Outcome After Thrombectomy and Intravenous Thrombolysis in Patients With Acute Ischemic Stroke
A Prospective Observational Study
Background and Purpose—In patients with ischemic stroke, randomized trials showed a better functional outcome after endovascular therapy with new-generation thrombectomy devices compared with medical treatment, including intravenous thrombolysis. However, effects on mortality and the generalizability of results to routine clinical practice are uncertain.
Methods—In a prospective observational register-based study patients with ischemic stroke treated either with thrombectomy, intravenous thrombolysis, or their combination were included. Primary outcome was the modified Rankin scale score (0 [no symptoms] to 6 [death]) at 3 months. Ordinal logistic regression was used to estimate the common odds ratio as treatment effects (shift analysis). Propensity score matching was applied to compare patients treated either with intravenous thrombolysis alone or with intravenous thrombolysis plus thrombectomy.
Results—Among 2650 recruited patients, 1543 received intravenous thrombolysis, 504 underwent thrombectomy, and 603 received intravenous thrombolysis in combination with thrombectomy. Later time-to-treatment was associated with worse outcomes among patients treated with thrombectomy plus thrombolysis. In 241 pairs of propensity score–matched patients with a proximal intracranial occlusion, thrombectomy plus thrombolysis was associated with improved functional outcome (common odds ratio, 1.84; 95% confidence interval, 1.32–2.57), and reduced mortality (15% versus 33%; P<0.0001) compared with intravenous thrombolysis alone. Results were similar in various sensitivity analyses accounting for missing outcome data and different analytic methods.
Conclusions—Results from this large prospective registry show that also in routine clinical care thrombectomy plus thrombolysis compared with thrombolysis alone improved functional outcome and reduced mortality in patients with ischemic stroke. Earlier treatment was associated with better outcomes.
Strategies for revascularization in patients with acute ischemic stroke include intravenous thrombolysis and endovascular treatments. Intravenous thrombolysis with tissue-type plasminogen activator (tPA) has been the only therapy with proven clinical efficacy for 2 decades.1 However, its effectiveness is limited because of low recanalization rates, especially in severe stroke caused by large intracranial vessel occlusions.2 Although endovascular therapies can improve successful reperfusion, earlier trials, using first-generation thrombectomy devices and intra-arterial thrombolysis, had neutral findings with respect to clinical outcomes.3–5 More recent studies reported better neurological outcomes by applying newest-generation thrombectomy devices, referred to as stentretrievers, compared with conservative care, including intravenous thrombolysis.6–10 Randomized clinical trials provide the highest level of evidence for the efficacy of a new treatment, but generalizability to routine clinical care may be limited because of strict eligibility criteria of participating patients. Prospective observational studies and registries can extend the evidence from randomized trials and translate it into effectiveness in routine clinical care. We established the Register on Revascularization in Ischemic Stroke Patients (REVASK), a registry on endovascular treatments and intravenous thrombolysis using the established infrastructure of a large German stroke registry11 to compare clinical outcomes in ischemic stroke patients treated with thrombectomy, intravenous tPA, or their combination. We further assessed the association of time-to-treatment with outcome because larger benefit after earlier reperfusion indicates effectiveness of recanalization therapies.12
The REVASK registry was established as a multicenter, prospective, observational study based on the structure of the Stroke Register of Northwestern Germany (Qualitätssicherung Schlaganfall Nordwestdeutschland [QSNWD]).11 QSNWD is part of a legal act implemented in Germany through which hospitals participate in programs for quality assurance based on anonymized data collection. Details of the QSNWD have been published previously.11 For the REVASK registry those hospitals of the QSNWD, which provide endovascular treatments and/or intravenous thrombolysis in patients with acute stroke were invited to participate. Additional hospitals, participating in other quality programs, were allowed to participate in the REVASK registry. Written informed consent for the centrally performed 3 months follow-up and pseudonymized data analysis at the Institute of Epidemiology and Social Medicine, University of Münster was asked from all patients. In patients who did not or were unable to consent because of symptoms or language problems documentation was done completely anonymized and no written follow-up was performed, whereas vital status (dead or alive) was assessed by the treating physician in each center as part of the quality assurance program. The ethics committee of the Westphalian Board of Physicians and the University of Münster, Germany, approved the study.
The study population included all patients with ischemic stroke undergoing endovascular treatment or intravenous thrombolysis or a combination of both at participating hospitals during the 12 months of study period. This period was placed in the time window from April 2012 to August 2013 to allow a flexible start point for the hospitals. The choice of revascularization therapy was left to the treating physicians. A standardized set of sociodemographic, clinical, and procedural variables as well as the discharge status was prospectively collected by the treating hospital physician (for a full-item list see in the online-only Data Supplement). We excluded patients who received intra-arterial thrombolysis but neither intravenous thrombolysis nor thrombectomy.
The primary outcome was disability, assessed by the modified Rankin scale (mRS) at 3 months. The mRS is a 7-level scale ranging from 0 (no symptoms) to 6 (death). Three months follow-up was performed centrally by the University of Münster through mailed questionnaire. In case of no response, the patients’ vital status was assessed in the respective municipal registry. Further efficacy outcomes included the following: partial or complete recanalization (according to recanalization of the primary arterial occlusive lesion), National Institutes of Health Stroke Scale (NIHSS), and mRS at discharge, in-hospital mortality, and discharge destination. Safety end points were any periprocedural intracranial hemorrhage, any intracranial hemorrhage during hospitalization, vessel perforation, intramural artery dissection, embolization to previously uninvolved territory, device failure (in vivo breakage and stent dislocation), and access-site complications.
Patients were stratified according to 3 treatment groups: (1) intravenous tPA alone, (2) thrombectomy alone, and (3) combination of thrombectomy and intravenous tPA. Baseline characteristics and patient outcome were compared between treatment groups by the use of Pearson χ2 test for categorical variables and Student t test or Mann–Whitney U test or 1-way ANOVA for continuous variables.
We imputed missing values of baseline and outcome variables by the use of multiple imputation models (Methods section in the online-only Data Supplement). In sensitivity analyses, we performed complete case and last observation carried forward analyses. The latter was chosen because functional status at discharge is strongly correlated to disability outcome at 3 months.13
The analysis of the association of time-to-treatment and mRS at 3 months is described in the Methods section in the online-only Data Supplement. To assess differences in the primary outcome (mRS at 3 months) between patients treated with intravenous tPA alone and intravenous tPA plus thrombectomy, we used propensity score matching followed by ordinal logistic regression analyses. The propensity score–matched approach was used to ensure homogenous treatment groups in the outcome analyses. We restricted inclusion to patients in the tPA alone group to those suitable for thrombectomy and patients in thrombectomy groups to those suitable for thrombolysis. Patients were eligible for inclusion in propensity score analyses if they had received tPA within 4.5 hours after the onset of symptoms (or last known well) and had a proximal intracranial occlusion (internal carotid artery, M1 or M2 middle cerebral artery, anterior cerebral artery, posterior cerebral artery, basilar artery, and vertebral artery), thus patients of the thrombectomy alone group were excluded. Propensity scores for the probability that a patient received thrombectomy were estimated using logistic regression models (models are provided in the Methods section in the online-only Data Supplement).14 A description of propensity score matching is provided in the Methods section in the online-only Data Supplement. For the primary analysis, shifts across the full range of the mRS at 3 months were analyzed by ordinal logistic regression analysis using proportional (resulting in a common odds ratio) and nonproportional odds models. Additional dichotomous outcome measures included mRS scores of 0 or 1, mRS scores of 0 to 2, and mortality at 3 months. Proportions of patients with mRS scores of these dichotomous outcomes in the 2 groups were compared by binary logistic regression analysis. For sensitivity analysis, we used standardized mortality ratio–weighting based on the propensity score.14 This method estimates treatment effects in the entire study population by standardizing the distribution of the baseline characteristics to that of the thrombectomy plus intravenous tPA group.
A total of 2666 patients were enrolled in 37 centers from April 2012 to August 2013. We excluded 16 patients treated with intra-arterial thrombolysis alone. The remaining 2650 patients constitute the study population. Table 1 shows their baseline demographic characteristics and time-to-treatment. Patients undergoing thrombectomy, either alone or in combination with intravenous thrombolysis, were, on average, younger, more often women, and they had less often hypertension, hyperlipidemia, and previous stroke but more often atrial fibrillation. The largest differences between groups were observed for stroke severity (NIHSS score) and location of vessel occlusion. Patients in the thrombectomy groups had higher symptom severity and more often internal carotid and M1 segment middle cerebral artery occlusions. Time to intravenous thrombolysis did not differ between patients with and without additional thrombectomy. Among patients treated with thrombectomy, those with additional intravenous thrombolysis had shorter times to arterial puncture.
Of 37 participating centers, 21 (56.8%) used perfusion computed tomography in at least some patients. However, whether the treatment decision for individual patients was based on perfusion computed tomography was not recorded.
Devices used for thrombectomy are provided in the online-only Data Supplement (Table I in the online-only Data Supplement). Stentretrievers were used in 876 (79.1%) of 1107 patients treated with thrombectomy.
Observed Efficacy and Safety Outcomes
Unadjusted efficacy and safety outcomes are shown in Table 2. There were significant differences in most outcomes because of clearly higher stroke severity in the thrombectomy groups at baseline. At discharge neurological status (NIHSS mean, mRS score of 0 or 1 and mRS score of 0–2), in-hospital mortality, and the proportion discharged home was less favorable after thrombectomy, either alone or in combination with tPA, compared with tPA alone (all P values <0.001). The proportion with partial or complete recanalization was 60.1% for tPA alone and 90.9% and 92.4% in both thrombectomy groups. A comparison of recanalization rates should be made with caution because time and method of recanalization assessment differed among groups (Table II in the online-only Data Supplement). Three months data on vital status were missing in 146 patients (5.5%). Three months mortality was 14.0% after intravenous tPA alone, 27.8% after thrombectomy alone, and 17.8% after thrombectomy plus intravenous tPA (P<0.001). Information on 3 months of mRS was missing in 639 patients (29.6%) because of nonresponse to the follow-up questionnaire for a variety of reasons. Proportions of patients with mRS score of 0 or 1 and mRS score of 0 to 2 were 45.0% and 59.9% after tPA alone, 23.5% and 38.1% after thrombectomy alone, and 32.4% and 47.5% after thrombectomy plus intravenous tPA, respectively. We found no substantial differences with respect to outcome after multiple imputation of missing values or when last observations were carried forward (Tables III and IV in the online-only Data Supplement).
Table 2 lists safety outcomes including periprocedural complications. The proportions of any intracerebral hemorrhage were 7.5% after tPA alone, 14.7% after thrombectomy alone, and 15.8% after thrombectomy plus intravenous tPA (P<0.001).
Effect of Time-to-Treatment on Outcome
Longer time-to-treatment was significantly associated with a shift in the distribution of the mRS toward worse outcome in patients treated with thrombectomy plus tPA (Figure 1). Compared with treatment initiation within the first 1.5 hours, the adjusted common odds ratios for a start of treatment after 1.5 to 3.0, 3.0 to 4.5, 4.5 to 6.0, and >6.0 hours were 0.71 (95% confidence interval [CI], 0.48–1.03), 0.39 (95% CI, 0.23–0.68), 0.25 (95% CI, 0.10–0.63), and 0.29 (95% CI, 0.15–0.56), respectively. In patients treated with tPA alone or thrombectomy alone, we found no significant association between time-to-treatment and outcome (Figure 1; Table IV in the online-only Data Supplement). These results were almost identical in patients with complete 3-month outcome data and in those with 3-month outcome imputed by last observation carried forward with the exception that the latter analysis also showed worse outcome after later treatment initiation in patients treated with thrombectomy alone (Table V in the online-only Data Supplement).
Primary Outcome in Propensity-Matched Groups
On the basis of propensity scores, 241 patients treated with thrombectomy plus tPA were matched to 241 patients treated with tPA alone. Baseline characteristics were well balanced after matching (Table 3). There was a shift in the distribution of the mRS at 3 months in favor of thrombectomy plus tPA compared with tPA alone (common odds ratio, 1.84; 95% CI, 1.32–2.57; P=0.0004; Figure 2). The shift toward better outcome was not consistent for all categories of the mRS with stepwise increasing odds ratios, indicating greater efficacy in patients with severe stroke (Figure I in the online-only Data Supplement). The proportion of patients with an mRS score of 0 to 2 at 3 months was 51% in the tPA plus thrombectomy group and 40% in tPA alone group (odds ratio, 1.56; 95% CI, 1.06–2.30; P=0.03). Mortality was lower in patients with combination therapy compared with the tPA alone group (15% versus 33%; odds ratio, 0.34; 95% CI, 0.22–0.53; P<0.0001). We found no significant difference between groups with respect to an mRS score of 0 or 1 (odds ratio, 1.37; 95% CI, 0.88–2.12; P=0.16). Sensitivity analyses performed with the use of standardized mortality ratio–weighted groups yielded similar results (Table VI in the online-only Data Supplement). Our results also remained robust in patients with complete 3-month outcome data and those with 3-month outcome imputed by last observed carried forward (Table V in the online-only Data Supplement).
Using the setting of a large, prospective stroke register, this observational study shows that in patients with acute ischemic stroke treatment with mechanical thrombectomy plus intravenous thrombolysis compared with intravenous thrombolysis alone substantially improves the neurological outcome and reduces mortality at 3 months. In the first group, earlier treatment was associated with improved outcome.
Our findings should be interpreted in the context of recent randomized trials comparing endovascular treatments with best medical therapy, including intravenous thrombolysis. After 3 earlier randomized, controlled trials of endovascular treatment failed to show a benefit,3–5 recently 5 trials reported improved outcomes in patients treated with endovascular therapies.6–10 The negative findings in the first trials were attributed to the use of first-generation devices in contrast to the predominant or even exclusive use of stent retrievers in the later trials. Our results extend the findings of the positive trials, in which patients had to fulfill selected inclusion criteria, to the setting of routine clinical care. In the randomized trials the effect sizes differed, with common odds ratios for shift analyses of the mRS score distribution varying from 1.7 to 2.6 and odds ratios for a favorable outcome, defined by an mRS score of 0 to 2, varying between 1.7 and 4.2.6–10 The differences between studies might be explained by different patient inclusion criteria. The Extending the Time for Thrombolysis in Emergency Neurological Deficits–Intra-Arterial (EXTEND-IA) trial for instance used restrictive inclusion criteria with patients being only eligible if they could receive intravenous thrombolysis within 4.5 hours and had a small infarct core and evidence for salvageable brain tissue on imaging. Patients with these characteristics have the largest benefit from recanalization.
In our observational study, patient characteristics in the thrombectomy plus thrombolysis group were similar to those in recent randomized trials in terms of age, initial stroke severity, time-to-treatment, and vessel occlusion pattern.6–10 Our observed effect size was comparable with that in the positive trials. Both, similarity of patient characteristics and of outcomes indicate a good generalizability of results from randomized trials to routine clinical care. Our results also confirm that endovascular therapy reduces mortality, which was shown by only one of the randomized trials.8
In cerebral ischemia, tissue damage expands rapidly over time until reperfusion is achieved.12 A larger benefit after early initiation of reperfusion therapies indicates their effectiveness, as demonstrated for intravenous thrombolysis in randomized trials and observational studies.12,15 In accordance with a previous observational study, we found a larger benefit after early treatment in patients who received the combination of intravenous thrombolysis and thrombectomy.16 No robust effects of treatment time were observed in patients treated with intravenous thrombolysis alone or thrombectomy alone. Although previous studies found such association in patients treated with intravenous thrombolysis, the effect size was rather small.12,15 Our intravenous thrombolysis group might not be large enough to detect such a small effect. The thrombectomy alone group in this study includes patients not suitable for intravenous thrombolysis. Therefore, the majority of patients in this group received treatment rather late (beyond the therapeutic time window for intravenous tPA) after a mean time-to-treatment interval of almost 5 hours. Thus, there were only few patients with early intervention in this group, which was probably not enough to identify a clear association of time-to-treatment with outcome.
This study has several limitations. Patients were not randomized to interventions, and therefore baseline characteristics differed between treatment groups. The choice of revascularization therapy was left to the treating physician and detailed reasons for this choice were not recorded for individual patients. Although the 2 propensity score–based approaches, matching and weighing, led to excellent balanced groups unmeasured confounding variables may have influenced our findings. However, all important variables in terms of choice of treatment and functional outcome were included in our models. In addition, the association of early treatment with a beneficial outcome provides further evidence for the efficacy of thrombectomy plus thrombolysis. Differences between sites, particularly between those providing endovascular therapy and those offering only intravenous thrombolysis, are a potential source of bias although treatment standards across hospitals are comparable because of participation in strictly controlled programs for quality assurance. A further limitation is the proportion of missing data for the 3-month outcomes—in particular the mRS. However, our primary approach for the imputation of missing outcome data, multiple imputation by chained equations, is an adequate method because the functional status at discharge was almost completely available in this study. It correlates strongly with the 3-month outcomes.13 Finally, different sensitivity analyses including complete cases and imputation by last observation carried forward yielded similar results.
In conclusion, this prospective register study conducted in a routine clinical care setting shows that in patients with acute ischemic stroke thrombectomy in addition to thrombolysis improves functional outcomes and reduces mortality. Highest benefit can be achieved by early treatment. These findings confirm the efficacy of thrombectomy for patients with acute ischemic stroke in recent randomized clinical trials and extend it into effectiveness in settings offering routine clinical care.
We thank Marianne Kalic for her efforts in data management and her technical support.
Sources of Funding
No external funding was received for this study. The study was supported by own resources of each participating institution. Dr Minnerup is supported by the Else Kröner-Fresenius-Stiftung (2014_EKES.16).
Dr Minnerup has received grants from Deutsche Forschungsgemein schaft, Bundesministerium für Bildung und Forschung (BMBF), Else Kröner-Fresenius-Stiftung, EVER Pharma Jena GmbH, Ferrer International, travel grants from Boehringer Ingelheim and speaking fees from Bayer Vital; Dr Wersching receives a research grant from the German Federal Ministry of Education and Research (BMBF);Dr Eyding has received honoria for oral presentations by Penumbra Europe and remuneration for advisory boards by Boehringer Ingelheim; Dr Weber received speaker Honoria from Covidien and from serving on a scientific advisory board of Covidien outside the submitted work; Dr Reimann has received honoraria from Boehringer Ingelheim and Medtronic/Covidien; Dr Weber has received speaker honoraria from Penumbra; Dr Kurth has received honoraria from the BMJ and Cephalalgia for editorial services; Dr Berger reports grants from the German Federal Ministry of Education and Research and Education (BMBF) and multiple institutions outside the submitted work. The other authors report no conflicts.
↵† A list of Register on Revascularization in Ischemic Stroke Patients (REVASK) investigators is given in the Appendix.
Guest Editor for this article was Giuseppe Lanzino, MD.
The online-only Data Supplement is available with this article at http://stroke.ahajournals.org/lookup/suppl/doi:10.1161/STROKEAHA.116.012619/-/DC1.
- Received January 4, 2016.
- Revision received March 24, 2016.
- Accepted March 28, 2016.
- © 2016 American Heart Association, Inc.
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