Background and purpose The present study was conducted with the objective of evaluating the safety of primary mechanical thrombectomy (MT) in patients with large vessel occlusion (LVO) stroke and comorbidities that preclude treatment with IV thrombolysis (IVT), compared with patients who received standard IVT treatment followed by MT. Secondary objectives were to analyse the recanalization rate and outcomes.
Methods A prospective observational multicenter study (FUN-TPA) that recruited patients treated within 4.5 hours of symptom onset was performed. Treatments were IVT followed by MT if occlusion persisted, or primary MT when IVT was contraindicated. Outcome measures were procedural complications, symptomatic intracranial hemorrhage (SICH), recanalization rate, National Institutes of Health Stroke Scale (NIHSS) score at 7 days, modified Rankin Scale (mRS) score and mortality at 90 days.
Results Of 131 patients, 21 (16%) had medical contraindications for IVT and were treated primarily with MT whereas 110 (84%) underwent IVT, followed by MT in 53 cases (40%). The recanalization rate and procedural complications were similar in the two groups. There were no SICHs after primary MT vs 3 (6%) after IVT+MT. Nine patients (43%) in the primary MT group achieved independence (mRS 0–2) compared with 36 (68%) in the IVT+MT group (p=0.046). Mortality rates in the two groups were 14% (n=3) vs 4% (n=2) (p=0.13). Adjusted ORs for independence in patients receiving standard IVT+MT vs MT in patients with medical contraindications for IVT were 2.8 (95% CI 0.99 to 7.98) and 0.24 (95% CI 0.04 to 1.52) for mortality.
Conclusions MT is safe in patients with potential comorbidity-derived risks that preclude IVT. MT should be offered, aiming for prompt recanalization, to patients with LVO stroke unsuitable for IVT.
Trial registration number NCT02164357; Results.
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IV thrombolysis (IVT) has been the first-line treatment for acute ischemic stroke within 4.5 hours from symptom onset in patients without contraindications.1 ,2 Based on results from recent clinical trials,3–7 current guidelines recommend mechanical thrombectomy (MT) using stent retrievers as an adjunct therapy to standard treatment with IVT for stroke patients with causative occlusion of the internal carotid artery (ICA) or proximal middle cerebral artery (MCA), in whom treatment can be initiated within 6 hours of symptom onset.1 ,8 ,9
Patients with intracranial large vessel occlusion (LVO) stroke not suitable for IVT can be considered for MT. However, individual clinical trials were not sufficiently powered to determine the clinical efficacy of MT with stent retrievers in patients who had not received prior IVT due to either late presentation beyond the 4.5 hours window of opportunity or to clinical contraindications for thrombolysis. Subsequent meta-analyses showed that these patients might also benefit from MT,10–12 and that MT is effective in LVO stroke independent of pretreatment with IVT.13 A comparison between primary MT and IVT+MT was made in a retrospective study in patients suitable for IVT,14 concluding that primary MT is equally effective as bridging therapy with lower rates of asymptomatic cerebral hemorrhage and mortality. However, patients unqualified for IVT due to medical contraindications (other than the time window) might be at higher risk if treated with MT due to the comorbidities that preclude IVT. This issue has not been systematically assessed. A randomized trial designed to compare thrombectomy with standard care in patients ineligible for thrombolysis was suspended due to recruitment failure.15
The present study was designed to compare the safety of early MT within the same window of opportunity for IVT (ie, 4.5 hours from symptom onset) in patients with medical contraindications for IVT, with standard MT treatment following IVT in patients with LVO stroke. Secondary objectives were to compare the recanalization rate and outcomes between groups.
Fast Thrombectomy in UNtreated TPA patients (FUN-TPA) (NCT02164357 https://clinicaltrials.gov/) is a prospective observational multicenter study. Included patients had intracranial LVO in the anterior or posterior circulation with and without contraindications for IVT who were considered for MT within 4.5 hours from symptom onset. The study was initiated when the benefits of MT over IVT had not been clearly demonstrated and was interrupted after publication of trials that consistently showed the efficacy of MT in addition to best medical treatment in LVO stroke.3–7
Patients were managed according to clinical protocols that followed current guidelines adhered to by all the participating centers that are part of the Madrid Stroke Network.16–19 The Madrid Stroke Network is a collaborative system of care in which MT is provided 24/7 by two nodes composed of three comprehensive stroke centers (CSCs) covering approximately 3.2 million people each, in a weekly rotating shift.19 In this collaborative system, every stroke patient is dispatched to the nearest CSC by emergency medical services. Secondary transfers for MT are performed when the nearest CSC is not the one on call for MT.
On arrival, a plain CT was obtained to set the indication for reperfusion therapies and patients were allocated to standard IVT or to primary MT as first choice when there were clinical contraindications for IVT. Immediately after the plain CT, LVO was diagnosed using CT angiography (CTA) or transcranial Doppler (TCD) as a screening tool, followed by CTA for confirmation. Initiation of treatment (whether IVT or primary MT) needed to be within 4.5 hours of symptom onset. IVT was started immediately after plain CT in patients without contraindications. Protocols for endovascular treatment were launched as soon as LVO was confirmed in patients with contraindications for IVT, and immediately after the start of IVT in patients who received bridging thrombolysis. Proceedings for MT were aborted if recanalization of the previously occluded vessel was verified by TCD monitoring, CTA, or during the pre-procedural angiography.
The study received approval from the ethics committees of all the participating centers and was authorized by the Spanish Agency for Drugs and Health Products (Agencia Española de Medicamentos y Productos Sanitarios; AEMPS). It was conducted according to the Declaration of Helsinki. Patients or their proxies provided written informed consent.
The study was supported by the Clinical Trials Unit of the University Hospital Ramón y Cajal, Madrid, Spain with respect to regulatory and pharmacovigilance aspects, as well as monitoring of performance and safety issues.
The data collected included demographic characteristics, risk factors, clinical severity on admission according to the National Institutes of Health Stroke Scale (NIHSS), severity of ischemic changes graded using the Alberta Stroke Program Early CT Score (ASPECTS) in baseline non-contrast CT (NCCT) and CTA source images,20 ,21 site of occlusion, treatment received, reasons for exclusion from IVT (when applicable), time from symptom onset to diagnostic and therapeutic procedures, recanalization achieved (or not), and time to verification of recanalization (when applicable).
Vessel occlusion or recanalization was graded according to the Thrombolysis in Brain Ischemia (TIBI) grading system22 and/or the Thrombolysis in Cerebral Infarction (TICI) grading system.23 Successful recanalization was considered to be TIBI 4 or 5 and TICI 2b or 3. Timing from symptom onset to recanalization was precisely recorded in patients undergoing MT. For patients who did not undergo MT because of recanalization, time to recanalization was considered as the point in time at which patency of a previously occluded vessel was verified using TCD or CTA. A follow-up CT scan was performed at 24 hours from symptom onset or earlier, in case of worsening, to rule out cerebral hemorrhage. Hemorrhagic transformation after treatment was classified according to SITS-MOST criteria.24 Recorded safety variables included symptomatic intracerebral hemorrhage (SICH), defined as parenchymal hemorrhage associated with a neurological deterioration of ≥4 points from the lowest NIHSS score from baseline or leading to death, early mortality (within 7 days), and complications arising from procedures. Outcome variables analysed included recanalization rate, NIHSS score at 7 days or at discharge from hospital, and mRS score at 3 months. Good outcomes were considered to be a significant improvement of >10 points in the NIHSS score at 7 days or at discharge compared with baseline, or an NIHSS score of 0–1 and independence at 3 months (mRS 0–2).
Sample size estimation and data analyses
The study sample size was calculated based on a standard test of non-inferiority (one-tailed test). Considering α=0.025, a power of 80% and δ=12%, 62 patients per cohort of treatment (primary MT or IVT) needed to be included. Data are expressed as median and IQRs for continuous variables or as absolute and relative frequencies for categorical variables. Baseline characteristics were compared between patients with and without contraindications for IVT (ie, those receiving primary MT and those receiving IVT as the initial treatment). For the purpose of the study, comparisons of outcomes were made between primary MT and IVT+MT, and patients receiving only IVT not followed by MT due to recanalization or any exclusion criteria for MT were excluded from the analysis of outcomes. The Student's t-test, Mann-Whitney U test, Pearson's χ2 test or Fisher's exact test were used as appropriate.
To analyse differences in outcomes after MT in patients with and without contraindications for IVT, predictive models were adjusted using backward stepwise multivariate logistic regression. Variables considered in the multivariate models were treatment approach (ie, standard treatment with IVT+MT vs MT) and those showing significant differences in the univariate comparison.
All analyses were performed with the Stata/SE V.12.1 statistical package (StataCorp LP, USA).
Recruitment extended from July 2012 to February 2015 and was stopped after the publication of the first three randomized trials demonstrating effectiveness and safety of MT in addition to standard treatment (MR CLEAN, ESCAPE, and EXTEND-IA)3–5 and because of the low recruitment rate in the primary MT group. In total, 137 patients were included. Excluded from the overall study group were four patients in whom LVO was not confirmed, one patient in whom recanalization was not verified following tissue plasminogen activator (tPA) treatment, and one patient in whom primary MT was initiated more than 4.5 hours after symptom onset. The final study sample consisted of 131 patients.
The flow of patients through the study is shown in figure 1. Primary MT with stent retrievers was used in 21 patients with contraindications for IVT (16%) and IVT in 110 patients (84%). Contraindications for IVT in patients treated with primary MT were platelet count <100 000 in one case, recent major surgery in three, a history of recent stroke within the previous 3 months in one, history of intracranial hemorrhage in one, previous anticoagulant treatment in nine cases, and other non-specified causes in six. Among patients treated with IVT, 38 (35%) achieved recanalization and 72 (65%) did not; 53 (40% of the total sample) underwent MT following IVT and 19 did not. Reasons for exclusion from MT after failure of IVT are shown in figure 1. Although IA thrombolysis was not excluded in the initial study protocol, all patients who received endovascular treatment were treated with MT using stent retrievers and no patient received rescue therapy with IA tPA. The choice of stent was at the discretion of the neurointerventionist. Most patients were treated with Solitaire (Medtronic) or Trevo (Stryker) retrievable stents. Twenty-five patients (35%) were treated under conscious sedation (7 in the primary MT group and 18 in the IVT+MT group), while 46 (65%) were treated under general anesthesia (13 in the primary MT group and 33 in the IVT+MT group).
Table 1 summarizes the baseline characteristics, risk factors, and time to procedures in the overall cohort as well as segregated with respect to treatment arm.
The recanalization rate was 81% in patients treated with primary MT and 35% in those treated with IVT (p<0.001), and 91% after combined IVT+MT (p=0.25).
Sites of occlusion in the overall study cohort and in each treatment arm are shown in table 2. The imbalance observed in the proportion of terminal ICA occlusions and M2 occlusions in the group receiving combined IVT+MT treatment reflects the lower efficacy of IVT in larger vessel occlusions compared with more distal occlusions such as M2.
Recanalization rates segregated with respect to occluded artery in each treatment arm are shown in table 3. Recanalization was the primary predictor of good outcome. Early significant improvement was 72% vs 14% (p<0.001), mortality rate was 5% vs 21% (p=0.005) and independence at 3 months 69% vs 32% (p<0.001) in patients who achieved recanalization compared with those who did not.
There were 23 complications associated with the endovascular procedure. The rate of complications did not differ between the groups: 14 transient vasospasms (3 (14%) after primary MT and 11 (21%) after combined treatment, p=0.7); 3 vessel dissections or perforations (1 (4%) after primary MT and 2 (4%) after combined treatment); 2 distal embolisms (1 in each group (4% vs 2%), p=1); and 4 groin hematomas (all in the combined treatment group (8%), p=0.57). None of these complications resulted in poorer clinical status or in death.
Intracranial hemorrhages within the first 24 hours from symptom onset occurred in two patients (9%) treated with primary MT and in 22 (20%) treated with IVT followed or not by MT (p=0.36). Hemorrhages were symptomatic in five patients (4%), all treated with IVT. The rate of SICH was 6% in patients treated with IVT+MT. No symptomatic hemorrhages occurred in patients treated with primary MT.
Other systemic complications (eg, fever, pneumonia, urinary tract infections) occurred in eight cases (38%) in the primary MT group and 12 (23%) in the combined treatment group (p=0.17).
The rate of early mortality in the study population was 5%. All cases of early death were a consequence of the severity of the infarct. Early mortality rates did not differ between groups.
Outcomes including time to recanalization in patients treated with primary MT and after bridging IVT are summarized in table 4.
Time to recanalization was greater in patients undergoing bridging IVT, which reflects the longer time to initiation of treatment, as shown in table 1. More patients in the bridging therapy group showed early significant improvement, but the differences were not significant. A higher rate of independence (mRS 0–2) was observed in patients treated with IVT+MT compared with primary MT (OR 2.8; 95% CI 0.99 to 7.98; p=0.05), with a tendency towards lower mortality (OR 0.24; 95% CI 0.04 to 1.52; p=0.12) (figure 2).
Predictive models using multivariate logistic regression analysis included age, time to reperfusion, treatment with anticoagulants, NIHSS on admission, and type of treatment. After adjustment for covariates, no significant difference in predicting a good outcome after MT was found between patients with and without contraindications for IVT (OR 0.68; 95% CI 0.11 to 4.13; p=0.68).
Our study shows that primary MT is safe in patients with LVO stroke and medical contraindications for IVT. The rate of complications from the interventional procedures was low and did not differ between groups, although there was a tendency to a higher frequency of vasospasm in those in whom MT was performed after bridging thrombolysis. There was also a higher frequency of groin hematoma development as well as a higher rate of intracranial bleeding in patients treated primarily with IVT. The differences did not reach statistical significance in our study, which can be explained by the low frequency of events and the small sample size; however, the results are in accordance with previous data indicating a higher frequency of SICH in patients undergoing MT after IVT.14 ,25 It is noteworthy that, despite the potential risks derived from previous anticoagulant treatment or a previous history of ischemic or hemorrhagic stroke that precluded IVT in the majority of patients treated with primary MT, the rate of cerebral hemorrhage was very low and there were no SICHs in this group.
The systemic complications were primarily infectious diseases, which were more frequent in patients treated with primary MT. The complications might be related to the greater severity of stroke or to the comorbidities that precluded the application of IVT in these patients. Differences were not significant, however, and the potential risks appear to be outweighed by the benefits of successful and prompt recanalization achieved after MT, given the odds of a good outcome did not differ between groups after adjustment for confounders. In agreement with earlier data, we noted that MT achieves higher recanalization rates than IVT, and recanalization is the most important predictive factor of a good outcome. Our study therefore subscribes to the recommendation of rapid endovascular treatment with MT for patients with LVO stroke unsuitable for IVT.
Safety issues were not reported for primary MT in the recent clinical trials that recruited patients who were not receiving IVT (MR CLEAN, ESCAPE, REVASCAT).3 ,4 ,7 ,10–13 However, differential analyses by subgroups, particularly considering patients with contraindications other than the time window for IVT, have not been provided. Our study offers some evidence that primary MT in these patients can be safely applied.
Our results are consistent with previous retrospective studies showing that complication rates and long-term favorable outcomes were similar in patients receiving IVT+MT and in those receiving MT alone.25–27 One of these studies recorded a trend toward poorer outcomes among patients with clinical contraindications for IVT.26 The rates of mortality in this study were much higher (26.7% in the IVT+MT group and 37.7% in the MT group) and the rates of independence were much lower (35.2% and 32%, respectively) than in our series. Our outcomes (independence and mortality) were more comparable to the results in the abovementioned recent trials.3 ,4 ,7
Comparison of outcomes was a secondary objective of our study. Despite earlier recanalization and a lower hemorrhagic complication rate, patients treated with primary MT showed poorer outcomes than those treated after standard IVT. Comorbidities that preclude IVT and severity on admission in the primary MT cohort might account for this difference, which was not significant in the multivariate analysis. Due to the small sample size, however, this study might be underpowered to demonstrate significant differences regarding outcomes. In light of results similar to ours from previous studies showing similar recanalization rates and outcomes after primary MT as after bridging thrombolysis with fewer bleeding complications, it has been suggested that bridging IVT might be unnecessary in patients with LVO stroke if direct MT is rapidly available.14 ,25 However, this hypothesis has yet to be confirmed. In the absence of a randomized clinical trial comparing direct MT with bridging therapy, our data support the indication of primary MT only in patients in whom IVT is contraindicated.
The primary limitation of our study is that few patients undergoing primary MT were included. It limits its statistical power and ability to draw conclusions. Further, the study was observational, in which the best available treatment was indicated for every patient; therefore, we cannot categorically rule out significant differences in outcomes between groups. A propensity score matching analysis would be more appropriate, but the small sample size does not allow it. The strength of the study, however, is that it is prospective and no patients were lost to follow-up, allowing accurate interpretation of outcomes. Also, it reflects clinical practice so the results regarding safety can be generalized.
Our study shows that primary MT is safe for patients with medical contraindications for IVT, with lower rates of hemorrhagic complications. These findings increase support for the recommendation of rapid endovascular MT, aiming for prompt recanalization, in patients with LVO stroke unsuitable for IVT.
Maria Angeles Galvez and Itziar de Pablo (Ethics Committee, University Hospital Ramón y Cajal, Madrid, Spain) provided support with the regulatory documentation. Marta Del Álamo, Raquel Molina, Elisa Lorente and Marisa Serrano (Clinical Trials Unit, University Hospital Ramón y Cajal, Madrid, Spain) monitored the study. Editorial assistance was provided by Peter R Turner of Tscimed.com and Juliette Siegfried and her team at ServingMed.com.
Contributors All authors have made substantial contributions to the design of the work; acquisition, analysis, or interpretation of data; drafting the work or revising it critically for important intellectual content. All authors have approved the final version to be published. All authors agree 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. Individual contributions: MAdL: overall responsibility for the manuscript, study concept and design, data acquisition, statistical analyses and interpretation, drafting the manuscript, final critical review of the manuscript. PM-S: study concept and design, data acquisition, final critical review of the manuscript. AG-P: study design, data acquisition, final critical review of the manuscript. MMK: data acquisition, statistical analysis and interpretation, revision of the manuscript. PC, BES-C, FD-O, GR-A and AG-N: data acquisition, revision of the manuscript. RF, FS-H and EF: radiological data acquisition, revision of the manuscript. ED-T: contribution to design of the work, revision of the manuscript. BF: data acquisition, drafting the manuscript, final critical review of the manuscript.
Funding This work was supported by Fundación Mutua Madrileña.
Competing interests None declared.
Ethics approval Ethical approval was obtained from the Ethics Committee University Hospital Ramón y Cajal and the Spanish Agency for Drugs and Health Products (Agencia Española de Medicamentos y Productos Sanitarios; AEMPS).
Provenance and peer review Not commissioned; internally peer reviewed.
Data sharing statement The study protocol is available upon request from the corresponding author.