VISTA-Endovascular Feedback Form 5

Therapeutic benefit of intra-arterial thrombolysis in patients undergoing mechanical thrombectomy: Multivariate and propensity adjusted analyses

Adnan I. Qureshi MD

Intra-arterial thrombolytics are used in 10-20% of mechanical thrombectomy procedures in patients with acute ischemic stroke.1,2 Intra-arterial thrombolytics were introduced to deliver a high concentration of thrombolytics in the matrix of the thrombus, and vascular regions beyond the occlusion where intravenous thrombolytics could not delivered.3,4 A synergistic action was postulated between intra-arterial thrombolytics and mechanical thrombectomy.5 Mechanical maneuvers were expected to increase the penetration of intra-arterial thrombolytics within the matrix of the thrombus. Concurrently, intra-arterial thrombolytics were expected to lyse distal emboli and prevent re-occlusion after mechanical thrombectomy. Kaesmacher et al.2 performed a systematic review and meta-analysis of six observational cohort studies and three observational datasets of mechanical thrombectomy randomized-controlled trial data reporting on intra-arterial thrombolytics with mechanical thrombectomy. The analysis included 2797 patients (405 with additional intra-arterial thrombolytics (100 urokinase, 305 tissue plasminogen activator, and 2392 patients without intra-arterial thrombolytics). Of 405 mechanical thrombectomy patients treated with additional intra-arterial thrombolytics, 209 (51.6%) received prior intravenous tissue plasminogen activator. The authors did not observe an increased risk of symptomatic intracranial hemorrhage after administration of intra-arterial thrombolytics as an adjunct to mechanical thrombectomy (OR 1.06, 95% CI 0.64 to 1.76), nor excess mortality (0.81, 95% CI 0.60 to 1.08). Despite the heterogeneity, some studies observed improved reperfusion after intra-arterial thrombolytics. However, the quality of evidence was considered low and limited to observational data. There was no increase in symptomatic intracranial hemorrhage observed, but there was a large uncertainty. Zaidi et al.6 analyzed data from the Systematic Evaluation of Patients Treated with Neurothrombectomy Devices for Acute Ischemic Stroke (STRATIS) registry. A total of 212/984 (21.5%) patients received rescue therapy, of which 83 (39.2%) and 129 (60.8%) did not receive or did receive intra-arterial thrombolytics, respectively. The median intra-arterial recombinant tissue plasminogen activator dose was 4 mg (interquartile range = 2–12 mg). A trend toward higher rates of substantial reperfusion (modified thrombolysis in cerebral infarction ≥ 2b) (84.7% versus 73.0%, P = .08), good functional outcome (59.2% versus 46.6%, P = .10), and lower rates of mortality (13.3% versus 23.3%, P = .08) was seen in the patients who received intra-arterial thrombolytics. Rates of symptomatic intracranial hemorrhage did not differ according to whether intra-arterial thrombolytics were used or not (0% versus 1.6%, P = .54). There continues to be ambiguity whether intra-arterial thrombolytic treatment adds any additional value to mechanical thrombectomy. The questions that remains are: 1/, Whether there is higher rate of angiographic recanalization with intra-arterial thrombolytic treatment; 2/. Whether there is higher rate of symptomatic intracerebral hemorrhages with intra-arterial thrombolytic treatment; and 3/. Whether there is a higher rate of functional independence at 3 months with intra-arterial thrombolytic treatment after adjustment for other prognostic variables.

We hypothesize that there is a higher rate of higher rate of angiographic recanalization with intra-arterial thrombolytic treatment without an increased rate of symptomatic intracerebral hemorrhages; and there is a higher rate of functional independence at 3 months with intra-arterial thrombolytic treatment after adjustment for other prognostic variables.

Patient population We propose to analyze the data come from the Virtual International Stroke Trials Archive—Endovascular database (VISTA-Endovascular, URL: www.virtualtrialsarchives.org): anonymized data of approximately 1,788 patients with acute ischemic stroke enrolled in randomized controlled trials focused on mechanical thrombectomy. We request anonymized data from the archive based on the availability of pre-specified variables of interest for the current analysis. A template of table with variables requested for analysis is provided at the end of the document. Clinical and imaging endpoints For this analysis, the site of arterial occlusion will be categorized into four groups; internal carotid artery (ICA) only; internal carotid artery with involvement of M1 segment of the middle cerebral artery (MCA) or M1 segment only or M1 along with several M2 segments afflicted; single M2 segment only; and other proximal vessel occlusions i.e., proximal occlusion of the anterior cerebral artery (ACA) or M3 segment. Successful recanalization will be defined as the Thrombolysis in Cerebral Infarction (TICI) grade 2B or 3 on angiography 24-hour post-treatment. Successful reperfusion will be defined as modified Thrombolysis in Cerebral Infarction (mTICI) grade 2B or 3 on 24-hour follow-up scan. The main outcome of interest will be the modified Rankin Scale (mRS; an ordered nominal score ranging from 0 to 6 with 0 indicating no symptoms and 6 indicating death) assessed 90 days post-stroke on an ordinal scale and good outcome defined as a binary variable (mRS ≤/> 2). Second outcomes of interest include functional independence (mRS ≤ 2) and mortality (mRS = 6) also assessed at 90 days. Tertiary outcomes of interest include angiographic recanalization and reperfusion rates post-treatment, and lesion progression. We will perform a subgroup analysis using lesion volumes which are provided by the selected randomized controlled trials; lesion progression was calculated in milliliters and specified by the variable’s relative infarct growth (follow-up lesion volume/baseline lesion volume) and absolute infarct growth (follow-up lesion volume—baseline lesion volume). Statistical analyses For all two-group univariate analyses (patients who received or did not receive intra-arterial thrombolysis) will be performed. Categorical and continuous data will be presented as mean with standard deviation (SD) and percentages with 95% confidence interval (CI) and compared with Chi-square tests or Fisher’s exact test, and one-way analysis of variance, respectively, with Bonferroni correction for multiple comparisons. Ordinal logistic regression analysis and non-parametric Kruskal-Wallis tests will be used to identify any differences in the distribution of mRS grades between patients who received or did not receive intra-arterial thrombolytics. We will perform regression analyses for all pre-defined outcome measures and reported unadjusted and adjusted odds ratios (OR) for intra-arterial thrombolytic use. Prespecified variables to be included in the model are age (7, last known well-puncture time: early time window (≤6 hours) and extended time window (>6 hours), site of angiographic occlusion (ICA only; ICA with involvement of M1 segment of the MCA or M1 segment only or M1 along with several M2 segments afflicted; single M2 segment only; and other proximal vessel occlusions i.e., proximal occlusion of the ACA or M3 segment, and the baseline NIHSS score (<10, 10-19 and ≥20). Additional variables that will be included are those that were significantly different between the two groups in the univariate analysis. We will also perform a propensity matched analysis. Propensity score matching will be used to balance the 2 groups at a 1:1 ratio, without replacement, by the nearest neighbor algorithm with a caliper width equal to 0.20. Propensity scores will be calculated for each patient based on the probability for intra-arterial thrombolysis using multivariable logistic regression model including baseline characteristics listed as covariates. The balance between the 2 groups will be calculated based on the absolute standardized difference. Covariates with absolute standardized difference 6 hours), site of angiographic occlusion (ICA only; ICA with involvement of M1 segment of the MCA or M1 segment only or M1 along with several M2 segments afflicted; single M2 segment only; and other proximal vessel occlusions i.e., proximal occlusion of the ACA or M3 segment, and the baseline NIHSS score (<10, 10-19 and ≥20). Significance will be set at P<0.05, and all P will be 2-sided. Statistical analyses will be performed using SPSS 27 software (IBM Armonk, NY) and University Edition of SAS statistical software (SAS Institute, Inc). Template of table with variables requested for analysis Patients who received intra-arterial thrombolytics Patients who did not receive intra-arterial thrombolytics Age, mean (SD), y Female NIHSS, median (IQR) Medical history Atrial fibrillation Hypertension Diabetes Hyperlipidemia Current smoker Prior stroke or TIA Antiplatelet use Systolic blood pressure, mean (SD), mmHg Diastolic blood pressure, mean (SD), mmHg Left side occlusion ASPECTS, mean (SD) ASPECTS, mean (IQR) Location of occlusion Carotid M1 M2 or M3 Posterior circulation Serum glucose, mean (SD), mg/dL Platelets, mean (SD), × 103 /μL Hospital arrival to groin puncture ≤90 min Groin puncture to reperfusion ≤45 min Outcome variables Symptom onset to hospital arrival (time in min IQR) Partial/complete recanalization mTICI 2b or 3 mTICI 3 >3 passes with stent retriever Vasospasm Symptomatic ICH Any parenchymal hemorrhage mRS 0-1 mRS 0-2 Mortality Abbreviations: SD – standard deviation, IQR – interquartile range, mTICI – modified treatment in cerebral infarction, NIHSS- National Institutes of Health Stroke Scale, ICH – symptomatic intracranial hemorrhage. mRS – modified Rankin Scale

Analysis will be funded via local intuitional funding

1. Bracard S, Ducrocq X, Mas JL, et al. Mechanical thrombectomy after intravenous alteplase versus alteplase alone after stroke (THRACE): a randomised controlled trial. The Lancet Neurology 2016;15(11):1138-1147. DOI: https://doi.org/10.1016/S1474-4422(16)30177-6.

2. Kaesmacher J, Meinel TR, Kurmann C, et al. Safety and efficacy of intra-arterial fibrinolytics as adjunct to mechanical thrombectomy: a systematic review and meta-analysis of observational data. J Neurointerv Surg 2021;13(12):1073-1080. (In eng). DOI: 10.1136/neurintsurg-2020-016680.

3. Furlan A, Higashida R, Wechsler L, et al. Intra-arterial prourokinase for acute ischemic stroke. The PROACT II study: a randomized controlled trial. Prolyse in Acute Cerebral Thromboembolism. Jama 1999;282(21):2003-11. (In eng). DOI: 10.1001/jama.282.21.2003.

4. Qureshi AI, Ali Z, Suri MF, et al. Intra-arterial third-generation recombinant tissue plasminogen activator (reteplase) for acute ischemic stroke. Neurosurgery 2001;49(1):41-8; discussion 48-50. (In eng). DOI: 10.1097/00006123-200107000-00006.

5. Qureshi AI, Siddiqui AM, Suri MF, et al. Aggressive mechanical clot disruption and low-dose intra-arterial third-generation thrombolytic agent for ischemic stroke: a prospective study. Neurosurgery 2002;51(5):1319-27; discussion 1327-9. (In eng). DOI: 10.1097/00006123-200211000-00040.

6. Zaidi SF, Castonguay AC, Jumaa MA, et al. Intraarterial thrombolysis as rescue therapy for large vessel occlusions: analysis from the North American solitaire stent-retriever acute stroke registry. Stroke 2019;50(4):1003-1006.