Temporal trends in results of endovascular treatment of anterior intracranial large cerebral vessel occlusion: A 7-year study

Abstract

Background:

Technical improvements in devices, changes in angiographic grading scales and various confounding factors have made difficult the detection of the temporal evolution of angiographic and clinical results after endovascular treatment (EVT) for acute ischemic Stroke (AIS). We analyzed this evolution in time using the Endovascular Treatment in Ischemic Stroke (ETIS) registry.

Materials and Methods:

We analyzed the efficacy outcomes of EVT performed from January 2015 to January 2022, and modelized the temporal trends using mixed logistic regression models, further adjusted for age, intravenous thrombolysis prior to EVT, general anesthesia, occlusion site, balloon catheter use and the type of first-line EVT strategy. We assessed heterogeneity in temporal trends according to occlusion site, balloon catheter use, cardio embolic etiology, age (<80 years vs ⩾80 years) and first-line EVT strategy.

Results:

Among 6104 patients treated from 2015 to 2021, the rates of successful reperfusion (71.1%–89.6%) and of complete first pass effect (FPE) (4.6%–28.9%) increase, whereas the rates of patients with >3 EVT device passes (43.1%–17.5%) and favorable outcome (35.8%–28.9%) decrease significantly over time. A significant heterogeneity in temporal trends in successful reperfusion according to the first-line EVT strategy was found (p-het = 0.018). The temporal trend of increasing successful reperfusion rate was only significant in patients treated with contact aspiration in first-line (adjusted overall effect p = 0.010).

Conclusion:

In this 7-year-old large registry of ischemic stroke cases treated with EVT, we observed a significant increase with time in the rate of recanalization whereas there was a tendency toward a decrease in the rate of favorable outcome over the same period.

Background

The goal of endovascular treatment (EVT) for stroke due to Large Vessel Occlusion is to achieve recanalization of the occluded vessel as quickly and completely as possible. ¹ The first studies that proved the efficacy of EVT in 2015 considered a partial recanalization (TICI 2b) at the end of the procedure, whatever the number of passes,^2–6 as a technical success. Then, many mono- or multicentric studies, performed with different sample sizes and according to either an external core lab or self-adjudication grading of recanalization, reported almost complete final recanalization rates (TICI 2b/3 > 90%) at the end of procedure.^7–10 More recently, a new standard of treatment efficiency has emerged: achievement of complete recanalization in one pass (first pass effect, FPE), that is clearly associated with increased rates of good patient outcomes at 3 months. ¹¹ However, this more ambitious recanalization endpoint is only reached in less than half of the cases. ¹²

Along with this improvement in angiographic results, there has also been a refinement and increased precision in the grading of reperfusion evaluated during EVT. Thus, we moved from TIMI, TICI, mTICI to eTICI, with these reperfusion graduations providing a consistently better correlation with good patient outcomes.^13–16 Furthermore, several factors still influence recanalization rates and the number of passes necessary such as occlusion location, age, anesthetic regimen and prior intravenous thrombolysis.^8,17,18

Taken together, these elements associated with the expanding of EVT indications, have made it difficult to detect the temporal evolution of angiographic outcomes and clinical results after EVT for stroke.

Since 2015, the ETIS registry has exhaustively recorded all procedures performed in France in a network of expert centers. In this 7-year-old, nationwide registry of ischemic stroke treated with EVT, we analyzed the temporal evolution of angiographic recanalization results, clinical outcomes and the disparities in terms of subgroups.

Material and methods

Data availability statement

The data that support the findings of this study are available from the corresponding author upon reasonable request.

Study population

From January 2015 to January 2022, we collected clinical and imaging data from 26 different comprehensive stroke centers taking part in the ETIS registry (Endovascular Treatment in Ischemic Stroke). Prospectively gathered data were then retrospectively analyzed.

Patients included in our study presented with acute ischemic stroke caused by an anterior circulation occlusion proven on cerebral imaging (magnetic resonance imaging or computed tomography with angiographic sequences) and treated by EVT. Only patients harboring proximal middle cerebral artery occlusion (M1), with or without intracranial carotid occlusions (ICA), were included. However, we only considered the more proximal location. Hence, M1 with ICA are ICA, M1 without ICA are M1 occlusions.

Prior administration of intravenous thrombolysis was decided according to usual international guidelines. ¹⁹

Absence of LVO during the first run of Angio DSA as initial TICI > 2a, patients with (M2) occlusions, posterior circulation, isolated extracranial and tandem occlusions were excluded because of technical specificities that preclude reliable comparisons with other locations of occlusion. Age, baseline modified Rankin Scale (mRS), admission National Institutes of Health Stroke Scale and infarct core volume were not considered as exclusion criteria per se.

EVT was performed by neurointerventionalists in comprehensive stroke centers according to the guidelines prevailing at the time.^19,20 All endovascular procedures were performed under a dedicated anesthesiological protocol that encompassed conscious sedation or general anesthesia. First-line EVT was chosen at the operator’s discretion using either an aspiration catheter, a stent retriever or both, and a balloon guide catheter (BGC) or not.

Outcomes

The primary outcomes were successful reperfusion at the end of procedure (mTICI 2b/3), complete FPE (mTICI three in one pass), total number of passes >3 and favorable outcome defined as an mRS score of 0–2 or equal to pre-stroke Rankin score. Since the TICI grade 2c only appeared in 2017 we did not consider this grade as a relevant endpoint to analyze in our inclusion period. ¹⁴ For safety outcomes we used both the radiological classification of intracranial hemorrhage (any ICH) ²¹ and the ECASS III criteria for symptomatic intracranial hemorrhage (sICH) defined as any new intracranial hemorrhage on follow-up imaging with a clinical deterioration within the first 7 days. ²²

Statistical analysis

Categorical variables were expressed as frequencies and percentages. Quantitative variables were expressed as means (standard deviation), or medians (interquartile range) for non-normal distribution. Normality of distributions was assessed graphically and by using the Shapiro-Wilk test.

To assess the temporal trends from January 2015 to January 2022 in patient outcomes, we categorized the study period (time) into trimesters. We examined the shape of temporal trends for each outcome by using smooth curves fitted by a generalized additive model (binomial distribution with a logit link function) with a cubic smoothing spline term. Since we observed J-shaped temporal trends for mTICI ⩾ 2B at the end of EVT, FPE, favorable outcomes, and 90-day mortality, we modelized the temporal trends using mixed logistic regression models with center as random effect, and by including linear and quadratic time terms (a second-order polynomial regression model). The overall temporal effects were examined using linear contrast. For the rate of patients treated with more than three device passes, a linear temporal trend was found and we modelized the temporal trends with a mixed logistic regression including center as random effect and a linear time term only. Temporal trends were further adjusted for main patient characteristics known to impact angiographic outcomes (age, cardio embolic etiology, prior intravenous thrombolysis, general anesthesia, occlusion site, BGC use, and the type of first-line EVT strategy) or to impact favorable outcome and 90-day mortality (age, cardio embolic etiology, admission NIHSS score, admission ASPECT score, onset to groin puncture time, prior intravenous thrombolysis, and occlusion site). After adjustment on pre-specified covariates, favorable outcome, and 90-day mortality showed a linear temporal trend and were then modelized with a mixed logistic regression including center as random effect and a linear time term only.

We assessed heterogeneity in temporal trends for the rate of successful reperfusion, complete FPE and favorable outcome according to the key patient and procedural characteristics (occlusion site, balloon catheter use, cardioembolic etiology, age (<80 years vs ⩾80 years) and first-line EVT strategy) by including the corresponding interaction terms with time (and quadratic time terms for successful reperfusion and complete FPE) in the multivariable mixed logistic regression models.

Missing values in pre-specified covariates and outcomes were handled in multivariate analyses by multiple imputation using a regression switching approach (chained equations with m = 10). ²³ Imputation procedure was performed under the missing at random assumption using all baseline characteristics variables and outcomes with a predictive mean matching method for quantitative variables and multinomial or binary logistic regression models for categorical variables. Estimates obtained in the different imputed data sets were combined using Rubin’s rules. ²⁴

Statistical testing was performed at the two-tailed α level of 0.05. Data were analyzed using the SAS software package, release 9.4 (SAS Institute, Cary, NC).

Results

From January 2015 to January 2022, 6104 patients with an occlusion in M1-MCA or intracranial ICA were consecutively treated by EVT in the 26 centers participating in the prospective ETIS registry (Supplemental Table 1). The ETIS registry includes 26 centers of EVT of Stroke among the 38 centers in France. Supplemental Table 2 shows characteristics of the patient population according to calendar year and shows changes in patient or treatment characteristics over time, with patients being older, rate of wake-up strokes higher, rate of prior IVT lower, and rate of balloon guide catheter use higher.

Baseline characteristics are presented in Table 1. Briefly, mean age was 71.5 ± 14.8 years old and 35.0% (n = 2132) of patients were over 80. Seventy-eight percent (78%) of the patients were treated for M1-MCA occlusion and 22% for ICA intracranial occlusion. 52% (n = 2709) had a cardio embolic etiology and 48% had other causes of stroke. First line EVT strategy was stent-retriever alone for 9% of patients (n = 500), contact aspiration alone for 43% (n = 2432) and a combination of stent-retriever and contact aspiration for the remaining 48% (n = 2726). Regarding study outcomes, 87.3% (95% CI 86.5–88.2, n = 5167) of patients had a successful reperfusion (mTICI ⩾ 2B) at the end of the procedure and 25.6% (95% CI 24.3–16.9, n = 1116) had a complete FPE. More than three EVT device passes were required in 21.0% (95% CI 19.8–22.2, n = 930) of cases and 27.9% (95% CI 36.7–29.2, n = 1380) of patients achieved a favorable outcome at 3 months.

Table 1.

Baseline characteristics and outcomes of study population (N = 6104).

Baseline demographics and medical history	N (%) of missing data	Values
Age, years	0.3
mean ± SD		71.5 ± 14.8
>80 years		2132 (35.0)
Men	0.2	2824 (46.4)
Hypertension	3.8	3536 (60.2)
Diabetes mellitus	4.8	984 (16.9)
Dyslipidemia	5.3	1803 (31.2)
Current smoking	8.9	992 (17.8)
History of stroke or TIA	0	903 (14.8)
History of CAD	0	941 (15.4)
Pre-stroke antithrombotic medication	0	2604 (42.7)
Current stroke event
Admission Systolic BP, mmHg, mean ± SD	17.0	147.1 ± 26.6
Admission Diastolic BP, mmHg, mean ± SD	17.4	81.9 ± 17.4
Admission NIHSS score, median (IQR)	3.5	17 (12–21)
Admission ASPECTS, median (IQR)	12.2	8 (6–9)
Wake-up stroke or unknown symptom onset	2.8	2034 (34.3)
Site of occlusion
M1-MCA	0	4764 (78.0)
Intracranial ICA	0	1340 (22.0)
mRS pre-stroke 0–1	0	5367 (87.9)
Cardio-embolic etiology	15.3	2709 (52.4)
Prior IVT	0.7	2938 (48.5)
General anesthesia	1.4	1184 (19.7)
Balloon-Guide catheter use	5.2	1563 (27.0)
Procedural times. min. median (IQR)
Onset to puncture	10.2	255 (191–335)
Groin puncture to reperfusion	17.2	35 (23–56)
Onset to reperfusion	16.2	300 (235–384)
Outcomes
Successful reperfusion (mTICI ⩾ 2B)	3.1	5167 (87.3)
Complete First pass effect (mTICI = 3)	28.5	1116 (25.6)
Number of passes > 3	27.3	930 (21.0)
Favorable outcome at 3 months	19.7	1380 (27.9)
90-day mortality	19.1	1187 (24.0)
Safety outcomes
Any ICH	20.7	2138 (44.2)
sICH	20.7	430 (8.9)
PH2	23.6	254 (5.4)

ASPECTS: Alberta Stroke Program Early CT Score; BP: blood pressure; CAD: coronary artery disease; IQR: interquartile range; mTICI: modified treatment in cerebral ischemia; MCA: middle cerebral artery; NIHSS: National Institutes of Health Stroke Scale; SD: standard deviation; TIA: transient ischemic attack; IVT: intravenous thrombolysis; sICH: symptomatic intracranial hemorrhage; PH2: parenchymal hemorrhage type 2 according to the ECASS III classification.

Values are expressed as numbers (%) unless otherwise indicated.

Temporal trends in main outcomes from January 2015 to January 2022

The rate of successful recanalization was 71.1% (95% CI 64.2–77.4) in 2015 by comparison to 89.6% (95% CI 84.4–93.5) in January 2022. As shown in Table 2, the rate of successful recanalization varied significantly over time, with a non-linear temporal trend. As shown in Figure 1(a), a decelerating slope increase was observed, with a linear increase from 2015 to 2017 and a plateau effect after 2018. (Supplemental Figure 1 and Supplemental Table 2).

Table 2.

Temporal trends in primary angiographic and clinical outcomes from January 2015 to January 2022 in patients treated by EVT for M1-MCA or intracranial ICA occlusions.

Outcomes	Terms	β (95% CI)	p-Values	Adjusted β (95% CI)*	p-Values*
Successful reperfusion (mTICI ⩾ 2B) at end of procedure
	Linear	0.11 (0.06–0.16)	<0.001	0.10 (0.05–0.15)	<0.001
	Quadratic	−0.002 (−0.003 to −0.0005)	0.008	−0.002 (−0.004 to −0.0005)	0.008
	Overall effect		<0.001		<0.001
Complete first pass effect
	Linear	0.27 (0.19–0.36)	<0.001	0.26 (0.17–0.35)	<0.001
	Quadratic	−0.006 (−0.007 to −0.003)	<0.001	−0.005 (−0.007 to −0.003)	<0.001
	Overall effect		<0.001		<0.001
Total number of passes > 3	Linear	−0.07 (−0.08 to −0.05)	<0.001	−0.07 (−0.08 to −0.05)	<0.001
Favorable outcome*	Linear	−0.06 (−0.11 to −0.01)	0.017	−0.01 (−0.03 to −0.001)	0.033
	Quadratic	0.002 (0.00005–0.003)	0.043
	Overall effect		0.021
90 days mortality**	Linear	0.05 (−0.009–0.10)	0.10	0.002 (−0.01–0.02)	0.75
	Quadratic	−0.001 (−0.003–0.0002)	0.094
	Overall effect		0.24

β indicates the regression coefficient associated with the treatment period (expressed per trimester increase) calculated from mixed logistic regression models including center as random effect.

^*Adjusted on age, cardioembolic etiology, prior intravenous thrombolysis, general anesthesia, occlusion site, use of balloon-guide catheter and first-line EVT strategy for final successful reperfusion and number of device passes > 3, and on age, cardioembolic etiology, admission aspect score, admission NIHSS, onset to groin puncture time, prior intravenous thrombolysis and occlusion site for favorable outcome, and 90-day mortality (calculated after handling missing values by multiple imputations).

^**After adjustment on admission ASPECT score, relation with time was linear.

Figure 1.

Predicted probabilities of outcomes over time from January 2015 to January 2022. Dashed line represent 95% CI.

The curves figure the predicted probabilities of TICI ⩾ 2b/3 at the end of the procedure (1-a), of complete First Pass Effect (FPE) (1-b), of use more than three passes (1-c), favorable outcome (1-d), and 90 days mortality (1-e) using mixed logistic regression models with center as random effect and adjusted for main patient characteristics known to impact angiographic outcomes (age, cardio embolic etiology, prior intravenous thrombolysis, general anesthesia, occlusion site, BGC use, and the type of first-line EVT strategy) or to impact favorable outcome and 90-day mortality (age, cardio embolic etiology, admission NIHSS score, admission ASPECT score, onset to groin puncture time, prior intravenous thrombolysis, and occlusion site).

In the same way, the rate of complete FPE significantly increased over time, with 4.6% (1.0–12.9) in 2015 by comparison to 28.9% (22.3–36.3) in January 2022. As shown in Figure 1(b), a decelerating slope increase was found, with a linear increase from 2015 to 2020 and a plateau after January 2020.

The percentage of patients having undergone >3 EVT device passes decreased over the years from 43.1% in 2015 to 17.5% in 2021, with a significant linear time effect (regression coefficient = −0.06; 95% CI −0.08 to −0.05, p < 0.001; Table 2 and Figure 1). Concerning the favorable outcome, after adjustment on pre-specified covariates, we found a significant decrease in rate over time (regression coefficient = −0.01; 95% CI −0.03 to −0.001, p = 0.033; Table 2 and Figure 1). No change was found for 90-day mortality over time in univariate and multivariate analyses (Table 2 and Figure 1).

Similar results were found in sensitivity analyses performed in the population with pre-stroke MRS 0–1 (sensitivity analyses 1, Supplemental Table 6) and in the population included in a center which recruited patients since 2015 (sensitivity analyses 2, Supplemental Table 7), except that the rate of favorable outcome did not increase over time in sensitivity analyses 1 (p = 0.12).

Temporal trends in successful reperfusion, complete FPE and favorable outcome according to key subgroups

Temporal trends from January 2015 to January 2022 in successful reperfusion at the end of procedure, complete FPE and in favorable outcomes according to key subgroups are presented in Supplemental Tables 3–5. A significant heterogeneity of temporal trends in successful reperfusion according to first-line EVT strategy was found (p-het = 0.018). The increasing temporal trend observed in successful reperfusion rates was only significant in patients treated with contact aspiration as first-line (adjusted overall effect p = 0.010) (Supplemental Table 3 and Figure 2). No heterogeneity was found according to occlusion site, use or not of BGC, cardioembolic etiology and age subgroups (p for heterogeneity all >0.26, Supplemental Table 3). Regarding the complete FPE and favorable outcome, we found no evidence of temporal trends whatever the subgroups (Supplemental Tables 4 and 5).

Figure 2.

Predicted probabilities of successful final reperfusion (mTICI ⩾ 2B) over time from January 2015 to January 2022 according to the first-line EVT strategy.

The curves figure the predicted probabilities of TICI ⩾ 2b/3 at the end of the procedure using mixed logistic regression models with center as random effect and adjusted for main patient characteristics known to impact angiographic outcomes (age, cardioemboliccardio embolic etiology, prior intravenous thrombolysis, general anesthesia, occlusion site, and BGC use).

Discussion

In this 7-year-old large multicenter registry of ischemic stroke patients treated with EVT, we analyzed the temporal evolution of angiographic recanalization results. We found a significant increase over time in the rate of successful recanalization and complete FPE as well as a significant decrease in the rate of >3 device passes. Furthermore, we highlight disparities of temporal trends only in successful reperfusion rates at the end of the procedure regarding the first-line strategy chosen. We found no such heterogeneities comparing different ages, location of occlusion, use of BGC, or stroke etiology for the rate of successful reperfusion rates at the end of the procedure, the FPE or the rate of >3 device passes.

Considering the rate of mTICI2b at the end of the procedure, we observed in our study a decelerating slope increase, with a linear increase up to 2017 and a plateau effect after 2018. Indeed, a significant subset of clots still remain recalcitrant to current strategies that is, typically fibrin rich or calcified thrombi.^25–27 This failure is because, during retrieval, devices remain compressed by the organized clot and slide between it and the vessel wall without any removal effect. Novel stent retrievers designed to improve the incorporation and removal of organized thrombi appear to be promising strategies to improve FPE, number of passes, and final TICI.^28,29

The rate of complete FPE significantly increased over time until January 2020 and the rate of patients requiring >3 EVT device passes decreased with a significant linear time effect until the last period considered in the study (January 2022). These observations point to the relevance of more ambitious endpoints than the final (at the end of the procedure) « substantial perfusion with distal branch filling of ⩾50% of territory visualized » (TICI 2b) previously considered as technically successful EVT. ³⁰ Indeed, although since 2020 the rate of complete perfusion with normal filling of all distal branches in one pass (true FPE TICI 3) stagnates, there may still be room for improvement to avoid exceeding three passes. Indeed, previous studies have suggested that occurrence of hemorrhagic transformation increases when the degree of revascularization decreases and when the number of device passes increases beyond 3.^17,31

Our study, based on a real-life registry, is the first to investigate longitudinally and over several years the evolution of angiographic and clinical results after EVT in such a large population. Recently, an analysis of the MR CLEAN registry found better recanalization rates since July 2016 compared to the slot between 2014 and June 2016. ³² However, in this study, there were no continuous or longitudinal assessments of the temporal evolution of angiographic recanalization results. Furthermore, we have been able to adjust our longitudinal analysis on different potential confounding factors that may have influenced the recanalization rates, such as occlusion location, age, anesthetic regimen, and prior intravenous thrombolysis. Hence, operators’ learning curves and improvement of medical devices are reliably and clearly highlighted as independent explanations for observed temporal trends in outcomes after EVT in this population. This is the main finding of our study because such an analysis has never been performed in this way.

Of note, at the individual level, the operator’s learning curve has also been emphasized. In the ETIS registry and two additional high-volume stroke centers, authors recently found that among 36 operators having performed a median of 97.5 EVT procedures, increasing experience in EVT is associated with significantly shorter procedural duration and better recanalization rates during the operator’s first 100 EVT procedures. ³³ However, this latter study did not consider the potential evolution of « macroscopic » results of EVT over the study period as we have highlighted in this study.

Regarding the favorable outcome, one can assume that the improvement in recanalization rates would translate into better clinical outcomes. Despite this assumption, we observed a tendency toward a decrease in the rate of favorable outcome from January 2015 to January 2017 and thereafter no significant change over time. We attempted to adjust our analysis for age, admission NIHSS score, onset to groin puncture time, prior intravenous thrombolysis and occlusion site. However, it is important to integrate the expanding indications since 2015, with EVT progressively being considered for increasingly older patients, more extensive ischemic cores and later time-windows.^34–36 The evidence of a preserved therapeutic benefit in these subgroups, usually associated with an a priori poorer prognosis, is likely to have influenced the clinical outcome over the study period. Furthermore, IVT rates have decreased markedly over the years in the observed population of EVT treated patients. Contraindications to IVT, apart from being a marker for the proportion of patients arriving >4.5 h, is also a marker of general comorbidity, which supports the fact that the population has changed (see Supplemental Table 2).

It is noteworthy that our timeline of inclusion covered the COVID epidemic in France that induced a significant decrease in the number of patients treated with EVT during the first stages and alarming indicators of lengthened care delays. ³⁷ However, there was no difference in the rate of successful reperfusion (82.3% vs 82%; p = 0.932) or in-hospital mortality (12.9% vs 17.3%; p = 0.124) before compared to during the epidemic period. The evolution of EVT devices, including the use of BGC and more complex SR designs, certainly led to improved recanalization rates, but it appears that it was principally the use of larger diameter aspiration catheters that drove the improvement of recanalization results during the study period. ³⁸

Based on a description of EVT outcomes in a large multicenter national registry, our study provides reliable and detailed endpoints for EVT result assessments over time. Indeed, efforts should focus on the rate of FPE for which there is still room for improvement. To a larger extent, our work reveals another aspect of the temporal trends for results of Endovascular treatment of large cerebral vessel occlusion. The use of SR alone dramatically decreased over time due to the seducing good results when SR is associated with CA (i.e. CAPTIVE, ARTS, SOLUMBRA, or SAVE).^39–42 However, we may question whether, in the absence of this association, the strategy of the simple SR alone would still have benefited from the improvement of complex stent retriever designs along the period of our study. The curves of recanalization improvements for each different device are censored due to the increasing utilization of new devices. It appears that technical innovation progresses faster than the interventionists’ learning curves with a given device (e.g. SR and CA). It is noteworthy that a recent Chinese study found, among 1069 LVO patients treated by SR as first-line in EVT and assessed by an external core-lab, rates of successful recanalization after all procedures of 91.2%, complete recanalization after all procedures of 70.2%, and first-pass complete recanalization of 34.8%. The aspiration catheter was not widely used throughout China between 2017 and 2019; interventionists preferred to use the SR alone for the first-line EVT procedure during this study period. ⁴³

Limitations of our study include the lack of core lab evaluation for TICI grade scaling after EVT. Moreover, precise information concerning the CA and SR devices (manufacturer, length, diameters) were not included in our analysis. Finally, there was neither imaging data nor thrombus histology available to demonstrate the previously suggested relationship of recanalization results with thrombus type.^44,45 In our study, we focused on the temporal evolution of angiographic recanalization results. Besides, it would also be very interesting to use the same longitudinal methodology applied to the intra-hospital delay with milestones at the arrival in CSC, imaging, entrance to the angiosuite, and groin puncture. Furthermore, data from years 2015 to 2021 are complete but for 2022, only January data were used. Last, our analysis focused only on the first-line strategy of EVT. We did not account for second line strategies after one or more passes.

Conclusion

In this 7-year-old large registry of ischemic stroke patients treated with EVT, we analyzed the temporal evolution of angiographic outcomes and found a significant decrease over time in the rate of >3 device passes as well as a significant increase in complete FPE and in final successful reperfusion. The improvement of CA devices appears to have played an important part in this latter temporal trend.

Appendix.

Centres	Intervenants
001-Foch	Bertrand LAPERGUE
001-Foch	Adrien WANG
001-Foch	Arturo CONSOLI
001-Foch	Oguzhan COSKUN
001-Foch	Federico DI MARIA
001-Foch	Silvia PIZZUTO
001-Foch	Alessandro SGRECCIA
001-Foch	Charline BENOIT
001-Foch	Lucas GORZA
001-Foch	David WEISENBURGER-LILE
001-Foch	Waliyde JABEUR
001-Foch	TCHIKVILADZE Maia
001-Foch	Serge EVRARD
001-Foch	Georges RODESCH
002-FOR	Raphaël BLANC
002-FOR	Jean-Philippe DESILLES
002-FOR	Michel PIOTIN
002-FOR	Stanislas SMAJDA
002-FOR	Simon ESCALARD
002-FOR	Benjamin MAIER
002-FOR	Hocine REDJEM
002-FOR	Mikael MAZHIGI
002-FOR	François DELVOYE
002-FOR	Amira AL RAAISI
002-FOR	William BOISSEAU
003-Lyon	Omer EKER
003-Lyon	Tae-Hee CHO
003-Lyon	Laurent DEREX
003-Lyon	Julia FONTAINE
003-Lyon	Laura MECHTOUFF
003-Lyon	Norbert NIGHOGHOSSIAN
003-Lyon	Elodie ONG
003-Lyon	Lucie RASCLE
003-Lyon	Roberto RIVA
003-Lyon	Françis TURJMAN
003-Lyon	Morgane LAUBACHER
003-Lyon	Mehdi BEYRAGUED
003-Lyon	Yves BERTHEZENE
003-Lyon	Marc HERMIER
003-Lyon	Ameli ROXANNA
003-Lyon	Alexandre BANI-SADR
003-Lyon	Andrea FILIP
003-Lyon	Matteo CAPPUCCI
004-Nantes	Romain BOURCIER
004-Nantes	Benjamin DAUMAS DUPORT
004-Nantes	Pierre Louis ALEXANDRE
004-Nantes	Cédric LENOBLE
004-Nantes	Hubert DESAL
004-Nantes	Solene DE GAALON
004-Nantes	Benoît GUILLON
004-Nantes	Cécile PRETERRE
004-Nantes	Guillaume TESSIER
004-Nantes	Arthur LIONNET
005-Nancy	Benjamin GORY
005-Nancy	Lisa HUMBERTJEAN-SELTON
005-Nancy	René ANXIONNAT
005-Nancy	Anne-Laure DERELLE
005-Nancy	Liang LIAO
005-Nancy	Emmanuelle SCHMITT
005-Nancy	Sophie PLANEL
005-Nancy	Sébastien RICHARD
005-Nancy	Gioia MIONE
005-Nancy	Jean-Christophe LACOUR
005-Nancy	Marian DOUARINOU
005-Nancy	Gabriela HOSSU
005-Nancy	Bailiang CHEN
005-Nancy	Gérard AUDIBERT
005-Nancy	Agnès MASSON
005-Nancy	Lionel ALB
005-Nancy	Marine BEAUMONT
005-Nancy	Adriana TABARNA
005-Nancy	Marcela VOICU
005-Nancy	Grégoire BARTHEL
005-Nancy	Iona PODAR
005-Nancy	Madalina BREZEANU
005-Nancy	Marie REITTER
005-Nancy	François ZHU
006-Bordeaux	Gaultier MARNAT
006-Bordeaux	Jean-Sébastien LIEGEY
006-Bordeaux	Pierre BRIAU
006-Bordeaux	Lisa PAPILLON
006-Bordeaux	Igor SIBON
006-Bordeaux	Xavier BARREAU
006-Bordeaux	Jean PAPAXANTHOS
006-Bordeaux	Jérome BERGE
006-Bordeaux	Sabrina DEBRUXELLES
006-Bordeaux	Stephane OLINDO
006-Bordeaux	Mathilde POLI
006-Bordeaux	Pauline RENOU
006-Bordeaux	Sharmila SAGNIER
006-Bordeaux	Thomas TOURDIAS
006-Bordeaux	Thomas COURRET
006-Bordeaux	Ludovic LUCAS
007-Montpellier	Cyril DARGAZANLI
007-Montpellier	Vincent COSTALAT
007-Montpellier	Isabelle MOURAND
007-Montpellier	Caroline ARQUIZAN
007-Montpellier	Lucas CORTI
007-Montpellier	Adrien TER SCHIPHORST
007-Montpellier	CAGNAZZO Federico
008-Kremlin Bicêtre	Laurent SPELLE
008-Kremlin Bicêtre	Jildaz CAROFF
008-Kremlin Bicêtre	Christian DENIER
008-Kremlin Bicêtre	Vanessa CHALUMEAU
008-Kremlin Bicêtre	Cristian MIHALEA
008-Kremlin Bicêtre	Nicolas LEGRIS
008-Kremlin Bicêtre	Augustin OZANNE
008-Kremlin Bicêtre	Leon IKKA
008-Kremlin Bicêtre	Olivier CHASSIN
008-Kremlin Bicêtre	Sophie GALLAS
008-Kremlin Bicêtre	Laura VENDITTI
008-Kremlin Bicêtre	Mariana SAROV
008-Kremlin Bicêtre	Jonathan CORTESE
009-Rennes	Jean-Christophe FERRE
009-Rennes	Stephane VANNIER
009-Rennes	Thomas RONZIERE
009-Rennes	Maria Veronica LASSALLE
009-Rennes	Jean-Yves GAUVRIT
009-Rennes	Clément TRACOL
009-Rennes	Abdelghani Fakhreddine BOUSTIA
009-Rennes	Cécile MALRAIN
009-Rennes	Edouard BEAUFRETON
009-Rennes	Thibault LAPOTRE
009-Rennes	Quentin ALIAS
009-Rennes	Julien HISSIER
009-Rennes	Maud GUILLEN
010-Amiens	Cyril CHIVOT
010-Amiens	Audrey COURSELLE
010-Amiens	Elisa OUIN
010-Amiens	Chantal LAMY
010-Amiens	Kevin DELAFORGE
010-Amiens	Manuel FERNANDEZ
010-Amiens	Jérémie VIAL
010-Amiens	Quentin LAFARTE
010-Amiens	Xavier DESDOIT
011-Brest	Serge TIMSIT
011-Brest	Aurore JOURDAIN
011-Brest	Jean-Christophe GENTRIC
011-Brest	Julien OGNARD
011-Brest	Irina VIAKHIREVA
011-Brest	Jordan CORIS
011-Brest	Sabine PRUD’HON
011-Brest	François-Mathias MERRIEN
011-Brest	Denis MARECHAL
011-Brest	Marie BRUGUET
011-Brest	Pierre Yves ROUSSEAU
011-Brest	Philippe GOAS
012-Caen	Marion BOULANGER
012-Caen	Emmanuel TOUZE
012-Caen	Denis VIVIEN
012-Caen	Charlotte BARBIER
012-Caen	Romain SCHNECKENBURGER
012-Caen	Fabrizio SALARIS
012-Caen	Julien COGEZ
012-Caen	Sophie GUETTIER
012-Caen	Estelle LA PORTE
012-Caen	Jean BOUCHART
013-Limoges	Charbel MOUNAYER
013-Limoges	Aymeric ROUCHAUD
013-Limoges	Suzana SALEME
013-Limoges	Géraud FORESTIER
014-Pitié-Salpêtrière	Frédéric CLARENCON
014-Pitié-Salpêtrière	Charlotte ROSSO
014-Pitié-Salpêtrière	Sara LEDER
014-Pitié-Salpêtrière	Flore BARONNET
014-Pitié-Salpêtrière	Sophie CROZIER
014-Pitié-Salpêtrière	Anne LEGER
014-Pitié-Salpêtrière	Kevin PREMAT
014-Pitié-Salpêtrière	Shotar EIMAD
014-Pitié-Salpêtrière	Stéphanie LENCK
014-Pitié-Salpêtrière	Nader SOUROUR
014-Pitié-Salpêtrière	Laure BOTTIN
014-Pitié-Salpêtrière	Sam GHAZANFARI
014-Pitié-Salpêtrière	Marion YGER
014-Pitié-Salpêtrière	Sonia ALAMOWITCH
014-Pitié-Salpêtrière	Stephen DELORME
014-Pitié-Salpêtrière	Aymeric WITTWER
014-Pitié-Salpêtrière	Christine VASSILEV
016-Ste Anne	Olivier NAGGARA
016-Ste Anne	Guillaume TURC
016-Ste Anne	Wagih BEN HASSEN
016-Ste Anne	Basile KERLEROUX
016-Ste Anne	Denis TRYSTRAM
016-Ste Anne	Christine RODRIGUEZ-REGENT
017-Rouen	Ozlem OZKUL-WERMESTER
017-Rouen	Chrysanthi PAPAGIANNAKI
017-Rouen	Evelyne MASSARDIER
017-Rouen	Aude TRIQUENOT
017-Rouen	Margaux LEFEBVRE
017-Rouen	Julien BUREL
018-Toulouse	Alain VIGUIER
018-Toulouse	Christophe COGNARD
018-Toulouse	Anne Christine JANUEL
018-Toulouse	Jean-François ALBUCHER
018-Toulouse	Lionel CALVIERE
018-Toulouse	Jean-Marc OLIVOT
018-Toulouse	Jean DARCOURT
018-Toulouse	Nicolas RAPOSO
018-Toulouse	Fabrice BONNEVILLE
018-Toulouse	Guillaume BELLANGER
018-Toulouse	Louis FONTAINE
018-Toulouse	Philippe TALL
019-Bayonne	Frédéric BOURDAIN
019-Bayonne	Patricia BERNADY
019-Bayonne	Guillaume BALLAN
019-Bayonne	Stephanie BANNIER
019-Bayonne	Emmanuel ELLIE
019-Bayonne	Olivier FLABEAU
019-Bayonne	Julia POTENZA
019-Bayonne	Antoine SOULAGES
019-Bayonne	Laurent LAGOARDE-SEGOT
019-Bayonne	Hélène CAILLIEZ
019-Bayonne	Louis VEUNAC
019-Bayonne	David HIGUE
020-Vannes	Anthony LEBRAS
020-Vannes	Sarah EVAIN
020-Vannes	Benoit PEGAT
020-Vannes	Arnaud LE GUEN
020-Vannes	François CHEDEVILLE
020-Vannes	Jérémy JOUAN
021-Pau	Stéphanie DEMASLES
021-Pau	Johann Sebastian RICHTER
021-Pau	Bruno Thierry BARROSO
021-Pau	Camille DAHAN
021-Pau	Alexis GONNET
021-Pau	Régis HUBRECHT
021-Pau	Zoé LEPINE
021-Pau	Hélène CASTAGNET
021-Pau	Raluca MARASESCU
022-Grenoble	Olivier HECK
022-Grenoble	Pauline CUISENIER
022-Grenoble	Olivier DETANTE
022-Grenoble	Isabelle FAVRE WIKI
022-Grenoble	Clémentine BONAZ
022-Grenoble	GARAMBOIS Katia
022-Grenoble	Loic LEGRIS
022-Grenoble	Adrian KASTLER
022-Grenoble	Kamel BOUBAGRA
022-Grenoble	Corentin BERTHET
022-Grenoble	Stephane Charara
024-Strasbourg	Valérie WOLFF
024-Strasbourg	Raoul POP
024-Strasbourg	Véronique QUENARDELLE
024-Strasbourg	Valérie LAUER
024-Strasbourg	Raoul POP
024-Strasbourg	Irène PIERRE-PAUL
024-Strasbourg	Roxana GHEOCA
024-Strasbourg	Malwina TRZECIAK
026-Reims	Solène MOULIN
026-Reims	HUA Vi Tuan
026-Reims	Paolo PAGANO
026-Reims	Alexandre DOUCET
026-Reims	Christophe GELMINI
026-Reims	Pierre-François MANCEAU
026-Reims	Laurentiu PAIUSAN
026-Reims	Isabelle SERRE
026-Reims	Sébastien SOIZE
026-Reims	Thi Ngoc Phuong NGUYEN
026-Reims	Maher SAHNOUN
026-Reims	Nathalie CAUCHETEUX
028-Clermont-Ferrand	Anna FERRIER
028-Clermont-Ferrand	Abderrahim ZERROUG
028-Clermont-Ferrand	Ricardo MORENO
028-Clermont-Ferrand	Emmanuel CHABERT
028-Clermont-Ferrand	Elie LTEIF
028-Clermont-Ferrand	Pauline PARIS
028-Clermont-Ferrand	Nathalie BOURGOIS
028-Clermont-Ferrand	Marie RAQUIN
029-Angers	Anne PASCO-PAPON
029-Angers	Jean Baptiste GIROT
029-Angers	Alderic LECLUSE
029-Angers	Sophie GODARD
029-Angers	Vincent L’ALLINEC
030-Tours	Kevin JANOT
030-Tours	Richard BIBI
030-Tours	Marie GAUDRON
030-Tours	Arnaud BRETONNIERE
030-Tours	Mariam ANNAN
030-Tours	Héloïse IFERGAN
030-Tours	Grégoire BOULOUIS
030-Tours	Marco PASI
030-Tours	Séverine DEBIAIS
030-Tours	Elisabeth MOLINIER
032-Bar le Duc	Anthony WIETRICH
032-Bar le Duc	Valérie RUCHE
032-Bar le Duc	Karine LAVANDIER
033-Dijon	Yannick BEJOT
033-Dijon	Brivale LEMOGNE
033-Dijon	Fédéric RICOLFI
033-Dijon	Laura BAPTISTE
033-Dijon	Pierre THOUANT
033-Dijon	Gaulthier DULOQUIN
033-Dijon	Pierre olivier COMBY
034-Besançon	Guillaume CHARBONNIER
034-Besançon	Louise BONNET
034-Besançon	Nicolas RAYBAUD
034-Besançon	Benjamin BOUAMRA
034-Besançon	Thierry MOULIN
034-Besançon	Alessandra BIONDI