Background There is conflicting evidence on the utility of intravenous (IV) alteplase in patients with emergent large vessel occlusion (ELVO) treated with mechanical thrombectomy (MT).
Methods This was a post hoc analysis of the COMPASS: a trial of aspiration thrombectomy versus stent retriever thrombectomy as first-line approach for large vessel occlusion. We compared clinical, procedural and angiographic outcomes of patients with and without prior IV alteplase administration.
Results In the COMPASS trial, 235 patients had presented to the hospital within the first 4 hours of stroke symptom onset and were eligible for analysis. On univariate analysis, administration of IV alteplase prior to MT was found to be significantly associated with favorable outcomes (modified Rankin scale (mRS) 0–2 at 3 months; 55.6% vs 40.0% in the MT-only group, P=0.037). However, on multivariate analysis, only baseline (pre-stroke) mRS, admission National Institutes of Health Stroke Scale (NIHSS) score and age were identified as independent predictors of favorable outcomes at 3 months. We found higher final thrombolysis in cerebral infarction (TICI) 2b/3 rates in patients without the use of alteplase prior to the aspiration first approach (100.0% vs 87.9% in IV altepase +aspiration first MT, P=0.03). In the stent retriever first group, final TICI 2b/3 rates were identical in patients with and without IV alteplase administration (87.5% and 87.5%, P=1.0).
Conclusions Prior administration of IV alteplase may adversely affect the efficacy of aspiration, but does not seem to influence the stent retriever first approach to MT in patients with anterior circulation ELVO.
Data availability statement
Data are available upon reasonable request.Requests for data availability should be addressed to COMPASS principal investigators.
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Both intravenous (IV) thrombolysis with alteplase and mechanical thrombectomy (MT) are currently recommended in patients with acute ischemic stroke (AIS) from emergent large vessel occlusion (ELVO). There is conflicting evidence on the utility of IV alteplase in patients with ELVO treated with MT. Three recent randomized trials of direct MT versus combination therapy with IV alteplase and MT (Direct Intraarterial Thrombectomy in Order to Revascularize Acute Ischemic Stroke Patients with Large Vessel Occlusion Efficiently in Chinese Tertiary Hospitals (DIRECT-MT),1 the Randomized Study of EVT With vs Without Intravenous Recombinant Tissue-Type Plasminogen Activator in Acute Stroke With ICA and M1 Occlusion (SKIP)2 and Multicenter Randomized Trial of Direct endovascular treatment versus bridging therapy for Acute Ischemic Stroke Due to Anterior Circulation Large Vessel Occlusion Presenting within 4.5 hours of Symptom Onset (DEVT)3) indicated similar efficacy and safety of the two treatment approaches. However, many concerns were raised in the medical stroke community regarding the generalizability and interpretation of these results.4 5
Many studies including meta-analyses of randomized trials of the combined versus MT-only approaches, and secondary analyses of randomized MT trials and prospective registries, also showed equivalent outcomes, raising concerns regarding the added role of IV altepase in patients with ELVO.6–9 At the same time, several studies have reported benefit of IV alteplase in patients treated with MT.10–13 Numerous explanations of the advantage (“softening” the clot, lysis of distal emboli) or adverse influence (clot breakdown, creation of distal emboli, increase in bleeding risks) of IV alteplase use prior to thrombectomy have been proposed.4 5 14
COMPASS Trial: a Direct Aspiration First Pass Technique was a prospective, multicenter, randomized, open-label, blinded outcome, core laboratory-adjudicated, non-inferiority trial to compare clinical, procedural and technical outcomes of patients with anterior circulation ELVO stroke within the first 6 hours of symptom onset treated with aspiration versus stent retriever (SR) MT as the first-line approach.15 The goal of this study was to examine whether there were differences in procedural and technical outcomes of MT depending on whether patients received IV alteplase prior to intervention using the COMPASS dataset.
COMPASS trial design
The study protocol and consent were approved by the institutional review board at each participating center. The methodology and final results of the COMPASS trial have been previously published.15 Briefly, patients presenting with ELVO within the first 6 hours of symptom onset, an Alberta Stroke Program Early CT Score (ASPECTS) ≥6 and occlusion of the internal carotid artery or middle cerebral artery M1 segment were randomly assigned (1:1) to aspiration thrombectomy (“aspiration first”) or SR thrombectomy (“SR first”). The operators were requested to do three passes with the assigned approach. In cases of persistent occlusion, any rescue therapy was allowed according to operator preference.
The primary outcome in COMPASS was functional independence at 90 days measured by achieving the modified Rankin scale (mRS) 0–2. In COMPASS, angiographic assessments of MT were performed by an independent core laboratory in a blinded manner using the thrombolysis in cerebral infarction (TICI) grading scale.16 The core laboratory defined TICI 2b as 50%–89% reperfusion, TICI 2 c as 90%–99% reperfusion and TICI 3 as 100% reperfusion, respectively. First pass effect (FPE) and modified FPE (mFPE) were defined as TICI 2c/3 and TICI 2b/3 recanalization after a single (first) pass of the treatment device, respectively.17 18 A total of 270 patients were assigned to treatment: 134 to aspiration first pass and 136 to SR first line. The primary study end point (mRS 0–2 at 90 days) was achieved by 69 patients (52.0%) in the aspiration group and 67 patients (50.0%) in the SR group, thus showing that aspiration as first pass was non-inferior to SR thrombectomy (Pnon-inferiority=0.0014).
Description of subgroup analysis
In COMPASS, in patients who were eligible for systemic thrombolysis, IV alteplase (0.9 mg/kg over 1 hour, with 10% initial bolus) was administered before MT according to the guidelines. In order to compare outcomes in patients treated with MT according to the use of IV altepase, only patients presenting to the emergency department (ED) of the first hospital of arrival within 4 hours of stroke symptom onset or last known normal were included in our analysis. This ensured that an additional 30 min were allowed for the initial clinical and imaging assessment of patients before the 4.5 hour window for IV alteplase administration. This ensured that patients who were not eligible for IV thrombolysis because of late hospital presentation outside of its recommended time window were excluded from analysis. Reasons for alteplase exclusion in patients who arrived within the time window but did not receive IV thrombolysis were not available and thus were not analyzed.
We compared procedural, angiographic and clinical outcomes in patients treated with IV alteplase plus MT versus MT alone. Patients who presented within 4 hours of symptom onset were selected for this post hoc analysis. A descriptive analysis was performed on patients with or without IV alteplase prior to MT. Percentage and proportions were used to represent categorical variables. The distribution of data was assessed using the Shapiro–Wilk test. We used means and standard deviations for continuous data. We intended to use median and interquartile ranges to describe data with skewed distribution.
Baseline characteristics, angiographic outcomes and clinical outcomes at 3 months were compared between groups with and without alteplase prior to MT. Independent t-test was used to compare continuous variables while Chi-square test was used to compare categorical variables. These variables were further compared for SR and aspiration first cohorts. We further performed multivariate analysis to determine if alteplase administration independently predicted favorable outcomes at 3 months after MT. Multinominal regression analysis was carried out. Functional independence at 3 months was the outcome of interest. The model included variables associated with functional independence with a P value of <0.1 on univariate analysis. The statistical analysis was performed using SPSS version 25. P<0.05 was considered statistically significant.
Of the 270 patients included in the COMPASS trial, 235 (87%) arrived to the ED within the first 4 hours of stroke symptom onset and were eligible for the post hoc analysis. (115 patients in the aspiration first and 120 in the SR first groups, respectively). Table 1 describes baseline demographic, clinical, imaging and procedural characteristics of the combined (IV alteplase +MT) and MT-only treatment groups. Atrial fibrillation was more frequently seen in the MT-only group when compared with the combined group (65.5% vs 38.6%, respectively, P<0.001). Other vascular risk factors, age, National Institutes of Health Stroke Scale (NIHSS) severity and the distribution of occlusion sites showed no statistically significant difference.
There was no difference between aspiration first and SR first groups as regards percentage of patients transferred from another facility for MT (44/115, 38.3% vs 48/120, 40.0%, respectively; P=0.78). In the aspiration first group, of the patients who received IV alteplase, 32.5% were transferred from an outside facility while 67.5% were direct arrivals (P=0.42). In the SR first group of patients who received IV alteplase, 36.4% were transferred from an outside facility while the remaining 63.6% of patients who received IV alteplase were direct arrivals.
Procedural details and angiographic outcomes are described in table 2. The frequency of FPE (38.6% vs 35.9%, P=0.26), mFPE (52.6% vs 53.1%, P=0.94) and the average number of passes (2.1±1.9 vs 1.9±1.4, P=042) was similar in patients with versus without alteplase administration.
Based on the univariate analysis, administration of IV alteplase prior to MT was found to be significantly associated with favorable outcomes (mRS 0–2) at 3 months (55.6% vs 40.0% in the MT-only group, P=0.037). However, multivariate analysis showed that only baseline (pre-stroke) mRS, admission NIHSS score and age were independent predictors of favorable outcomes at 3 months (table 3).
Next, procedural outcomes were analyzed separately depending on the type of MT assigned through randomization (table 4). Final TICI 2b/3 recanalization rates were higher in patients without the use of alteplase prior to the aspiration first approach when compared with the angiographic outcomes of patients receiving IV alteplase before aspiration thrombectomy (100.0% vs 87.9%, P=0.03). By contrast, in the SR first group, final successful recanalization rates TICI 2b/3 were identical in patients with and without IV alteplase administration (87.5% and 87.5%, P=1.0). Demographic and clinical features of the aspiration first and SR first groups are shown in the online supplemental tables 1 and 2).
The main finding of this post hoc analysis is that aspiration and SR first approaches to MT in patients with anterior circulation ELVO may “react” differently in the presence or absence of prior IV alteplase administration. Judging by the rates of final successful recanalization (TICI 2b/3), SR thrombectomy remains equally effective regardless of systemic thrombolysis administration, whereas aspiration first is significantly more effective in the absence of prior IV alteplase administration. One potential explanation is that alteplase indeed “softens” the thrombus, as previously proposed, and by doing so increases the chances of clot fragmentation while retrieving the aspiration catheter and diminishing the overall success rate of aspiration thrombectomy. Using the FPE metric of procedural success, although the differences did not reach statistical significance, there were also trends in higher FPE in the aspiration first group patients who did not receive the alteplase, whereas the opposite trend could be observed in the SR-only group (tendency towards higher FPE rates in patients treated with IV alteplase). This further supports the hypothesis that alteplase may indeed “soften” the clot, which in a case of SR could be more beneficial by allowing the struts of the device to deeper permeate the clot.
The COMPASS trial design did not include collection of retrieved thrombi at the end of successful MT cases thus this critical piece of data regarding the influence of clot composition on the effect of thrombolysis remains to be determined. For instance, one intriguing direction of future research is to study whether IV thrombolysis mainly negatively affects red blood cell-rich thrombi treated with aspiration, whereas in cases of ELVO treated with SR, it proves beneficial.
The strengths of this study are the use of high-quality data that were collected prospectively and independently adjudicated by an imaging core laboratory in a blinded fashion. Individual operators tend to greatly overestimate the degree of angiographic reperfusion after MT.19 Relying on imaging data that are independently evaluated by a core laboratory is imperative for accurate interpretation of results. Besides, both treatment arms (aspiration and SR first) were subject to randomization, reducing the risk of bias.
The main limitation of this study is its relatively small sample size, which did not allow us to study the effects of imaging characteristics of occlusion site (thrombus), as well as lack of histologic data on thrombus composition. The insufficient sample size might explain why no statistical significance was seen in FPE or mFPE as regards the use of IV alteplase. However, in table 4, we do observe non-significant trends towards higher FPE and mFPE in the aspiration first group and lower FPE and mFPE in the SR first groups of patients who did not receive IV alteplase. Further studies are needed to ascertain our hypothesis of the opposite effects of alteplase on the efficacy of these two thrombectomy approaches.
The findings only reflect the effect of systemic thrombolysis seen with the use of alteplase, and should not be extrapolated to cases treated with another thrombolytic, tenecteplase (TNK), which is becoming more commonly used in modern practice. TNK appears to have much stronger evidence of its positive effect in ELVO patients treated with MT. Also, the COMPASS trial was not powered to detect the effect of IV alteplase on MT.
Prior administration of IV alteplase may adversely affect the efficacy of aspiration, but does not seem to influence the SR first approach to MT in patients with anterior circulation ELVO. The findings highlight the need for further evidence that could potentially change the standard of care for the treatment of ELVO.
Data availability statement
Data are available upon reasonable request.Requests for data availability should be addressed to COMPASS principal investigators.
Patient consent for publication
The study was approved by the IRB of Medical University of South Carolina (MODCR00001512).
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Contributors MM, MW, JM, AHS, AT: study concept and design. MM, MW: manuscript writing. MW, MM: statistical analysis. All authors edited the manuscript and approved the final version. AHS as guarantor accepts full responsibility for the work and/or the conduct of the study, had access to the data, and controlled the decision to publish.
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 MM: Grant NIH R21NS109575. Consultant: Medtronic, Cerenovus. Stock options: Brain Q, Endostream Serenity Medical, Synchron. Assistant Editor for JNIS. MW: None. JTF: Consultant: Stryker, Penumbra, Microvention. Stocks: Cerebrotech, The Stroke Project. RDL: Consultant: Cerenovus, Stryker, Penumbra, Imperative Care, Siemens. Stock options: Synchron, Endostream, Q’Apel. Social Media Editor for JNIS. DF: Consultant: Balt USA, Penumbra, Cerenovus, Stryker, Genentech, Shape Memory Medical, Marbelhead, Medtronic, MENTICE, Neuorogami, RAPID AI, Rapid Medical, Phenox. Associate Editor for JNIS. EIL: Consultant: Penumbra, NextGen Biologics, Rapid Medical, Cognition Medical, Three Rivers Medical, Stryker, MedX, Endostream Medical. KS: Consultant: Penumbra, Canon Medical Systems, Medtronic, Jacobs Institute, Neurovascular Diagnostics. RAH: Consultant: Penumbra, Endostream, Cerebrotech, Synchron, InNeuroCo, Medtronic, Microvention, Stryker, Cerenovus; Elum, Three Rivers. KW: Consultant: Penumbra. IC: Consultant: Medtronic, Microvention, Penumbra. Stocks: Cerenovus, Serenity Medical, Cerebrotech, Three Rivers Medical, Q’apel. ATR: Consultant: Penumbra, Microvention, Stryker. DF: Consultant: Penumbra, Cerenovus, Stryker, Genentech, Shape Memory Medical, Siemens. JEDA: Consultant: Penumbra, Medtronic. MK: Consultant: Penumbra, Medtronic, Endostream. ASA: Consultant: Cerenovus, Medtronic, Microvention, Penumbra, Scientia, Siemens, Stryker. Stocks: Bendit, Cerebrotech, Endostream, Magneto, Marblehead, Neurogami, Serenity, Synchron, Triad, Vascular Simulations. BWB: Consultant: Penumbra, Medtronic, Stryker, Cerenovus, Viz.ai, 880 Medical, Route 92, Artio Medical. JE: Consultant: Penumbra, Medtronic, Stryker, Route 92 Medical. IL: Consultant: Penumbra, Medtronic, Stryker, Microvention, InNeuroCo, Three Rivers. KMF: Associate Editor for JNIS. AT: Consultant: Cardinal Consulting, Cerenovus, Corindus, Medtronic, Siemens, 880 Medical. Stock: Cerebrotech, Endostream. Imperative Care, Three Rivers Medical, Vastrax, Shape Memory, Synchron, Serenity Medical, Blink TBI, Echovate, RIST, Apama, Q’Apel, VizAi, Early Bird Medical, Rapid Medical, Spinnaker Medical. AHS: Stocks: Adona Medical, Inc., Amnis Therapeutics, Bend IT Technologies, Ltd, BlinkTBI, Inc., Buffalo Technology Partners, Inc., Cardinal Consultants, LLC, Cerebrotech Medical Systems, Inc., Cerevatech Medical, Inc., Cognition Medical, CVAID Ltd, Endostream Medical, Ltd, Imperative Care, Inc., Instylla, Inc., International Medical Distribution Partners, Launch NY, Inc., NeuroRadial Technologies, Inc., Neurotechnology Investors, Neurovascular Diagnostics, Inc., PerFlow Medical, Ltd, Q’Apel Medical, Inc., QAS.ai, Inc., Radical Catheter Technologies, Inc., Rebound Therapeutics Corp. (purchased 2019 by Integra Lifesciences, Corp.), Rist Neurovascular, Inc. (purchased 2020 by Medtronic), Sense Diagnostics, Inc., Serenity Medical, Inc., Silk Road Medical, SongBird Therapy, Spinnaker Medical, Inc., StimMed, LLC, Synchron, Inc., Three Rivers Medical, Inc., Truvic Medical, Inc., Tulavi Therapeutics, Inc., Vastrax, LLC, VICIS, Inc., Viseon, Inc. Consultant/Advisory Board: Amnis Therapeutics, Apellis Pharmaceuticals, Inc., Boston Scientific, Canon Medical Systems USA, Inc., Cardinal Health 200, LLC, Cerebrotech Medical Systems, Inc., Cerenovus, Cerevatech Medical, Inc., Cordis, Corindus, Inc., Endostream Medical, Ltd, Imperative Care, Integra, IRRAS AB, Medtronic, MicroVention, Minnetronix Neuro, Inc., Penumbra, Q’Apel Medical, Inc., Rapid Medical, Rebound Therapeutics Corp., Serenity Medical, Inc., Silk Road Medical, StimMed, LLC, Stryker Neurovascular, Three Rivers Medical, Inc., VasSol, Viz.ai, Inc., W.L. Gore & Associates. JM: Stock options: Cerebrotech, Imperative Care, Endostream, Viseon, BlinkTBI, Serenity, Cardinal Consulting, NTI, RIST, Viz.ai, Synchron. Consultant: Imperative Care, Cerebrotech, VIseon, Endostream, Vastrax, RIST, Synchron, Viz.ai, Perflow, CVAid. Associate Editor for JNIS.
Provenance and peer review Not commissioned; externally peer reviewed.
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