6%) had symptomatic intracranial hemorrhage (2 per study group) and death occurred in 10 cases (15%) at 90 days with no difference between the 2 groups. Regarding the clinical efficacy outcomes, significantly more patients treated by IVT 1 MET presented early neurologic improvement than patients treated by MET alone (75% versus 48%, P 5 .023). However, the between-group difference in rate of favorable outcome did not reach the significance level (Table 1), despite a significant impact of successful recanalization. The rate of favorable outcome was 70% (39 of 56) in patients with successful recanalization in comparison with 8% (1 of 12) in patients without (P , .001). Stand alone thrombectomy (n 5 40) was indicated in cases of contraindication of IV rtPA such as wake-up stroke (n 5 12, 30%). The benefit and risk of recanalization treatment of wake-up stroke patients are currently largely debated. Among these 12 patients, the median of estimated onset-to-groin puncture time was 235 minutes (180-262), favorable outcome was 50% (6 of 12), and 1 symptomatic Intracerebral Hemorrhage was reported. These data did not differ significantly from the overall population.
Discussion This study suggests that combined IVT 1 MET decreases the duration of the endovascular procedure versus MET alone, without increasing hemorrhagic or embolic complications. Shorter duration of MET procedure was associated with a lower number of passes
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Table 1. Baseline characteristics and clinical outcomes of patients treated by mechanical endovascular therapy with and without previous intravenous thrombolysis Bridging therapy
Number of patients Baseline characteristics Age, y, mean 6 SD Men Hypertension Diabetes Hypercholesterolemia Current smoking NIHSS, median (IQR) Systolic BP, mm Hg, mean 6 SD Diastolic BP, mm Hg, mean 6 SD Glucose, mmol/L, median (IQR) Onset-to-groin puncture time, min, median (IQR) Clinical outcomes Successful recanalization No Partial Complete Early NI Favorable outcome* Symptomatic ICH 90-Day mortality
All (N 5 68)
No (MET alone)
Yes (IVT 1 MET)
68
40
28
67.2 6 13.9 26 (38.2) 28 (41.1) 4 (5.9) 20 (29.4) 15 (23.8) 16 (10-20) 152 6 23 80 6 13 6.7 (5.6-7.8) 213 (180-280)
64.6 6 15.3 15 (37.5) 17 (42.5) 2 (5.0) 10 (25.0) 9 (25.0) 15 (10-20) 146 6 22 80 6 14 6.7 (5.5-8.2) 204 (175-290)
69.2 6 13.5 11 (39.3) 11 (39.3) 2 (7.1) 10 (35.7) 6 (22.2) 18 (13-19) 155 6 22 80 6 10 6.8 (5.8-7.5) 240 (187-275)
56 (82.4) 12 (17.7) 10 (14.7) 46 (67.7) 40 (58.8) 40 (58.8) 4 (5.9) 10 (14.7)
29 (72.5) 11 (27.5) 7 (17.5) 22 (55.0) 19 (47.5) 21 (52.5) 2 (5.0) 7 (17.5)
27 (96.4) 1 (3.6) 3 (10.7) 24 (85.7) 21 (75.0) 19 (67.9) 2 (7.1) 3 (10.7)
P
.24 .88 .79 1.00 .34 .80 .39 .24 .88 .96 .62 .011 .013
.023 .21 1.00 .51
Abbreviations: BP, blood pressure; ICH, intracerebral hemorrhage; IQR, interquarlite range; IVT, intravenous thrombolysis; MET, mechanical endovascular therapy; mRS, modified Rankin Scale; NI, neurologic improvement; NIHSS, National Institutes of Health Stroke Scale; SD, standard deviation. Values are number (%) unless otherwise indicated. *Favorable functional outcome was defined as a 90-day mRs of 2 or lower.
with the thrombectomy device in the IVT 1 MET group and a higher rate of recanalization. Time from groin puncture to maximal recanalization was 46 minutes (24.5-85) in our cohort. This was similar with the time from groin puncture to maximal recanalization of 40 minutes (30-54) reported in the stent retriever–based retrospective studies of Davalos et al3 with 141 patients treated by Solitaire, or 47.8 minutes
Figure 1. Number of passes of the thrombectomy device according to prior use of intravenous thrombolysis. *P value for the comparison in number of passes was calculated using the Mann–Whitney U test (before categorization done for the presentation). Abbreviations: IVT, intravenous thrombolysis; MET, mechanical endovascular therapy.
(Trevo group) and 47.3 minutes (Merci group) in the Trevo2 trial.1 This suggests that our technical results of MET procedures are reliable and comparable with those previously reported. A significantly shorter duration of the MET procedure after IVT versus stand alone thrombectomy was also reported in the study of Pfefferkorn et al.5 Among 49 patients with acute AIS and carotid artery/MCA occlusion
Figure 2. Time from groin puncture to maximal recanalization according to prior use of intravenous thrombolysis. *P value for the comparison in time from groin puncture to maximal recanalization was calculated using the Mann–Whitney U test. Bars indicate the median values. Abbreviations: IVT, intravenous thrombolysis; MET, mechanical endovascular therapy.
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(n 5 19), or basilar artery occlusion (n 5 30), and with successful recanalization, combined IVT 1 MET decreased endovascular procedure time (defined as the interval between the onset of thrombus manipulation by suction, retrieval or mechanical fragmentation, and recanalization) by 20 minutes (44.2 6 40.5 versus 24.8 6 22.8, P 5 .042). We replicate this finding among our stroke patient cohort. In contrast with the report by Pfefferkorn, only stroke patients with proximal MCA/Intracranial Internal Carotid Artery occlusion were included and treated uniquely by Solitaire (no heterogeneity in device use). Our primary outcome was the reduction in procedure duration (groin puncture to recanalization) and this reduction in time was around the same (20 minutes) as in study by Pfefferkorn. This suggests that the impact of IVT on procedure time was not dependant on difficulties related to thrombus access (arterial tortuosity). Moreover, to minimize bias due to nonrandomized design of our study, only MCA/intracranial carotid artery occlusions were included without ipsilateral carotid artery occlusion or critical stenosis. Taken together, these 2 studies underline the potential additional effect of IVT 1 MET. Indeed, we observed a lower number of passes in the IVT 1 MET versus MET alone (P for trend 5 .080). In the IVT 1 MET group, successful revascularization was achieved in 71.4% of procedures after 1 or 2 passes against 55.2% in the MET alone group. This was consistent with results reported in the retrospective cohort study using Solitaire for MET in AIS.3 The IVT 1 MET group also had a higher rate of successful recanalization (96.4% versus 72.5%; P 5 .011). Interestingly, Pfefferkorn et al did not report an effect of combined IVT 1 MET on recanalization rate (74% versus 77%). This may be explained by different stent retriever devices used in their study. Dorn et al7 also observed that the recanalization rate was higher when IVT was administered before MET. As previously reported by others, the failure of recanalization remains high (17.7%) in our cohort of proximal MCA occlusion. The composition and length of the clot may explain these results. Riedel et al8 reported that among 128 patients with acute MCA stroke, IVT has no potential to recanalize occluded vessels if thrombus length exceeds 8 mm. The length of the thrombus may also affect the rate of complete recanalization with thrombectomy in AIS. These data are scarce and future studies about recanalization treatment in acute stroke should be focused on the characteristics of clot (composition, length, and imaging features). Four cases (10%) of emboli in a previously unaffected vascular territory were noted in the MET alone group but none occurred in the IVT 1 MET group (P 5 .14). This is similar to the 12.5% (18 cases) reported by Gascou et al9 among 144 patients treated by Solitaire but the per-
centage of emboli in this study were not impacted by prior IVT (P 5 .35). Our study has the limitations of being retrospective and of nonrandomized design. Despite 3 negative randomized control trials about endovascular approach in AIS reported in 2013, our results confirm high rate of recanalization and additive effect with IVT 1 MET approach.10-12 However, the combined effect of IVT 1 MET now needs to be assessed in larger patient populations. Recruitment in randomized trials of endovascular therapy as compared with standard therapy is thus urgently required.
Conclusion Our study shows that prior IVT may facilitate the MET procedure (duration and recanalization rate). Our study also suggests that a lower risk of distal embolization exists when MET is performed after prior IVT. Further studies on MET in AIS should include its combination with IVT and assess the direct impact of IVT on the subsequent endovascular procedure. Acknowledgments: We thank Mary Osborne-Pellegrin for help in editing the final draft of the article.
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