Perot Charline; Romero Gwendoline; Gazzola Sébastien; Laksiri Nadia; Rey Caroline; Doche Emilie; Mahagne Marie-Hélène; Pelletier Jean; Faivre Anthony; Robinet-Borgomano Emmanuelle; Suissa Laurent

Research Article

Austin J Cerebrovasc Dis & Stroke. 2018; 5(1): 1078.

Clinical Benefits of Bridging Therapy for Acute Ischemic Stroke: A Real Life Study from the French Riviera

Perot Charline^1#, Romero Gwendoline^2#, Gazzola Sébastien³, Laksiri Nadia¹, Rey Caroline¹, Doche Emilie¹, Mahagne Marie-Hélène², Pelletier Jean¹, Faivre Anthony³, Robinet-Borgomano Emmanuelle¹ and Suissa Laurent^2*

¹Stroke Unit, University Hospital of Marseille, France

²Stroke Unit, University Hospital of Nice, France

³Stroke Unit, Teaching Military Hospital of Toulon, Saint Anne Hospital, France

^#Perot C and Romero G had contributed equally to the work

*Corresponding author: Suissa Laurent, Pasteur 2 Hospital, Stroke Unit, France

Received: February 23, 2018; Accepted: April 04, 2018; Published: May 07, 2018

Abstract

Background: The proof of the efficacy of the bridging associating intravenous thrombolysis and mechanical thrombectomy (IVTMT) vs. intravenous thrombolysis (IVT) alone has been recently introduced changing our practices in the management of ischemic stroke. We present here a multicenter study in “real life” to evaluate efficacy and safety of IVTMT.

Methods: A multicenter study was carried out from 2012 to 2016 in the stroke units of Marseille, Toulon and Nice. Consecutive patients treated in acute phase of ischemic stroke due to proximal occlusion arteries (MCA M1-M2 and/or IC) were included. Patients treated with IVTMT were comparated with patients treated with IVT alone before systematic use of IVTMT proposed by the recommendations. The primary efficacy endpoint was the mRS≤2 at 3 months. The safety was apprehended by the mortality and the symptomatic intracranial haemorrhage (SIH) rate.

Results: 557 patients were included, 269 (48.3%) in the IVTMT group and 288 (51.7%) in the IVT control group. At 3 months, 136/269 (50.6%) patients in the IVTMT group had mRS≤2 vs. 123/288 (42.7%) patients in the control group. After adjustment (age, sex, NIHSS and tandem occlusion), the odds ratio calculated was 1.95[1.29-2.95]. The recanalization rate at 24H was significantly higher in the IVTMT group (85.8% vs. 56.9%). The mortality (aOR: 0.63 [0.38- 1.06]) and the SIH rate (aOR: 2.12[0.79-5.63] were not significantly different in both groups. In subgroup analysis, tandem occlusions were be in favor of IVTMT strategy (aOR: 5.31[2.06-13.67]), whereas the moderate clinical severity (NIHSS <10) was in favour of IVT alone (aOR: 0.35[0.13-0.93]).

Conclusion: This study confirms in « real life » the efficacy and the safety of the bridging therapy demonstrated by the previous randomized trials. Our results discuss the inhomogeneity of IVTMT depending of the arterial occlusion site and the initial clinical severity.

Keywords: Ischemic stroke; Acute stroke; Acute therapy; Endovascular treatment; Thrombolysis

Introduction

Ischemic stroke is a devastating condition with a high risk of neurologic disability and death. Since 1995, the gold standard therapy for ischemic stroke in acute phase was intravenous administration of Alteplase, a tissue plasminogen activator (rt-PA), within 4.5 hours of stroke onset, so called intravenous thrombolysis (IVT) [1,2]. Effectiveness of IVT is reduced in case of large proximal vessel occlusion due to a poor rate of early recanalization (one third of cases) with thrombolysis in this condition [3-5]. Then, intra-arterial therapy has been developed in addition to IVT, so called the bridging therapy. First randomized control studies trials (RCTs), as IMS III in 2013, failed to demonstrate clinical benefits of bridging therapy. In 2015, new randomized controlled trials (RCTs) with more performing mechanical devices and more restricted inclusion criteria [6-12], have strongly demonstrated the significant clinical benefit of combination therapy. In line with these results, new guidelines by European Stroke Organisation (ESO) now recommend (13) that MT, in addition to IVT within 4.5h when eligible, must be performed routinely to treat acute stroke patients with large artery occlusions in the anterior circulation up to 6 h after symptom onset. Medico-economic approaches were carried out, based on RCTs and Meta-analyzes [14] but these results have not been yet confirmed in real world setting. The purpose of our study performed in the in the south of France, was to assess the clinical benefits of bridging therapy demonstrated by RCTs, through a real life multicenter controlled study.

Methods

Patient’s selection and procedure

Three academic hospitals were involved in this retrospective but controlled multicenter observational study: University Hospital of Marseille, University Hospital of Nice and Sainte Anne Military Teaching Hospital of Toulon. In “Provence Alps Côte d’Azur” region (5 million inhabitants), these three centres alone have a comprehensive stroke unit and are entitled to deliver endovascular treatment in acute phase of stroke. We included in the study the consecutive patients aged over 18 years, who underwent a recanalization treatment in stroke units from January 2012 to December 2016, with a documented stroke and a proximal occlusion of the anterior circulation. Proximal occlusion site had to be documented by vascular imaging such as three-dimensional time of flight (TOF) magnetic resonance (MR) angiography, and/or computed tomography (CT) or MR angiography (MRA) of supraaortic arteries according to each center habits. We have selected intra- and extra-cranial internal carotid artery (ICA) occlusions, middle cerebral artery (MCA) occlusions from M1 segment until M1-M2 junction and tandem occlusions (ICA and MCA occlusion at once). Two groups of patients were formed: the control group (IVT group), in which were included patients treated with systemic thrombolysis alone in the 4.5h time window; the intervention group (IVTM group) in which were included patients treated since 2015, according to ESO recommendations, with bridging therapy. This group also included patients in whom MT was performed as first-line therapy when systemic thrombolysis was contraindicated because of anticoagulation, recent surgery, recent hemorrhage or coagulation disorder. MT was performed by a trained operator using new devices as retrievable stents or aspiration. Each patient was clinically assessed by neurologist at baseline. We collected radiological data as stroke volume on MRI (DWI), MRI Alberta Stroke Program Early Computed Tomography Score (ASPECTS) [15] and occlusion site using 3DTOF and/or CT angiography and finally mTICI score before and after thrombectomy. Evaluation of the recanalization was done on CT angiography at 24 hours. All neuroimaging studies were reviewed by a neurologist in each center. At 3 months, mRS scale was calculated during a follow-up consultation by certified neurologist. When patients did not honor this consultation, they were contacted by phone using standardized interview. Although collection of initial clinical data was retrospective, it was done from our local stroke registry which is prospectively completed. Only imaging data and mRS were strictly retrospective. We excluded patients with posterior circulation occlusion, differential diagnosis, no clearly defined onset of symptoms, and patients lost to follow-up or with missing data at 3 months. The research was conducted according to the principles of the Declaration of Helsinki. Ethics approval was obtained from the local institutional review board. The board waived the need for patient consent for this non-interventional study.

Clinical and radiological Outcomes

The primary efficacy outcome was the proportion of patients with a modified Rankin scale score of 0-2, indicating functional independence, at 3 months after the intervention. The primary outcome was assessed at each center. The secondary efficacy outcomes included mRS gradual analysis and imaging outcomes defined by the absence of intracranial occlusion on follow-up CT angiography at 24h. Safety outcomes were represented by death at 3 months (mRS equal to 6) and symptomatic or asymptomatic intracranial haemorrhage (IH) at 24 hours. Haemorrhagic events were classified according to ECASS I [16] definition at 24 hours distinguishing haemorrhagic infarction (HI) and parenchymal haematoma (PH). Symptomatic IH was evaluated at 24 hours and defined as blood at any site in the brain on the CT control scan causing deterioration in the National Institutes of Health Stroke Scale (NIHSS) of 4 or more points.

Statistical analysis

Statistical analyses were conducted using statistical package STATA SE 10.0. To determine the statistically significant differences between IVT and IVTMT groups, Chi 2 test was assessed for categorical variables and Student’s t test for continuous variables. Nonparametric continuous variables were represented by medians and interquartile ranges and medians and standard deviation for parametric variables. Categorical variables are presented by absolute numbers (%). P<0.05 was considered significant. Binary outcomes were analyzed with logistic regression and were reported as odds ratios with 95% confidence intervals. In this real-life nonrandomized study unadjusted and adjusted odds ratios. The adjusted common odds ratios were adjusted for potential imbalances in the following major known prognostic variables between IVT and IVMT groups: age, sex, stroke severity (NIHSS at baseline) and tandem ICA/ MCA occlusion (yes vs. no). According to the definition of secondary clinical outcome, mRS gradual analysis was assessed by ordinal logistic regression. Treatment-effect modification was explored in prespecified subgroups of patients, defined by centers (Nice, Marseille, Toulon), age (<80, ≥80 y), gender (man, woman), diabetes mellitus (yes, no), arterial occlusion site (MCA, ICA/MCA, ICA alone), baseline NIHSS score (<10, 11-19, ≥20), MRI ASPECT score (<6, ≥6) and onset to imaging time (≤180, >180 mn). Differences between subgroups in the treatment effect were tested with interaction terms. Independent predictive variables of a good outcome (mRS≤2 at 3 months) were assessed by multivariate analysis by backward stepwise logistic regression (p<0.05). The regression model included all nonredundant variables associated to mRS≤2 at 3 months with p<0.1 in univariate analysis.

Results

Baseline characteristics

Between January 2012 to December 2016, 605 patients (281 from Nice, 203 from Marseille, and 121 from Toulon) met the inclusion criteria. 48 (7.93%) patients were excluded of the study according to exclusion criteria mentioned above. Among the remaining 557 stroke patients, 269 received combined therapy (IVTMT group) and 288 patients constituted the control group (IVT group). 510 (91.56%) patients underwent brain MRI at admission (261 in the IVTMT group and 249 in IVT group). Baseline characteristics of studied population are presented in Table 1. IVTMT patients were significantly younger than IVT group (mean age 66.08±13.60 years vs. 72.97±13.03 years, p< 0.001). There were 139 men (48.26%) in the IVT group and 147 men (44.44%) in the IVTMT group, with no significant difference between the 2 groups. The NIHSS score at baseline was significantly higher in the IVTMT group compared to the IVT group (16.69±4.97 vs 14.76±6.02; p<0.001). The IVT group had a higher proportion of hypertension, and smoking and the IVTMT group had a higher proportion of anticoagulant therapy. The other baselines characteristics did not differ between the two groups. Treatment procedure data are shown in Table 2.

Table 1: Baseline characteristics. * p<0.05.




  
    
    
    Control population (IVT) (n= 288) 
    Intervention population (IVTMT) (n=269) 
    p 
  
  
    Demographic characteristics 
    
    
    
    
  
  
    Age (Years) 
    * 
    72.97±13.03 
    66.08±13.60 
    <0.001 
  
  
    Men 
    
    139/288 (48.26%) 
    147/269 (54.65%) 
    0.132 
  
  
    Comorbidities ans risk factors 
    
    
    
    
  
  
    Hypertension 
    * 
    125/230 (54.35%) 
    96/126 (44.44%) 
    0.037 
  
  
    Diabetes mellitus 
    
    34/231 (14.72%) 
    23/216 (10.65%) 
    0.197 
  
  
    Smoking (recent or current) 
    * 
    41/229 (17.90%) 
    59/215 (25.44%) 
    0.016 
  
  
    Atrial fibrillation 
    
    36/229 (15.72%) 
    46/217 (21.40%) 
    0.124 
  
  
    Coronary disease 
    
    30/232 (12.93%) 
    30/216 (13.89%) 
    0.770 
  
  
    History of ischemic stroke 
    
    26/232 (14.21%) 
    32/216 (14.81%) 
    0.256 
  
  
    Hypercholesterolaemia 
    
    72/231 (31.17%) 
    58/216 (26.85%) 
    0.315 
  
  
    Anticoagulant therapy 
    * 
    12/230 (5.22%) 
    35/209 (16.75%) 
    <0.001 
  
  
    Clinical characteristics 
    
    
    
    
  
  
    Baseline NIHSS score 
    * 
    14.76±6.02 
    16.69±4.97 
    <0.001 
  
  
    Systolic blood pressure (mmHg) 
    
    157.34±27.56 
    154.58±27.51 
    0.322 
  
  
    Diastolic blood pressure (mmHg) 
    
    82.46±15.45 
    83.75±18.29 
    0.449 
  
  
    Blood glucose (g/L) 
    
    1.31±0.44 
    1.31±0.56 
    0.934 
  
  
    Imaging characteristics 
    
    
    
    
  
  
    Baseline imaging by MRI 
    
    261/288 (90.63%) 
    249/269 (93.57%) 
    0.410 
  
  
    Occlusion    site (MRI 3DTOF and/or CT-angiography) 
    
    
    
    
  
  
    Intracranial ICA 
    
    17/288 (5.90%) 
    12/269 (4.46%) 
    0.444 
  
  
    M1    segment middle cerebral artery segment 
    
    191/288 (66.32%) 
    167/269 (62.08) 
    0.297 
  
  
    ICA    with involvement of M1 middle cerebral artery segment 
    
    80/288 (27.78%) 
    90/269 (33.46%) 
    0.146 
  
  
    ASPECT Score (DWI) 
    
    8[7-9] 
    7[6-8] 
    0.322 
  
  
    DWI Volume (cm³) 
    
    61.86±5.94 
    47.91±4.52 
    0.062 
  
  
    Biological characteristics 
    
    
    
    
  
  
    Haemoglobin (g/dl) 
    
    13.61±1.66 
    13.59±1.96 
    0.948 
  
  
    Platelets count (G/l) 
    
    232.10±70.64 
    237.17±69.68 
    0.454 
  
  
    HbA1c (%) 
    
    6.01±0.97 
    5.93±1.02 
    0.436 
  
  
    Brain    Natriuretic Peptide BNP (pg/ml) 
    
    354.21±432.26 
    292.26±394.57 
    0.146



Table 1: Baseline characteristics. * p<0.05.

Efficacy outcome

The distribution of mRS scores at 3 months in each treatment group is presented in Figure 1. In IVTMT group, 50.56% of patients had a good clinical outcome (mRS≤2) at 3 months vs. 42.61% in IVT group (Table 3). This difference was significant (aOR: 1.95 [1.29-2.95] (p=0.001). For 449 patients, CT angiography at 24 hours was available (223 in the control group and 226 in the intervention group). The proportion of patient with intracranial recanalization on follow-up CT angiography at 24h was significantly higher in the IVTMT group (85.84% vs. 56.95%).

Figure 1: Modified Rankin Scale (mRS) score at 90 days.

    
    
    Figure 1:  Modified Rankin Scale (mRS) score at 90 days.

Table 2: Treatment procedure data’s.




  
    
    Control    population (IVT) (n= 288) 
    Intervention    population (IVTMT) (n=269) 
    p 
  
  
    Workflow    duration, mn 
    
    
    
  
  
    From onset to    admission 
    92.88±49.17 
    91.90±44.14 
    0.841 
  
  
    From onset to    clinical examination 
    100.50±52.13 
    105.21±58.94 
    0.392 
  
  
    From onset to    imaging 
    124.25±51.78 
    129.50±56.50 
    0.314 
  
  
    From onset to    intraveinous thrombolysis 
    161.62±51.59 
    155.49±51.83 
    0.262 
  
  
    From onset to    thrombectomy 
    
    238.37±68.86 
    
  
  
    From onset to    end of thrombectomy 
    
    304.53±82.64 
    
  
  
    Treatment    procedure 
    
    
    
  
  
    Systemic thrombolysis 
    
    
    
  
  
    Treatment with    intravenous alteplase 
    288/288 (100%) 
    206/269    (76.58%) 
    
  
  
    Intravenous    Nicardipine treatment 
    35/217 (16.13%) 
    15/130 (11.54%) 
    0.239 
  
  
    Injected dose    of alteplase (mg) 
    64.75±12.90 
    67.32±12.45 
    0.070 
  
  
    Mechanical thrombectomy 
    
    
    
  
  
    General    anesthesia with intubation 
    
    211/217    (97.24%) 
    
  
  
    TICI before thrombectomy 
    
    0 [0-1] 
    
  
  
    TICI at the end    of thrombectomy 
    
    2b [2b-3] 
    
  
  
    Stent retriever    system used 
    
    128/217    (58.99%) 
    

  
  
    Aspiration    system used 
    
    145/217    (66.82%) 
    
  
  
    Number of    thrombectomy device used per procedure 
    
    2 [1-2] 
    
  
  
    Number of    thrombectomy device attempts per procedure 
    
    2 [1-3] 
    
  
  
    Antithrombotic    therapy during thrombectomy 
    
    32/217 (14.74%) 
    
  
  
    Implantation of    intracranial stent 
    
    2/217 (0.92%) 
    
  
  
    Implantation of    extracranial stent 
    
    30/217 (13.82%)



Table 2: Treatment procedure data’s.

Table 3: Efficacy outcomes at 90 days.




  
    
    Control    population (IVT) n=288
    Intervention    population (IVTMT) n=269
    Unadjusted Odds    ratio 
    Adjusted Odds    ratio^*
  
  
    Primary outcome
    
    
    
    
  
  
    mRS ≤ 2 at 90 days
    123/288 (42.71%)
    136/269 (50.56%)
    1.37 [0.98- 1.92] 
    1.95 [1.29-2.95] 
  
  
    Secondary outcomes
    
    
    
    
  
  
    mRS (Median)
    3 [1-5]
    2 [1-4]
    1.38 [1.03-1.85] 
    1.80 [1.31-2.49] 
  
  
    mRS 0-1
    89/288 (30.90%)
    102/269 (37.92%)
    1.37 [0.96-1.94] 
    2.10 [1.37- 3.22] 
  
  
    Arterial    recanalization^† 
    127/223 (56.95%)
    194/226 (85.84%)
    4.58 [2.89-7.74] 
    7.11 [4.20-12.05] 
  
  
    ^*Odds ratios were adjusted for age, sex,    NIHSS at baseline and ICA occlusion
      ^†No intracranial    occlusion on follow-up CT angiography at 24 h



Table 3: Efficacy outcomes at 90 days.

Table 4: Safety outcomes at 90 days.




  
    
    Control population (IVT) n=288 
    Intervention population (IVTMT) n=269 
    Unadjusted Odds ratio [95% CI] 
    Adjusted Odds ratio [95% CI]^* 
  
  
    Intracranial hemorrhage (IH)^† 
    60/288 (20.83%) 
    62/269 (23.05%) 
    1.14 [0.76-170]  
    1.07 [0.70-1.65]  
  
  
    Hemorrhagic infarction type 1 
    14/288 (4.86%) 
    11/269 (4.09%) 
    0.83 [0.37-1.87]  
    0.85 [0.36-2.04]  
  
  
    Hemorrhagic infarction type 2 
    9/288 (3.13%) 
    12/269 (4.46%) 
    1.44 [0.60-3.49]  
    1.47 [0.57-3.75]  
  
  
    Parenchymal hematoma type 1 
    20/288 (6.94%) 
    12/269 (4.46%) 
    0.62 [0.30-1.31]  
    0.51 [0.24-1.13]  
  
  
    Parenchymal hematoma type 2 
    17/288 (5.90%) 
    27/269 (10.04%) 
    1.77 [0.95-3.34]  
    1.79 [0.91-3.49]  
  
  
    Symptomatic IH 
    8/288 (2.78%) 
    12/269 (4.46%) 
    1.63 [0.65-4.06]  
    2.12 [0.79-5.63]  
  
  
    Mortality 
    70/288 (24.31%) 
    42/269 (15.61%) 
    0.57 [0.37-0.88]  
    0.63 [0.38-1.06]  
  
  
    ^*Odds    ratios were adjusted for age, sex, NIHSS at baseline and ICA occlusion 
      ^†ECASS    I Intracranial hemorrhage at 24h



Table 4: Safety outcomes at 90 days.

Figure 2: Subgroup analysis (Forest plot showing adjusted treatment effect for mRS at 90 days in pre-specified subgroups).

    
    
    Figure 2:  Subgroup analysis (Forest plot showing adjusted treatment effect for mRS at 90 days in pre-specified subgroups).

Safety outcomes

The rate of symptomatic intracranial hemorrhage at 24h was 4.46% in IVTMT group, compared to 2.78% in IVT group, with no significant difference between both groups (Table 4). There was no significant difference between both groups concerning the different subtypes of asymptomatic intracranial hemorrhage defined by imaging at 24 h. At 3 months, mortality rate was not different in both groups (aOR: 0.63 [0.38-1.06]).

Subgroup analysis

Subgroup analysis did not show any appreciable difference between the three stroke units (Figure 2). It did not demonstrate any significant thrombectomy effect modification for sex, age, diabetes mellitus, ASPECT score and onset to imaging time. There was a significant difference in the NIHSS subgroup analysis (p <0.001), with an effect in favor of thrombectomy for the NIHSS ≥ 10 (aOR: 2.30 [1.38-3.86]), and an effect in favor of rtPA alone for NIHSS < 10 (aOR: 0.35 [0.13-0.93]). Concerning the site of arterial occlusion (p=0.035), we found that there was an effect in favor of thrombectomy for stroke patients with ICA-MCA tandem occlusion (aOR: 5.31 [1.57-17.9]).

Factors associated with good outcome

Independent factors associated at baseline of a good outcome (mRS≤2 at 3 months) were: NIHSS score (/4 pts, OR: 0.40 [0.28- 0.58]), systolic blood pressure (/10 mmHg, OR: 0.83 [0.73-0.96]), blood glucose (/1g/L, OR: 0.21 [0.06-0.73]), ICA/MCA occlusion (y/n, 0.31 [0.13-0.75]), MRI ASPECT score (/1 pt, OR: 1.49 [1.15- 1.92]), BNP level (/100pg/ml, OR:0.78 [0.68-0.90]) and endovascular treatment (y/n, OR: 2.23 [1.04-4,79]).

Discussion

The main result of the present study is that bridging therapy, namely intravenous thrombolysis followed by mechanical thrombectomy, performed in real life setting, significantly improves functional outcome in patients with acute ischemic stroke caused by proximal occlusion of anterior cerebral arteries, without increasing the risk of serious complication or death. It could be noted that although no statistically significant, there were trends toward lower mortality in IVTMT group what is consistent with RCTs. Recently, published data extracted from stroke-unit registers highlighted the safety and efficacy of bridging therapy [17,18]. Originally, this design allows assessing the clinical benefit of this therapeutic strategy in real life compared to rtPA alone. Indeed, in IVMT group, 50.56% of patients had a good clinical outcome at 3 months vs. 42.61% in IVT group (aOR 1.95 [1.29-2.95] in line with the results of the THRACE study performed in whole France (53.0% vs. 42.1%; aOR: 1.55[1.05- 2.30] [11]. In HERMES, pooled analysis of the five positive RCTs (MRCLEAN, ESCAPE, REVASCAT, SWIFT PRIME and EXTEND IA), 46% of patients were functionally independent at 90 days after bridging therapy against 26.5% in control population (aOR: 2.49[1.76-3.53]) [6-12,14].

Our results also confirm the safety of mechanical thrombectomy combined with IVT. The rate of symptomatic haemorrhages (4.46% in IVTMT group, and 2.78% in IVT group, p=0.131) was consistent with the results of HERMES pooled analysis (4.4% in IVTMT vs. 4.3% in control population, p=0.81) (14). There was no statistical difference between the two groups in terms of mortality (15.61% in IVTMT group vs. 24.31%, p=0.081) in line with RCT results such as THRACE study (12% vs. 13%) or HERMES analysis (15.3% vs. 18.9%) [11,14].

It is noteworthy to point out that the clinical benefit of bridging therapy in the present study appeared only after adjustment. Indeed, no significant differences were found between 2 groups through nonadjusted analysis (unadjusted ratio 1.37 [0.98-1.92], p=0.064). One might supposed that the inclusion in the IVTMT of patients with more severe stroke (baseline NIHSS 14.7±6.02 vs. 16.69±4.97) and the nonrandomized design of our study could explain this result. Therefore, it was already suspected that the clinical benefit of bridging therapy depends on the characteristic of the studied population. Indeed, it was one of the more relevant explanation for failure of the first RCTs published in 2013 (IMS III, Synthesis, MR RESCUE) in contrast with recent RCTs [19-21]. To answer this question, a subgroup analysis has been carried out with the aim to determine sub group(s) more likely to benefit from each treatment modality. First, this analysis didn’t show any significant difference between the three centres reflecting same practices and same patient recruitment. Secondly, we identified two pertinent parameters influencing the results: initial NIHSS score (p=0.001) and occlusion site (p=0.035). Discussion of bridging therapy when NIHSS is low is currently debated in the literature but data remains scarce and would justify dedicated RCTs [22-24]. Our study provides a part of answer since here, there is a benefit of IV thrombolysis alone in low NIHSS score (<10) (aOR: 0.35 [0.13-0.93]) whereas the benefit is in favor of bridging therapy for high NIHSS score. The analysis also identifies the initial arterial occlusion site as pertinent parameter. Clearly, ICA/MCA occlusions have a frank benefit in favor to bridging therapy (OR= 5.31 [2.06- 3.67]), which is not true for M1 or isolated ICA occlusions. This result reflects the recanalization failure in ICA/MCA occlusions with intravenous rt-PA alone as it has been already reported in older studies [3-5, 25]. In IMS III for instance, the rate of partial or complete recanalization at 24 hours was 81% for an occlusion in the ICA after combined treatment against 35% in the intravenous t-PA group [19]. In contrast, the rates of recanalization in IV thrombolysis alone group were 68% for an M1 occlusion, and 77% for an M2 occlusion. These results lead us to discuss a management strategy simplification in tandem occlusions. That means that, in case of high NIHSS score and/or tandem occlusion, patients should be sent as soon as possible to thrombectomy centers.

As in most trials, the other analyzed subgroups did not show any differences between the two strategies especially for the initial volume, as assessed by the MRI ASPECT score, and the DWI volume. DWI volume and MRI ASPECT score were well correlated in our study (data not shown), and we chose to select the score used in our clinical practice for presented analysis. This result does not seem surprising because the DWI volume at baseline, which is the preponderant element allowing penumbra evaluation, must be considered as a predictor of functional independence whatever the method of recanalization. Thus, this parameter was found to be inversely associated with the good functional outcome in multivariate analysis. Our multivariate analysis identified some other parameters associated with the good functional outcome, among which the use of thrombectomy. Unsurprisingly, and regardless of the recanalization type, we found predictive factors already known and reported in initial works about intravenous thrombolysis [13]. Of note, the delay did not appear in the proposed predictive model, apparently replaced by the initial volume. As described in the first negative trials (IMS III, Synthesis and MR RESCUE), we identified also the paradox that there is no linear correlation between the rate of 24 hours recanalization and clinical outcome [19-21]. In line with these findings, IVTMT was associated in our study with an increase of 30% of recanalization rate at 24H and an increase of 8% in proportion of good clinical outcome. This makes us highlight again the importance of patient’s selection before recanalization procedure on the basis of a penumbra imaging as proposed in MR RESCUE [21]. The initial volume, correlated with infarcted area growth rate, seems to take a major place in decisionmaking. Penumbra evaluation, based on the volume measure, and/ or control of this penumbra called “freezing penumbra”, are probably the key for the therapeutic decision and for functional prognosis improvement [26-30].

Conclusion

This study based on real life data confirms benefit and safety of the mechanical thrombectomy for ischemic stroke due to proximal occlusion of cerebral anterior arteries. We can conclude that benefit of MT observed in RCTs is also found in real world setting. However, adjustment has been necessary to demonstrate the benefit of combined strategy in our non-randomized population. These points out the importance of patient selection in order to improve medico-economic cost of these new strategies avoiding some futile procedures. For example, we highlighted the major benefit of IVTMT in ICA/MCA occlusion (cervical or intracranial), suggesting that IV Alteplase* is probably less useful in this situation. Subgroup analysis also shows that IVTMT benefit is expressed only in more severe patients, with high NIHSS scores, independently of occlusion site. Finally, for both strategies, outcome prediction model underlines the importance of the MRI ASPECT score (or DWI volume) which appears more determinant than time. This result reinforces the major role of patient’s selection based on ischemic penumbra derived from initial volume. It supports the concept of changing the face of stroke stopwatch [31].

Acknowledgment

The authors thank the following medical doctors for their contribution in this study: AllA P (Neurologist, St Anne Military Hospital, Toulon), Arteaga C (Radiologist, St Anne Military Hospital, Toulon), Bruder N (Intensive care anaesthetist, University Hospital of Marseille), Brunel H (Radiologist, University Hospital of Marseille), Chau Y (Radiologist, University Hospital of Nice), Sachet M (Radiologist, University Hospital of Nice), Sahuc P (Neurologist, St Anne Military Hospital, Toulon), Sedat J (Radiologist, University Hospital of Nice), Tourniaire P (Neurologist, Avignon Hospital), Veyrieres JB (Radiologist, St Anne Military Hospital, Toulon) and Viallet F (Neurologist, Aix-en-Provence Hospital).

References

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Citation: Perot C, Romero G, Gazzola S, Laksiri N, Rey C, Doche E, et al. Clinical Benefits of Bridging Therapy for Acute Ischemic Stroke: A Real Life Study from the French Riviera. Austin J Cerebrovasc Dis & Stroke. 2018; 5(1): 1078.

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