Background Anticoagulated patients (APs) are currently excluded from acute ischemic stroke reperfusion therapy with intravenous recombinant tissue plasminogen activator (IV-rtPA); however, these patients could benefit from mechanical thrombectomy (MT). Evidence for MT in this condition remains scarce. The aim of this study was to analyze the safety and efficacy of MT in APs.
Methods We analyzed three patient groups from two prospective registries: APs with MT (AP-MT group), non-anticoagulated patients treated with MT (NAP-MT group), and non-anticoagulated patients treated with IV-rtPA and MT (NAP-IVTMT group). Univariate and multivariate logistic regression were used to evaluate treatment efficacy with modified Rankin Scale (mRS) ≤2 and safety (radiologic intracranial hemorrhage (rICH), symptomatic intracranial hemorrhage (sICH) and death rate at 3 months) between groups.
Results 333 patients were included in the study, with 44 (12%) in the AP-MT group, 105 (31%) in the NAP-MT group, and 188 (57%) in the NAP-IVTMT group. Univariate analysis showed that the AP-MT group was older (P<0.001), more often had atrial fibrillation (P<0001), and had a higher ASPECTS (P<0.006 and P<0.002) compared with the NAP-MT group and NAP-IVTMT groups, respectively. Multivariate analysis showed that the AP-MT group had a lower risk of rICH (OR 2.77, 95% CI 1.01 to 7.61, P=0.05) but a higher risk of death at 3 months (OR 0.26, 95% CI 0.09 to 0.76, P=0.01) compared with the NAP-IVTMT group. No difference was found between the AP-MT and NAP-MT groups.
Conclusions With regard to intracranial bleeding and functional outcome at 3 months, MT in APs seems as safe and efficient as in NAPs. However, there is a higher risk of death at 3 months in the AP-MT group compared with the NAP-IVTMT group.
- mechanical thrombectomy
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For many years intravenous thrombolysis (IVT) with recombinant tissue plasminogen activator (rtPA) administered within 4.5 hours after symptom onset has been the only reperfusion therapy with proven efficacy in patients with acute ischemic stroke (AIS).1 Due to a higher risk of intracranial hemorrhage, one of the main contraindications of rtPA is a previous effective anticoagulation treatment2 with heparin, vitamin K antagonists (VKA), or non-VKA oral anticoagulants (NOACs) (International Normalized Ratio (INR) <1.7 in patients under VKA is allowed in the USA3).
Recently, randomized controlled trials (RCTs) have proven the efficacy and safety of mechanical thrombectomy (MT) in AIS patients with large vessel occlusion.4 In anticoagulated patients (APs), MT offers a safe and effective reperfusion approach without the use of pharmacological agents altering hemostasis. However, data about MT in APs are scarce. In the eight abovementioned RCTs, these patients were excluded or under-represented, accounting for only 88/1872 (4.7%) patients.5
We aimed to investigate the efficacy and safety of MT alone in APs compared with MT alone and IVT combined with MT in non-anticoagulated patients (NAPs) in two prospective registries.
Data were derived from two prospective registries, the Neuro Thrombectomy France (NTF) and Nantes University Hospital Thrombectomy registries, which included patients with AIS treated with MT. NTF is a French multicenter registry which included 229 patients between May 2013 and September 2014 in 18 centers. The Nantes University Hospital Thrombectomy registry included 138 patients between January 2014 and February 2016.
In both registries, stroke with occlusion of a large vessel was confirmed by vascular imaging (CT angiography or MR angiography). Clinical, imaging, and biological data at baseline, 24 hours and 3 months post-stroke were prospectively collected in all patients.
All patients had a non-enhanced CT scan (NECT) brain imaging within 24 hours post-treatment; additional NECT imaging could be performed at any time in case of neurological deterioration. For the purpose of this study, we included all patients aged over 18 without significant disability before stroke onset (defined by a modified Rankin Scale (mRS) score >2).
Three groups were analyzed and compared: APs treated with MT alone (AP-MT group), NAPs treated with MT alone (NAP-MT group), and NAPs receiving standard treatment with IV-rtPA and MT (NAP-IVTMT group).
The AP-MT group was treated with therapeutic doses of heparin, VKA or NOACs at the time of the stroke. Anticoagulation status was validated by medical history of anticoagulant treatment and/or a laboratory value consistent with anticoagulated state (INR >1.2, partial thromboplastin time (PTT) >1.2). Patients on NOACs were included with anamnestic criteria (agent, daily dosage, last intake within 24 hours, and reason for using).
Patients in the NAP-MT group had a contraindication to IVT for other reasons than an active anticoagulation such as recent bleeding, delay from onset, recent trauma, or surgery.
Mechanical thrombectomy procedure
MT was performed by experienced neurointerventionalists. Patients treated with first-generation devices such as MERCI retrievers were excluded. The use of intra-arterial thrombolysis (IAT, only alteplase), acute carotid stenting or periprocedural antithrombotic therapy (aspirin, clopidogrel or anti-GP IIb/IIIa) was recorded.
The following variables were recorded: baseline characteristics such as age, sex, cardiovascular risk factors (diabetes mellitus, hypertension, smoking, dyslipidemia), medical history (prior ischemic stroke, coronary arterial disease, chronic limb ischemia and atrial fibrillation), use of antiplatelet or anticoagulant therapy at the time of stroke onset, stroke severity assessed by the National Institutes of Health Stroke Scale (NIHSS) score before IVT/MT, arterial systolic and diastolic pressure and the TOAST (Trial of Org 10 172 in Acute Stroke Treatment) etiological classification of ischemic stroke,6 Alberta Stroke Programme Early CT Score (ASPECTS), occlusion site (divided into four groups: internal carotid artery (ICA), middle cerebral artery (MCA), basilar or vertebral artery (BA), and tandem occlusion), as well as time from symptom onset to IVT, symptom onset to groin puncture, and symptom onset to revascularization.
Laboratory measures analyzed from blood samples taken before IVT or MT included platelet count, creatinine, glycemia, INR, prothrombin time (PT), and partial thromboplastin time (PTT). Creatinine clearance was calculated with the modification of diet in renal disease (MDRD) equation.
The modified Thrombolysis in Cerebral Infarction score (mTICI) at the end of the procedure,7 antithrombotic treatment and stenting during the procedure were also recorded.
Efficacy of MT was evaluated as functional outcome at 3 months using the modified Rankin Scale (mRS). A favorable functional outcome was defined as a mRS score ≤2 at 3 months and an unfavorable outcome as a score of ≥3.
Safety of MT was evaluated by the rate of intracranial hemorrhage (ICH) on post-treatment imaging and mortality at 3 months. We used both the radiological classification of ICH (rICH)8 and the NINDS criteria of symptomatic ICH (sICH) defined as any new ICH on follow-up imaging with any clinical deterioration within the first 7 days.9
Continuous data were presented as mean (SD) or median (IQR) based on the distribution. Categorical variables were presented as number (%). The Mann–Whitney U test and Kruskall–Wallis tests were performed to test for statistical differences in continuous parameters between two groups or three groups. The χ2test or the Fisher exact test (based on expected frequency) were used to compare categorical variables between groups. A Bonferroni correction was used for multiple comparisons. We adjusted the P value level at 2.5% for two hypotheses tested. Outcome variables at 3 months were mRS scores (0–2 vs 3–6), mortality, rICH, and sICH. Univariate and multivariate logistic regression models were used to study predictive factors of outcomes. From univariate analysis we selected variables with a P value <0.25 (statistical criterion) and looked at multicollinearity between variables. The final model was adjusted on confounding factors. To ensure stability of our final model, we only used variables with at least 10 events. 2.5% and 5% levels of significance were used. SPSS version 19 and SAS version 9.4 were used for data analysis.
This study was approved by the Institutional Review Board of Nantes University Hospital for both registries (no RC17_0274) and by the Commission Nationale de l’Informatique et des Libertés (no 2017–028). Our data center has ruled out the possibility of patient overlap in our registries.
Of the 367 patients included in the NTF and Nantes University Hospital MT registries, 333 patients fulfilled the inclusion criteria (figure 1), of which 40 were in the AP-MT group (12%), 105 in the NAP-MT group (31%), and 188 in the NAP-IVTMT group (57%).
The mean age of the overall population was 64±15 years and the sex ratio was 1.4. Prior hypertension and atrial fibrillation were present in 178 (53%) and 80 patients (24%), respectively. Median NIHSS score on admission was 17±8 and mean ASPECT score was 7±2. The median time from stroke onset to groin puncture was 235 min (IQR 182–300) and the rate of recanalization with mTICI ≥2b was 78%. There were no differences between groups in the use of antiplatelets (aspirin, clopidogrel, and ticagrelor) before AIS. Antiplatelets were used in three patients in the AP-MT group (1%), nine in the NAP-MT group (9%), and 42 in the NAP-IVTMT group (12.6%).
Anticoagulation therapies in the AP groups were VKA in 30 patients (75%, mean INR 1.95±0.084), heparin in 6 (15%, mean TCA 2.15±0.88) and NOACs in 4 (10%).
Baseline characteristics were similar between groups, except for age which was significantly higher in the AP-MT group. The atrial fibrillation rate and ASPECT score were also significantly higher in the AP-MT group (table 1).
A significantly lower PT was found in the AP-MT group (AP-MT group: 45±17%; NAP-MT group: 94±12%; NAP-IVTMT group: 96±12%; P<0.001). According to the TOAST classification, the distribution of etiologies was significantly different between groups (P<0.001), with a higher rate of cardioembolic stroke in the AP-MT group (31/40, 82%).
Moreover, compared with the NAP-IVTMT group, the AP-MT group significantly more often had a history of stroke. We found a trend towards a shorter time from onset to groin puncture and higher use of IAT (table 1).
Efficacy and outcome
mRS at 3 months was available in 313 of 333 patients (94%); mRS ≤2 was found in 37% (14/38) of the AP-MT group, 51% (52/102) of the NAP-MT group, and 59% (102/173) of the NAP-IVTMT group (figure 2). Compared with the NAP-IVTMT group, patients in the AP-MT group had significantly lower rates of favorable 3-month outcome in univariate analysis (P=0.01) (table 2).
Multivariate analysis did not show significant differences between the three groups (table 3). However, there was a trend towards a lower risk of poor clinical outcome in the NAP-IVTMT group compared with the AP-MT-group (OR 0.29, 95% CI 0.10 to 0.87, P=0.07).
Age >80 years (P=0.003), rICH (P<0.001), lower ASPECTS (P=0.05), and NIHSS ≥16 were independent risk factors of an unfavorable functional outcome (see online appendix 1).
Supplementary file 1
The overall rICH rate was 29% and the overall sICH rate was 7%. There was no significant difference between groups for the rate of rICH or sICH in univariate analysis (table 1A). Multivariate analysis showed that the NAP-IVTMT group had a significantly higher risk of rICH compared with the AP-MT-group (OR 2.77, 95% CI 1.01 to 7.61, P=0.05). The risk of rICH was not significantly higher in the NAP-MT group compared with the AP-MT group. No difference between groups was found for the risk of sICH (table 3).
Higher creatinine clearance (P=0.008) and MCA occlusion compared with other arterial occlusion sites (P=0.004) remained independently associated with a lower risk of sICH after multivariate analysis (see online appendix 2).
Regarding mortality, there was a higher risk of death at 3 months in the AP-MT group (n=10/38, 26%) compared with the NAP-IVTMT group (n=14/173, 8%, P=0.001) in univariate analysis (table 1B). Multivariate analysis confirmed a higher risk of death at 3 months in the AP-MT group compared with the NAP-IVTMT group (OR 0.26, 95% CI 0.09 to 0.76, P=0.05), but there was no significant difference between the AP-MT and NAP-MT groups (table 3).
Thirty-seven patients died within 3 months post-stroke, 28 of them (76%) within the first month and 20 (54%) due to a neurologic cause. In the AP-MT group, 10 patients were dead at 3 months: seven patients (70%) died in the first month and six (60%) due to a neurologic cause.
Prior hypertension (P=0.04) was an independent risk factor for death at 90 days (see online appendix 3).
The main finding of our work is that MT in APs seems as safe and efficient as MT in NAPs. Our results are in line with recent studies analyzing the results of MT in APs.10 11 Of note, one can expect that recanalization of a large occlusion vessel in APs is at higher risk of ICH,12 but we found no difference in terms of rICH between the AP-MT group (23%) and the NAP-MT group (25%). Regarding the risk of rICH or sICH in this context, other studies also found no difference between APs and NAPs.13 14
In our study the rates of good clinical outcome (37%) and death at 3 months (26%) in the AP-MT group were similar to the most comparable study by Rebello et al.11 Of note, our study is the first to report a higher risk of death at 3 months in the AP-MT group compared with the NAP-IVTMT group (P=0.05). These findings cannot be explained by rICH or sICH because we found a lower risk of rICH (P=0.05) and a similar risk of sICH in the AP-MT group compared with the NAP-IVTMT group (P=0.77). Rates of poor clinical outcome and death in the NAP-IVTMT group were lower (41% and 8%, respectively) than those in the NAP-IVTMT group reported by Rebello et al (67% and 22%, respectively). This discrepancy might explain our findings regarding death at 3 months. Overall, and to explain the worse results in the AP-MT-group compared with the NAP-IVTMT-group, APs in our study had higher rates of cardiovascular (myocardial infarcts) and respiratory (acute pulmonary oedema) complications regarding age and comorbidities compared with patients in the NAP-IVTMT,group.
Compared with the AP-MT group, the NAP-IVTMT group had a longer time from onset to groin puncture (P=0.03). This is in line with previous studies that observed a 36 min delay from imaging to groin puncture due to use of IVT prior to MT compared with MT alone.15 16 However, we also found a trend toward a higher rate of good clinical outcome (mRS ≤2 at 3 months) in the NAP-IVTMT group (59%) compared with the AP-MT group (37%) (P=0.07). Whether IVT prior to MT is beneficial in patients with large vessel occlusion is still a matter of debate.17 18 Large RCTs will soon begin in order to gain more insight into this question.
In our study we studied APs with data from large multicentric prospective and consecutive registries. As an important strength of our study, the patients in the AP-MT group were not treated by any IVT, in contrast to recent studies analyzing MT in APs.10 14 17–21 Also, contrary to previous studies,22 our patients were treated by second-generation MT devices only. This allowed a more accurate comparison between groups, considering the difference in terms of bleeding risk, recanalization results and, as a consequence, clinical outcome.23
Some limitations should be noted in our analysis. First, our results have to be confirmed in a larger study since our sample size was probably too small in the AP-MT group to proof safety. Second, we used observational registries because a randomized study cannot be ethical in this context.
There were some differences in terms of baseline characteristics. As expected, patients in the AP-MT group were significantly older, had higher rates of stroke history and atrial fibrillation, a lower PT level, and a higher rate of cardioembolic stroke. These differences between groups are frequently found in this type of study because these characteristics are correlated and anticoagulation is the treatment to prevent ischemic stroke.24 25
The type of anesthesia procedure (general anesthesia or conscious sedation) was not recorded in the groups studied in our analysis. This could be a limitation in our analysis as worse outcomes after endovascular thrombectomy have been reported to be associated with general anesthesia.26 However, this finding is still a matter of debate.27
The ASPECT score was higher in the AP-MT group. This might be explained by a higher rate of CT as the initial imaging modality in the AP-MT group (AP-MT group: n=16/40, 44%; NAP-MT group: n=27/105, 32%; NAP-IVTMT group: 36/188, 16%; P=0.006). Indeed, compared with MRI, ASPECTS is probably overrated by CT.28 Moreover, patients in the AP-MT group were treated with different anticoagulation therapies (VKA 75%, heparin 15%, novel oral anticoagulants 10%). Last but not least, there was no core laboratory for ASPECTS, mTICI, rICH, or sICH evaluations and these were self-adjudicated.
Regarding intracranial bleeding and functional outcome, MT in APs seems as safe and efficient as MT in NAPs. As suggested by the guidelines,29 MT should be considered to treat APs with large vessel occlusion. However, there seems to be a higher risk of death at 3 months in APs compared with NAPs treated with IVT and MT. APs probably need specific post-procedural management in order to prevent an unfavorable outcome due to poorer baseline conditions. Larger prospective studies are needed to confirm our findings.
We acknowledge the previous and present colleagues who made this study possible. This study was supported by the Société Française de NeuroRadiologie (SFNR) and the Société Française de NeuroVasculaire (SFNV).
Contributors VLA had the concept of the study, collected data and wrote the manuscript. ME wrote and critically reviewed the manuscript, and corrected the spelling and grammar. MS-A collected data and critically reviewed the manuscript. NT collected data. BD-G performed the statistical analysis. BG, MM and HD critically reviewed the manuscript. RB wrote and critically reviewed the manuscript.
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 None declared.
Patient consent Not required.
Ethics approval This study was approved by the Institutional Review Board of Nantes University Hospital (no. RC17_0274) and by the Commission Nationale de l’Informatique et des Libertés (no. 2017-028).
Provenance and peer review Not commissioned; externally peer reviewed.
Collaborators Roy M, Gaultier A, Daumas-Duport B, Catar O, Lecluse A, Godard S, Guillaume M, Pasco A, Lemoine I, Ledure S, Rouanet F, Sibon I, Barreau X, Berge J, Menegon P, Dousset V, Lamande B, Ferrier A, Jean B, Chabert E, Gabrillarges J, Behechti N, Kazemi A, Ricolfi F, Proust M, Tahon F, Vasdev A, Boustia F, Kalsoum E, Aguettaz P, Leclerc X, Saleme S, Mounayer C, Saleme S, Gautier G, Brunel H, Tonnelet R, Anxionnat R, Bracard S, Moynier M, Riquelme C, Machi P, Arquizan C, Costalat V, Bonafe A, Arnoult G, Pierot L, Kestens F, Ronziere T, Gauvrit JY, Januel AC, Bonneville F, Cognard C, Papagiannaki C, Bibi R, Herbreteau D, Naggara O, Puccinelli F, Lapergue B, Coskun O, Guedin P, Rodesch G, Hosseini H, Tuilier T, Gallas S, Gaston A, Redjem H, Pellen AS, Abricard M, Blanc R, Piotin M, Gory B, Riva R, Di Maria F, Sourour N, Clarencon F, Blanchard L, Velasco S.
Correction notice Since this article was published online the list of collaborators has been updated in Pubmed.
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