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Abstract
Background Emerging data suggest that mechanical thrombectomy (MT) might also be safe and efficient for medium and distal occlusions. This study aims to compare average treatment effects on functional outcome of different degrees of recanalization after MT in patients with M2 occlusion and M1 occlusion.
Methods All patients enrolled in the German Stroke Registry (GSR) between June 2015 and December 2021 were analyzed. Inclusion criteria were stroke with primary M1 occlusion or M2 occlusion, and availability of relevant clinical data. 4259 patients were included, thereof 1353 with M2 occlusion and 2906 with M1 occlusion. Treatment effects were analyzed using double-robust inverse-probability-weighted regression-adjustment (IPWRA) estimators to control for confounding covariates. Binarized endpoint metrics were defined as good outcome with modified Rankin Scale (mRS) ≤2 at 90 days, and linearized endpoint metrics were defined as mRS shift pre-stroke to 90 days. Effects were evaluated for near complete recanalization (Thrombolysis In Cerebral Infarction scale (TICI) 2b) and complete recanalization (TICI 3).
Results Treatment effect estimation for TICI ≥2b versus TICI <2b in M2 occlusions showed an increase in the probability of a good outcome from 27% to 47% with a number-needed-to-treat (NNT) of 5. For M1 occlusions the probability of a good outcome increased from 16% to 38% with NNT 4.5. TICI 3 versus TICI 2b increased the probability of a good outcome by 7 percentage points in M1 occlusions; for M2 occlusions the beneficial effect was not significant.
Conclusions Results suggest that successful recanalization with TICI ≥2b versus TICI <2b after MT in M2 occlusions provides significant patient benefit with treatment effects comparable to M1 occlusions. The probability of functional independence increased by 20 percentage points (NNT 5) and stroke-related mRS increase was reduced by 0.9 mRS points. In contrast to M1 occlusions, complete recanalization TICI 3 versus TICI 2b had lower additional beneficial effect.
- stroke
- thrombectomy
- intervention
Data availability statement
Data may be obtained from a third party (GSR-ET registry) and are not publicly available. The data that support the findings of this study are available from the GSR-ET registry. Restrictions apply to the availability of these data.
This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/.
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WHAT IS ALREADY KNOWN ON THIS TOPIC
Emerging data suggest that mechanical thrombectomy (MT) might also be safe and efficient for medium and distal occlusions. However, treatment effects of successful recanalization have not been assessed in detail and effects of >50% reperfusion versus complete reperfusion were not evaluated. Little is known of the effects of MT in comparison to large vessel occlusions.
WHAT THIS STUDY ADDS
In patients with M2 occlusions successful recanalization (TICI ≥2b vs TICI <2b) increases the probability of good long-term functional outcome from 27% to 47% with number needed to treat (NNT) 5 compared with an increase from 16% to 38% with NNT 4.5 in patients with M1 occlusions. Stroke-related neurological impairment in terms of pre-stroke to 90-day modified Rankin Scale (mRS) increase was reduced by 0.9 mRS points in patients with TICI <2b for M2 occlusions and by 1.1 mRS points in patients with M1 occlusions. In contrast to M1 occlusions, complete recanalization with TICI 3 versus TICI 2b had lower additional beneficial effect on functional outcome in M2 occlusions.
HOW THIS STUDY MIGHT AFFECT RESEARCH, PRACTICE OR POLICY
Results of our study reflect large scale clinical experience from >4200 patients undergoing MT. Besides the findings from currently enrolling randomized controlled trials (DISTAL, ESCAPE-MEVO and FRONTIER-AP), our analysis confirming the significant beneficial effect of MT in M2 occlusions might contribute to establishing guidelines for thrombectomy in medium and distal occlusions.
Introduction
Treatment effects of successful recanalization after mechanical thrombectomy (MT) have been evaluated in randomized controlled trials (RCTs) for acute ischemic strokes with large vessel occlusion. Large vessel occlusions are defined as occlusions in the intracranial internal carotid artery (ICA) and the M1 segment of the middle cerebral artery (MCA).1 However, 24% to 40% of acute ischemic strokes are caused by medium and distal occlusions.2 Emerging data suggest that MT might also be safe and effective for medium and distal occlusions.3–8 Furthermore, MT has been recently emphasized by an international consensus as an encouraging option for medium and distal occlusions2 and is now increasingly performed for medium and distal occlusion strokes.9 A recent meta-analysis of RCTs on MT that also enrolled patients with M2 occlusions confirmed improved clinical outcome for patients receiving MT (n=195) versus best medical management (n=322).8 However, recanalization success and respective treatment effects were not considered in the analysis. Another recent publication suggests that MT in M2 occlusions might be safe and efficient, although treatment effects of successful recanalization were not reported.7
In this study based on large scale clinical data we estimate average treatment effects of successful recanalization after MT in M2 occlusions and compare results with corresponding treatment effects in patients with M1 occlusions. Double robust inverse-probability-weighted regression adjustment (IPWRA) estimators are used to control for confounding covariates. Conventionally, the procedural success of MT has been defined by a final Thrombolysis In Cerebral Infarction (TICI) score of better or equal to TICI 2b.10 However, several studies have reported improved clinical outcome in patients with complete recanalization (TICI 3) versus those with a final score of TICI 2b.10–15 We therefore evaluated different degrees of recanalization and compared the average treatment effects of complete recanalization TICI 3 with TICI 2b on long-term functional outcome.
We hypothesized that successful recanalization after MT in M2 occlusions has a significant effect on long-term functional outcome comparable to effects observed in M1 occlusions.
Methods
This study was approved by the ethics committee of the chamber of physicians at Ludwig-Maximillians University LMU, Munich (689-15) as the leading ethics committee, in accordance with the Declaration of Helsinki.16 Approval by local ethics committees or institutional review boards has been obtained for all participating sites according to local regulations. The analysis was conducted in accordance with the Transparent reporting of a multivariable prediction model for individual prognosis or diagnosis (TRIPOD) guidelines.17
Patients
All patients with anterior circulation stroke prospectively enrolled in the German Stroke Registry-Endovascular Treatment (GSR-ET) between May 2015 and December 2021 were analyzed. GSR-ET is an ongoing, open label, prospective, multicenter registry of 25 sites in Germany collecting consecutive patients undergoing MT (NCT03356392). A detailed description of the GSR-ET study design and the major findings have been published recently.18 19 The main inclusion criteria of GSR-ET are diagnosis of acute ischemic stroke due to large vessel occlusion, initiation of an endovascular procedure for treatment, and age ≥18 years, according to national guidelines. There are no exclusion criteria. For this analysis, all patients with either primary M1 (proximal or distal) or primary M2 occlusion, availability of neurological status at admission and 90 days, and recanalization status were included. The corresponding author has access to the registry data acquired in the above-mentioned enrollment period.
Clinical data
All clinical parameters including modified Rankin Scale (mRS), vessel occlusion status and location are site reported parameters.18 19 For MCA occlusions, the GSR-ET registry differentiates proximal M1, distal M1 and M2 occlusions. Differentiation of MCA segments is conducted by the treating physicians based on clinical experience. Reperfusion success is assessed using the consensus mTICI scoring system.20 TICI scores are assessed based on the initial occlusion location and the reperfusion success within the downstream territory of the initially occluded vessel/branch.
Statistics
Standard descriptive statistics were used for all study endpoints. Univariable distribution of metric variables was described with mean and IQR and categorical variables with absolute and relative frequencies. Accounting for large sample size and comparably low ordinal resolutions of mRS, Alberta Stroke Program early CT Score (ASPECTS) and National Institutes of Health Stroke Scale (NIHSS), means were used for sub-group comparisons. The average treatment effect of MT was analyzed using: (1) established binarized endpoint metrics with good outcome defined as mRS ≤2 at day 90 and excellent outcome defined as mRS ≤1 at day 90; and (2) linearized endpoint metrics defined as the mRS increase from pre-stroke status to 90 days. Treatment effects were reported as absolute increase in probability for good or excellent outcome/absolute risk reduction (ARR) in percentage points (pp) with number needed to treat (NTT) defined as 1/ARR and as shift in mRS points. Recanalization success was defined at three levels according to established conventions: unsuccessful recanalization with TICI <2b, >50% reperfusion with TICI 2b, and complete reperfusion with TICI 3. Average treatment effects for M1 and M2 occlusions were evaluated using double robust IPWRA estimators for multivalued treatments with logit regression for binarized outcome and Poisson regression for mRS increase. IPWRA estimators control for confounding covariates and allow treatment effect estimations based on observational data. IPWRA uses probability weights to obtain outcome-regression parameters that account for the missing data problem (each subject is observed in only one of the potential outcomes). The adjusted outcome-regression parameters are used to compute averages of treatment-level predicted outcomes. The contrasts of these averages provide estimates of the treatment effects. IPWRA estimators use a model to predict treatment status, and another model to predict outcomes (double-robust property). Control variables for IPWRA treatment effect estimation were selected by applying Akaike information criterion (AIC)-based procedures for the outcome model using (ordinal) logistic regression analysis (binarized functional outcome and mRS increase) and for the treatment model using ordinal logistic regression analysis with recanalization success (TICI <2b, TICI 2b, and TICI 3) as dependent variable. The following control variables were selected for the outcome model: age, sex, pre-stroke mRS, NIHSS at admission, comorbidity diabetes (yes/no), comorbidity hypertension (yes/no), ASPECTS at admission, intravenous thrombolysis (yes/no), number of passes, and adverse events during treatment—clot migration or embolization and intracerebral hemorrhage (ICH). For recanalization success (treatment model) the following control variables were selected: sex, pre-stroke mRS, NIHSS at admission, comorbidity diabetes (yes/no), comorbidity dyslipidemia (yes/no), comorbidity atrial fibrillation (yes/no), ASPECTS at admission, intravenous thrombolysis (yes/no), number of passes, and adverse events during treatment—dissection or perforation, clot migration or embolization and ICH. Statistical analyses were conducted using R version 4.1.3 and Stata/MP 17.0. Statistical significance level was set to P<0.05.
Results
A total of 4259 patients fulfilled the inclusion criteria, 2906 patients with M1 occlusion and 1353 with M2 occlusion (online supplemental figure 1). Demographics for the patient collective stratified for occlusion site and recanalization success are shown in table 1 and table 2.
Supplemental material
Study cohort clinical characteristics
Subgroup analysis by recanalization success.
Comparison of cohorts with M1 and M2 occlusions
Significant differences between subgroups with M1 and M2 occlusions were observed for sex female (56% vs 50%, P<0.001), NIHSS at admission (14.6 vs 10.8, P<0.001), comorbidity dyslipidemia (40% vs 47%, P<0.001), ASPECTS (8.3 vs 8.8, P<0.001), final TICI (2b: 32% vs 34%; 3: 56% vs 50%; P<0.001), 90-day mRS (3.5 vs 3.1, P<0.001), percentage of good outcome (36% vs 44%, P<0.001), percentage of excellent outcome (25% vs 30%, P<0.001) and mean mRS increase pre-stroke to 90 days (2.7 vs 2.3, P<0.001).
Comparison of cohorts with TICI <2b, TICI 2b, and TICI 3
In the M1 occlusion cohort, patients with TICI 2b in comparison to TICI <2b had a lower mean pre-stroke mRS (0.8 vs 1.0, P=0.004), a higher rate of intravenous thrombolysis (52% vs 38%, P<0.001), a lower mean number of passes (2.3 vs 3.2, P<0.001), lower rates of dissections or perforations (2% vs 7%, P<0.001), a lower mean 90-day mRS (3.6 vs 4.8, P<0.001), a higher rate of good outcome (32% vs 10%, P<0.001), a higher rate of excellent outcome (22% vs 6%, P<0.001), and a lower mean mRS increase pre-stroke to 90 days (3.8 vs 2.9, P<0.001). Patients with M1 occlusion and TICI 3 in comparison to TICI 2b were older (74.3 vs 73.1, P=0.034), had a higher rate of dyslipidemia (43% vs 38%, P=0.005), had a higher mean ASPECTS (8.5 vs 8.1, P<0.001), a lower mean number of passes (1.7 vs 2.3, P<0.001), a lower rate of clot migration or embolization (1% vs 4%, P<0.001), a lower mean 90-day mRS (3.1 vs 3.6, P<0.001), a higher rate of good outcome (44% vs 32%, P<0.001) and excellent outcome (30% vs 22%, P<0.001), and a lower mean mRS shift pre-stroke to 90 days (2.4 vs 2.9, P<0.001) (table 2).
In the M2 cohort, patients with TICI 2b in comparison to TICI <2b were younger (72.4 vs 75.3 years, P=0.005), had a lower mean pre-stroke mRS (0.6 vs 1.1, P<0.001), a lower NIHSS at admission (10.9 vs 11.9, P=0.042), a lower number of passes (2.1 vs 2.4, P=0.04), and a lower rate of dissections or perforations (3% vs 8%, P=0.015). TICI 2b was associated with a lower mean 90-day mRS (2.9 vs 4.1, P<0.001), a higher percentage of good outcome (48% vs 20%, P<0.001) and excellent outcome (31% vs 15%, P<0.001), and a lower mean mRS shift pre-stroke to 90 days (2.3 vs 3.2, P<0.001). Patients with M2 occlusions and TICI 3 in comparison to TICI 2b were older (75.2 vs 72.4 years, P<0.001), had a higher rate of antithrombotic medication (46% vs 39%, P=0.028), a higher rate of comorbidities (hypertension, diabetes, dyslipidemia and atrial fibrillation), a higher ASPECTS (8.9 vs 8.7, P=0.002), a lower number of passes (1.7 vs 2.1, P<0.001), and a lower rate of clot migration or embolization (2% vs 5%, P=0.004). No significant difference between patients with M2 occlusions and TICI 3 versus TICI 2b was observed for outcome metrics mean 90-day mRS and percentage of good and excellent outcome; however, mRS increase pre-stroke to 90 days was lower with 2.0 vs 2.3 (P=0.009) (table 2).
Figure 1 shows mRS shift diagrams for M1 and M2 occlusions pre-stroke to day 90. Data confirm significant beneficial effects of successful recanalization on outcome for M1 as well as for the M2 occlusions subgroup. In line with descriptive statistics, data do not suggest a significant improvement of good and excellent long-term outcome for patients with M2 occlusions and complete recanalization TICI 3 compared with patients with TICI 2b.
Study cohort mRS shift pre-stroke status to 90 days depending on recanalization success. mRS, modified Rankin Scale; TICI, Thrombolysis In Cerebral Infarction.
Average treatment effect estimation
For M1 occlusions average treatment effect estimation for TICI ≥2b versus TICI <2b suggests a 22 percentage points (pp) (95% CI 17 pp to 27 pp) increase of probability of good outcome (absolute risk reduction, ARR), corresponding to a NNT of 4.5 (95% CI 3.7 to 5.9). The increase of probability of excellent outcome (ARR) was estimated at 16 pp (95% CI 12 pp to 20 pp) with an NNT of 6.3 (95% CI 5.0 to 8.3), respectively. Pre-stroke to 90-day mRS shift was reduced by 1.1 points (95% CI 0.87 to 1.30) resulting in a mean 90-day mRS of 2.6 in comparison to 3.7 in patients with TICI <2 b (figure 2). Average treatment effect estimation for TICI 2b versus TICI <2b suggests an 18 pp (95% CI 12 pp to 23 pp) increase of probability of good outcome and a 14 pp (95% CI 9 pp to 18 pp) increase of probability of excellent outcome, respectively. Complete recanalization with TICI 3 versus TICI 2b further increased the probability of good outcome by 7 pp (95% CI 4 pp to 10 pp) and of excellent outcome by 4 pp (1 pp to 7 pp). Pre-stroke to 90-day mRS shift was significantly reduced by 0.88 points (95% CI 0.65 to 1.12) for TICI 2b versus TICI <2b. Results also suggest a further significant reduction of neurological impairment by complete recanalization with TICI 3 versus TICI 2b by 0.31 mRS points (95% CI 0.17 to 0.45) (figure 2).
Double robust inverse-probability-weighted regression-adjustment estimators for treatment effect of different degrees of recanalization. Increase of probability of good outcome/absolute risk reduction (ARR) is expressed in percentage points (pp). mRS, modified Rankin Scale; TICI, Thrombolysis In Cerebral Infarction.
For M2 occlusions average treatment effect estimation for TICI ≥2b versus TICI <2b suggests a 20 pp (95% CI 13 pp to 26 pp) increase of probability of good outcome with NNT of 5 (95% CI 3.8 to 7.7) and a 10 pp (95% CI 4 pp to 17pp) increase in probability of excellent outcome with NNT of 10 (95% CI 5.9 to 25), respectively. Successful recanalization with TICI ≥2b reduced pre-stroke to 90-day mRS increase by 0.89 points (95% CI 0.61 to 1.16), resulting in a mean 90-day mRS of 2.2 in comparison to a mean mRS of 3.1 in patients with TICI <2b (figure 2). Furthermore, an 18 pp (95% CI 11 pp to 25 pp) increase of probability of good outcome and a 8 pp (95% CI 1 pp to 15pp) increase of excellent outcome for TICI 2b versus TICI <2b was observed. Complete recanalization with TICI 3 versus TICI 2b did not further increase the probability of good outcome; however, the probability of excellent outcome increased by 5 pp (95% CI 0 pp to 10pp). TICI 2b reduced pre-stroke to 90-day mRS shift by 0.74 points (95% CI 0.44 to 1.04). Results suggest a slightly further reduction of neurological impairment by TICI 3 by 0.25 mRS points (95% CI 0.05 to 0.45) (figure 2).
Discussion
In our study including 4259 prospectively enrolled registry patients, average treatment effect estimation suggests that successful recanalization of M2 occlusions with TICI ≥2b versus TICI <2b increases the probability of good long-term functional outcome by 20 pp and the probability of excellent long-term outcome by 10 pp, corresponding to NNT of 5 and 10, respectively. In comparison, average treatment effect estimations for successful recanalization of M1 occlusions with TICI ≥2b versus TICI <2b suggest an increased probability of good long-term functional outcome of 22 pp and probability of excellent long-term outcome of 16 pp, corresponding to NNT of 4.5 and 5.3, respectively. In line with the study hypothesis, successful recanalization by MT substantially increased the probability of good and even excellent long-term functional outcome not only in patients with M1 occlusions, but also in patients with M2 occlusions.
Observed NNT of 4.5 for functional independence after MT in M1 occlusions corresponds to numbers reported for large RCTs21–25 with a range of 2.8 (DAWN26) to 7.4 (MR CLEAN27). Our results for M2 occlusions are in line with other MT studies that reported TICI 2b-3 recanalization to be an independent parameter related to favorable outcome.6 8 28
The average treatment effect estimation of successful recanalization for M2 occlusions was 2 pp lower for good and 6 pp lower for excellent long-term functional outcome compared with estimations for M1 occlusions; however, treatment effects were not significantly different.
If analyzed per TICI level, TICI 2b versus TICI <2b increased the probability of good long-term functional outcome from 27% to 45% (18 pp) in patients with M2 occlusions and from 16% to 33% (18 pp) in patients with M1 occlusions. Previous studies including patients with large vessel occlusions found a significant increase in the proportion of good clinical outcome for TICI 3 in comparison to TICI 2b.10 11 14 15 Accordingly, in our study, complete recanalization (TICI 3) versus TICI 2b in the M1 cohort further increased the probability of good outcome and excellent outcome and reduced the pre-stroke to 90-day mRS increase. In the M2 cohort, complete recanalization with TICI 3 in direct comparison to TICI 2b did not lead to a statistically significant increase in the probability of good outcome. However, the probability of excellent outcome was increased and mRS shift was decreased at comparably low significance levels. It can be assumed that the observed trends might reach statistical significance with higher case numbers. A reason for the observed lower average treatment effect of TICI 3 in the M2 cohort could be that the volume of hypoperfused brain tissue is smaller in M2 occlusions compared with M1 occlusions. Accordingly, it can be postulated that the average treatment effect of complete recanalization versus near-complete recanalization is lower as well. Furthermore, due to shorter routes over the convexity, collaterals might be more sufficient to compensate long term for persisting partial vessel occlusions, and therefore these patients still achieve good or even excellent clinical outcome with TICI 2b.2 In comparison, a previous study including 121 patients with M2 occlusions evaluated the association between TICI 2b versus TICI 3 with good functional outcome.29 According to their results, complete recanalization, but not TICI 2b, was associated with favorable outcomes. Another study by Mokin et al included 117 patients with M2 occlusion, and reported that the percentage of patients with TICI ≥2b and also TICI 3 differed significantly between the favorable and poor outcome groups.30 However, in their cohort, no regression analysis was conducted to test whether the efficacy of TICI 3 was statistically superior to TICI 2b.
Furthermore, to our knowledge, our study is the first to evaluate the treatment effect of TICI 2b recanalization in comparison to TICI 3 on functional outcome in patients with M2 occlusion.
Subgroup comparison stratified for final TICI scores suggests that better recanalization results are associated with lower pre-stroke mRS and higher ASPECTS; however, differences are only partly significant. Furthermore, better recanalization results were associated with a lower number of passes during the MT procedure in the M1 and M2 group. This observation is in line with previous studies reporting a higher number of retrievals for patients with final TICI 2b in comparison to TICI 3 in patients with large vessel occlusions.11 31 It can therefore be hypothesized that complete recanalization TICI 3 is often achieved after the first or second pass, while more complex cases require multiple passes and still do not achieve complete recanalization TICI 3. Further research is required to discriminate reported beneficial effects of complete recanalization with TICI 3 and first pass effects, especially in patients with M2 occlusion.
Limitations
Our study has some limitations. Our findings are based on a prospectively acquired registry. Only cases with availability of all required data points were included in the analysis. Exclusion of patients with missing data points (including lost to follow-up) might introduce bias to the reported results and might reduce generalizability of findings. Pre-defined inclusion criterion of the GSR registry is the intention to treat with MT. The decision to treat was made by the treating neurointerventionalist or neurologist. While cases with M2 occlusions and low clinical severity could more likely be managed only medically, primary M2 occlusions with severe baseline NIHSS might be associated with higher willingness of neurointerventionalists for endovascular therapy.32 33 All clinical parameters including mRS, vessel occlusion status and location were site-reported parameters that might suffer from site-related bias due to limited interrater reliability. It was shown that near complete reperfusion with TICI 2c might be an important factor for good outcome.34 However, the underlying registry data only reports the initial TICI consensus grades without TICI 2c. The study cohort was selected based on center assessments of the exact occlusion location. It is known that the exact anatomical M2 definition is a matter of debate. For MCA occlusions, the GSR-ET registry differentiates proximal M1, distal M1 and M2 occlusions. Due to numerous anatomical variants of the MCA, cohort definitions with exactly the same branching and vessel diameter parameters might not be possible. In addition, such a cohort selected by narrow criteria would only reflect specific study settings but would not reflect clinical practice where treating physicians typically differentiate vessel occlusions based on less specific criteria. Furthermore, the study aims to estimate treatment effects from clinical practice data in patients undergoing MT with M2 occlusions in comparison to M1 occlusions; the study does not aim to prove the safety and efficiency of a specific therapy.
Three RCTs currently upcoming and enrolling (DISTAL, ESCAPE-MEVO and FRONTIER-AP) will further enhance the understanding of safety and efficiency of MT in medium and distal vessel occlusions.
Conclusion
Average treatment effect estimation suggests that successful recanalization with TICI ≥2b versus TICI <2b increases the probability of good long-term functional outcome from 27% to 47% with NNT 5 in patients with M2 occlusions compared with an increase from 16% to 38% with NNT 4.5 in patients with M1 occlusions. Stroke-related neurological impairment in terms of pre-stroke to 90-day mRS increase was reduced by 0.9 mRS points in patients with M2 occlusions and by 1.1 mRS points in patients with M1 occlusions. In contrast to M1 occlusions, complete recanalization with TICI 3 versus adequate recanalization with TICI 2b had a lower additional beneficial effect on functional outcome in M2 occlusions; however, significantly higher rates of excellent outcome were observed.
Data availability statement
Data may be obtained from a third party (GSR-ET registry) and are not publicly available. The data that support the findings of this study are available from the GSR-ET registry. Restrictions apply to the availability of these data.
Ethics statements
Patient consent for publication
Ethics approval
This study involves human participants and was approved by the ethics committee of the chamber of physicians at Ludwig-Maximillians University LMU, Munich (689-15). Participants gave informed consent to participate in the study before taking part.
Acknowledgments
Authors acknowledge the German Stroke Registry (GSR) investigators and the GSR steering committee: Prof. Dr. med. Joachim Röther (Asklepios Klinik Altona, Hamburg); Prof. Dr. med. Bernd Eckert (Asklepios Klinik Altona, Hamburg); Dr. med. Michael Braun (Bezirkskrankenhaus Günzburg); Prof. Dr. med. Gerhard F. Hamann (Bezirkskrankenhaus Günzburg); PD Dr. med. Eberhard Siebert (Charité –Benjamin Franklin und Campus Charité); Prof. Dr. med. Christian Nolte (Charité –Benjamin Franklin und Campus Charité); Dr. med. Sarah Zweynert (Charité - Campus Virchow Klinikum, Berlin); Dr. med. Georg Bohner (Charité - Campus Virchow Klinikum, Berlin); Prof. Dr. med. Jörg Berrouschot (Klinikum Altenburger Land); Dr. med. Albrecht Bormann (Klinikum Altenburger Land); Dr. med. Christoffer Kraemer (Klinikum Lüneburg); PD Dr. med. Hannes Leischner (Klinikum Lüneburg); Dr. med. Jörg Hattingen (KRH Klinikum Nordstadt Hannover); Dr. med. Martina Petersen (Klinikum Osnabrück); Prof. Dr. med. Florian Stögbauer (Klinikum Osnabrück); PD Dr. med. Boeckh-Behrens (Klinikum r.d.Isar); Dr. med. Silke Wunderlich (Klinikum r.d.Isar); Dr. med. Alexander Ludolph (Sana Klinikum Offenbach); Dr. med. Karl-Heinz Henn (Sana Klinikum Offenbach); Prof. Dr. med. Christian Gerloff (UKE Hamburg-Eppendorf); Prof. Dr. med. Jens Fiehler (UKE Hamburg-Eppendorf); Prof. Dr. med. Götz Thomalla (UKE Hamburg-Eppendorf); Asklepios Klinik Altona, Hamburg (UKE Hamburg-Eppendorf); Dr. med. Anna Alegiani (Asklepios Klinik Altona, Hamburg); Dr. med. Maximilian Schell (UKE Hamburg-Eppendorf); PD Dr. med. Arno Reich (Uniklinik RWTH Aachen); Prof. Dr. med. Omid Nikoubashman (Uniklinik RWTH Aachen); Prof. Dr. med. Franziska Dorn (Uniklinik Bonn); Prof. Dr. med. Gabor Petzold (Uniklinik Bonn); Prof. Dr. med. Jan Liman (Klinikum Nürnberg); Dr. med. Jan Hendrik Schäfer (Uniklinik Frankfurt/ Main); Dr. med. Fee Keil (Uniklinik Frankfurt/ Main); Prof. Dr. med. Klaus Gröschel (Universitätsmedizin Mainz); Dr. med. Timo Uphaus (Universitätsmedizin Mainz); Prof. Dr. med. Peter Schellinger (Universitätsklinik Johannes Wesling Klinikum Minden); Prof. Dr. Jan Borggrefe (Universitätsklinik Johannes Wesling Klinikum Minden); Dr. med. Steffen Tiedt (Uniklinik München (LMU)); PD Dr. med. Lars Kellert (Uniklinik München (LMU)); PD Dr. med. Christoph Trumm (Uniklinik München (LMU)); Prof. Dr. med. Ulrike Ernemann (Universitätsklinik Tübingen); PD Dr. med. Sven Poli (Universitätsklinik Tübingen); Prof. Dr. med. Christian Riedel (Universitätsmedizin Göttingen); PD Dr. med. Marielle Sophie Ernst (Universitätsmedizin Göttingen).
References
Supplementary materials
Supplementary Data
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Footnotes
Twitter @noelvanhorn, @VincentGeest, @WinkelmeierMD, @Fie0815
Contributors Conception/design of the work: HK, SG; Data acquisition: LM, GB, TDF, MB, CB, FF, NvH, VG, LW, AA, MD-C, UH, GT, JF; Data analysis: LM, GB, JF; Interpretation of data: HK, SG, LM, JF; Drafting the work: HK, SG; Revising the work critically for important intellectual content: LM, GB, TDF, MB, CB, FF, NvH, VG, LW, AA, MD-C, UH, GT, JF; Final approval of the version to be published: HK, SG, LM, GB, TDF, MB, CB, FF, NvH, VG, LW, AA, MD-C, UH, GT, JF; Agreement to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved: HK, SG, LM, GB, TDF, MB, CB, FF, NvH, VG, LW, AA, MD-C, UH, GT, JF; Accept full responsibility for the work and the conduct of the study, had access to the data, and controlled the decision to publish: HK, SG.
Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.
Competing interests HK and FF are consultants for Eppdata GmbH. HK has financial interest in Eppdata GmbH. MD-C has received research grants from the Werner Otto Stiftung and serves in the advisory board of the PRECIOUS Trial. TDF has received research grants from the Deutsche Forschungsgemeinschaft/German Research Foundation. GT Thomalla received fees as consultant from Acandis, Boehringer Ingelheim, Bayer, and Portola, and fees as lecturer from Acandis, Alexion, Amarin, Bayer, Boehringer-Ingelheim, BMS/Pfizer, Daiichii Sankyo and Portola. He serves in the board of the TEA Stroke Study and of ESO. JF is consultant for Cerenovus, Medtronic, Microvention, Penumbra, Phenox, Roche and Tonbridge. He serves in the advisory board of Stryker and Phenox. He is stock holder of Tegus Medical, Eppdata and Vastrax. He serves as Associate Editor at JNIS.
Provenance and peer review Not commissioned; externally peer reviewed.
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