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Ischemic Stroke
Original research
Impact of pretreatment with intravenous thrombolysis on reperfusion status in acute strokes treated with mechanical thrombectomy
  1. Nitin Goyal1,2,
  2. Georgios Tsivgoulis3,
  3. Abhi Pandhi1,
  4. Konark Malhotra4,
  5. Rashi Krishnan1,
  6. Muhammad F Ishfaq1,
  7. Balaji Krishnaiah1,
  8. Christopher Nickele2,
  9. Violiza Inoa-Acosta2,
  10. Aristeidis H Katsanos5,
  11. Daniel Hoit2,
  12. Lucas Elijovich2,
  13. Andrei Alexandrov6,
  14. Adam S Arthur2
  1. 1 Department of Neurology, University of Tennessee Health Science Center, Memphis, Tennessee, USA
  2. 2 Department of Neurosurgery, University of Tennessee/Semmes-Murphey Clinic, Memphis, Tennesseee, United States
  3. 3 Second Department of Neurology, “Attikon” Hospital, School of Medicine, University of Athens, Athens, Greece
  4. 4 West Virginia University Health Sciences Center Charleston Division, Charleston, West Virginia, USA
  5. 5 Department of Neurology, University of Ioannina School of Medicine, Ioannina, Greece
  6. 6 Department of Neurology, University of Tennessee, Memphis, Memphis, Tennessee, USA
  1. Correspondence to Dr Nitin Goyal, Neurology, University of Tennessee Health Science Center, Memphis, TN 38163, USA; ngoyal{at}uthsc.edu

Abstract

Introduction We sought to evaluate the impact of pretreatment with intravenous thrombolysis (IVT) on the rate and speed of successful reperfusion (SR) in patients with emergent large vessel occlusion (ELVO) treated with mechanical thrombectomy (MT) in a high-volume tertiary care stroke center.

Methods Consecutive patients with ELVO treated with MT were evaluated. Outcomes were compared between patients who underwent combined IVT and MT (IVT+MT) and those treated with direct MT (dMT). The elapsed time between groin puncture to beginning of reperfusion (GPTBRT) and the numbers of device passes required to achieve SR were also documented.

Results A total of 287 and 132 patients were treated with IVT+MT and dMT, respectively. The IVT+MT group had higher SR (73.8% vs 62.9%; p=0.023) and 3-month functional independence (modified Rankin Scale score 0–2;51.6% vs 38.2%; p=0.008) rates. The median GPTBRT was shorter in the IVT+MT group (48 (IQR 33–70) vs 70 (IQR 44–98) min; p<0.001). Among patients who achieved SR (n=292), the median number of required device passes was lower in the IVT+MT subgroup (1 (IQR 1–1) vs 2 (IQR 1–2); p<0.001), while the rate of patients requiring ≤2 device passes was higher (98% vs 77%; p<0.001). IVT+MT was independently related to higher odds of SR (OR 1.64; 95% CI 1.03 to 2.61; p=0.036) and shorter GPTBRT (unstandardized linear regression coefficient −20.39; 95% CI −27.56 to –13.22; p<0.001) on multivariable analyses adjusting for potential confounders. Among patients with SR, IVT+MT was independently associated with a higher likelihood of ≤2 device passes (OR 14.63; 95% CI 4.46 to 48.00; p<0.001).

Conclusions IVT pretreatment appears to increase the rates of SR and shortens the duration of the endovascular procedure by requiring fewer device passes in patients with ELVO treated with MT.

  • stroke
  • thrombectomy
  • thrombolysis

https://doi.org/10.1136/neurintsurg-2019-014746

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    Introduction

    It currently remains unclear whether pretreatment with intravenous thrombolysis (IVT) using intravenous tissue plasminogen activator (tPA) provides any additional benefits to patients with emergent large vessel occlusion (ELVO)1 undergoing mechanical thrombectomy (MT). The randomized early window endovascular trials did not provide the data supporting the use of tPA in eligible patients with ELVO.2 Some studies have shown no benefit for IVT pretreatment for MT in patients with ELVO.3–5 The findings of these studies are contradicted by other reports indicating that combination therapy (IVT+MT) may be related to improved outcomes in patients with ELVO.6–8

    Potential hemorrhagic complications, clot fragmentation, distal embolization, and delay in the initiation of MT are some of the potential concerns regarding the addition of IVT prior to MT.7 In contrast, tPA-induced early recanalization averting the need for thrombectomy9 or shortening the duration of the endovascular procedure are the main arguments for the utility of IVT in patients with ELVO. Another theoretical advantage of combination therapy is related to the potential tPA-induced fibrin degradation leading to easier detachment of clot with fewer device passes.10 However, data supporting this hypothesis are scarce.7 In view of the former considerations, we sought to evaluate the impact of pretreatment with IVT on the rate and speed of successful reperfusion (SR) in patients with ELVO treated with MT in a high-volume tertiary care stroke center. We hypothesized that tPA-facilitated clot detachment could be assessed using the elapsed time between groin puncture and the beginning of reperfusion during MT and the number of device passes required for SR.

    Methods

    Study population and baseline characteristics

    We performed a retrospective analysis of a prospectively collected database of consecutive patients with ELVO who underwent MT at a tertiary care stroke center from January 2013 to December 2017. For the purpose of this study, the study cohort was divided into two groups: combination therapy (IVT+MT) and direct MT (dMT). Baseline demographic and clinical variables were collected. Stroke severity at hospital admission was documented using the National Institute of Health Stroke Scale (NIHSS) score by certified vascular neurologists. Baseline characteristics including demographics, vascular risk factors, history of prior stroke admission NIHSS scores, admission ASPECTS, pretreatment with IVT, admission serum glucose, admission systolic blood pressure (SBP) and diastolic blood pressure (DBP) levels, occlusion site (anterior vs posterior circulation occlusion) were recorded as previously described.11 Collateral scores were reported in a dichotomized fashion (good vs poor collaterals) for anterior circulation LVO using a methodology that has been shown to predict clinical outcome.11 The acute ischemic stroke patients with ELVO were treated according to the American Heart Association guidelines12 which advocate IVT for all eligible patients and subsequent MT if CT angiography shows confirmed LVO. In cases where IVT was contraindicated, patients underwent direct MT without IVT pretreatment. All eligible patients pretreated with IVT received a standard dose of IV tPA (0.9 mg/kg).

    Definition of outcomes

    Safety outcomes included symptomatic intracranial hemorrhage (sICH) and 3-month mortality, while efficacy outcomes were characterized by SR and 3-month functional independence defined as modified Rankin Scale (mRS) scores of 0–2. Recanalization at the end of the endovascular procedure was defined by modified Thrombolysis in Cerebral Infarction (mTICI) grades,11 which were obtained from the reports of endovascular specialists. SR was defined as mTICI grades 2b or 3. The elapsed time between groin puncture to beginning of any reperfusion (GPTBRT) was obtained for the whole sample. The number of device passes (DP) required to achieve SR was also documented. sICH was defined as the presence of a parenchymal hematoma type 2 (PH-2) on brain CT and/or MRI gradient recall echo sequence accounting for deterioration with an increase in NIHSS score of ≥4 points within 36 hours after treatment.13 Functional outcome was evaluated at 3 months using mRS scores by certified vascular neurologists. Functional status was evaluated in person either from a post hospital discharge clinic follow-up or from a hospital visit in all patients. Functional independenceI was defined as mRS scores of 0–2. Endovascular specialists grading the degree of reperfusion at the end of MT and vascular neurologists assessing NIHSS and mRS scores were unaware of the purposes of the study and performed treatments and assessments as part of their clinical duties.11

    The study was approved by the Institutional Review Board of the participating center and did not require patient consent.

    Statistical analyses

    All binary variables are presented as percentages, while continuous variables are expressed according to the presence of normality in their distribution either with median values and corresponding interquartile ranges (IQRs) or with mean values and corresponding standard deviations (SDs). Statistical comparisons between the two groups of patients were performed with the Pearson χ2 test, Mann–Whitney test or t-test, where appropriate. We used univariable and multivariable logistic regression models to assess the association between baseline characteristics with the probability of SR and SR with ≤2 DP, and simple and multiple linear regression models to evaluate the association of baseline characteristics with GPTBRT. As candidate variables for inclusion in all multivariable models we used all those baseline characteristics, including pretreatment with IV tPA, which were found to yield a p value <0.1 in the initial univariable analyses. The resulting multivariable models were tested under a two-sided statistical significance hypothesis with a significance level of 0.05. The Stata Statistical Software Release 13 for Windows program (StataCorp, College Station, Texas, USA) was used for all statistical analyses.

    Results

    A total of 287 patients (mean age 63.7±15.1 years, 49.8% men, median admission NIHSS score 16 points (IQR 11–20)) and 132 patients (mean age 64.3±13.9 years, 50.0% men, median admission NIHSS score 16 points (IQR 10–21)) were treated with IVT+MT and dMT, respectively. In our cohort, a combination of distal aspiration and stent retriever was used as the most common technique (also called the ‘solumbra’ technique) in 56% of cases. The second most commonly employed technique was the ADAPT (A Direct Aspiration First Pass Technique), which was used in 20% of the sample. Stent retrievers without distal aspiration were used in 19% of patients. The remaining cases were mostly cervical or intracranial carotid occlusions in which acute angioplasty and/or stenting was employed. Balloon guide was used in 8% of cases. MT was carried out under general anesthesia in 24% of cases while the remaining patients received conscious sedation (76%). Additional information regarding procedural details of MT in our center have been reported elsewhere.14 15

    The baseline characteristics and clinical outcomes of the two groups are presented in table 1 and table 2, respectively. Patients in the dMT group were more often on oral anticoagulants, had a lower median ASPECT score, and had longer onset-to-groin-puncture time compared with the IVT+MT group. The IVT+MT group had higher rates of SR (73.8% vs 62.9%; p=0.023) and 3-month functional independence (mRS score 0–2: 51.6% vs 38.2%; p=0.008). The median GPTBRT (48 (IQR  33–70) min vs 70 (IQR 44–98) min; p<0.001) and onset-to-recanalization time (285 (IQR 226–353) min vs 415 (308–601) min; p<0.001) were shorter in the IVT+MT group. Among patients who achieved SR (n=292), the median number of required DP was lower in the IVT+MT subgroup (1 (IQR 1–1) vs 2 (IQR 1–2); p<0.001), while the rate of patients requiring ≤2 DP was higher (98% vs 77%; p<0.001). The rates of sICH (9.1% vs 6.6%; p=0.368) and 3-month mortality (27.1% vs 19.9%; p=0.117) were not significantly different between the two groups.

    View this table:
    Table 1

    Baseline characteristics of patients with emergent large vessel occlusions treated with direct mechanical thrombectomy (MT) versus combination therapy (intravenous thrombolysis (IVT) +MT)

    View this table:
    Table 2

    Outcome variables of patients with emergent large vessel occlusions treated with direct mechanical thrombectomy (MT) versus combination therapy (intravenous thrombolysis (IVT) +MT)

    Univariable and multivariable associations of baseline characteristics with SR are shown in table 3. IVT pretreatment was independently related to a higher odds of SR (OR 1.64; 95% CI 1.03 to 2.61; p=0.036) on multivariable analyses adjusting for potential confounders (demographics, vascular risk factors, baseline ASPECTS, blood pressure and serum glucose levels, onset-to-groin-puncture time, location of occlusion, pretreatment with antiplatelets, anticoagulants and statins). Univariable and multivariable associations of baseline characteristics with GPTBRT are shown in table 4. IVT pretreatment was independently associated with shorter GPTBRT (unstandardized linear regression coefficient −20.39; 95% CI −27.56 to –13.22; p<0.001) on multivariable analyses adjusting for potential confounders. The univariable and multivariable associations of baseline characteristics with the likelihood of ≤2 DP to achieve SR in the subgroup of patients with SR at the end of the endovascular procedure (n=292) are shown in table 5. IVT pretreatment was the only predictor variable that was independently associated with a higher likelihood of ≤2 DP (OR 14.63; 95% CI 4.46 to 48.00; p<0.001). Although IVT pretreatment was found to be associated with a higher probability of functional independence (ie, mRS scores ≤2) at 90 days (OR 1.79; 95% CI 1.16 to 2.75; p=0.008), this association did not retain its statistical significance after adjustment for potential confounders (OR 1.33; 95% CI 0.70 to 2.52; p=0.377; table 6) on multivariable logistic regression models.

    View this table:
    Table 3

    Univariable and multivariable logistic regression analyses showing the associations of intravenous thrombolysis pretreatment and other baseline characteristics with successful recanalization (mTICI 2b or 3) after mechanical thrombectomy

    View this table:
    Table 4

    Simple and multiple linear regression analyses depicting the associations of intravenous thrombolysis pretreatment and other baseline characteristics with groin puncture to beginning of reperfusion

    View this table:
    Table 5

    Univariable and multivariable logistic regression analyses showing the predictors of ≤2 device passes to achieve successful recanalization (analysis conducted in the subgroup of patients with successful recanalization)

    View this table:
    Table 6

    Univariable and multivariable logistic regression analyses showing the predictors of 3-month functional independence (modified Rankin Scale score ≤2)

    Discussion

    This study indicates that IVT pretreatment shortens the duration of endovascular procedures by requiring fewer DP in patients with ELVO treated with MT. These associations remain independent after adjustment for multiple confounders including demographics, vascular risk factors, collateral status, onset-to-groin puncture time, location of occlusion, baseline blood glucose, blood pressure levels, and ASPECTS.

    These findings are in line with a recently published multicenter study (including data from out center) that provided observational data indicating that IVT+MT was associated with functional improvement and a lower likelihood of 3-month mortality in patients with ELVO compared with dMT.6 However, this study did not provide any evidence regarding the underlying mechanism that might explain the former association. The present report underscores that the better clinical outcomes in patients with ELVO treated with MT+IVT may be attributed to the shortened duration of the endovascular procedure and the smaller number of DP required to achieve SR. This observation is also supported by a recent French study which showed that GPTBRT was shorter in patients treated with combination therapy than in those treated with dMT.16 In addition, a Swiss study also reported that IVT pretreatment and lower number of thrombectomy passes were independently associated with SR in patients with ELVO treated with MT.17 Finally, a meta-analysis by Mistry et al showed that combination therapy was related to higher rates of SR and higher odds of achieving SR with ≤2 DP during the endovascular procedure.7

    Since the publication of landmark endovascular trials,2 the utility of tPA pretreatment for patients with ELVO has been questioned and is a topic of ongoing debate. Several concerns including the number of exclusion criteria for tPA therapy, its cost, delay in initiation of MT, and safety considerations have supported the question of whether tPA should be routinely given in cases undergoing MT.3–5 18 19 A retrospective study showed that tPA pretreatment did not improve the outcomes of patients with ELVO and the combined therapy (tPA +MT) was associated with significantly higher total and direct hospital costs than endovascular therapy alone.19 However, it is important to note that it was a single-center study with a small sample size and did not comment on the long-term cost effectiveness of one thrombectomy approach against another. Another study postulated that, for patients eligible for both tPA and MT presenting to comprehensive stroke centers (CSC) with efficient workflow processes, there may be superior patient value and overall healthcare benefit if proceeding directly with MT without IVT pretreatment.20

    Contrary to these studies, several other single-center and multicenter non-randomized studies6–8 have shown that tPA pretreatment improves functional outcomes in ELVO and also leads to SR in one of 10 patients with ELVO, negating the need for additional endovascular reperfusion therapy.9 We agree that, in the short term, the cost related to tPA administration would add to overall healthcare expenditure; however, this additional cost would be offset by a tPA-mediated decrease in long-term disability.21 This statement is further corroborated by findings of a meta-analysis of the non-interventional arm from the HERMES Collaboration where they showed that faster tPA delivery is associated with less disability at 3 months in patients with ELVO.22

    Another aspect of this debate is whether patients with suspected LVO should bypass to the nearest CSC with endovascular capabilities. In areas with greater geographic disparities and time obstacles, selective diversion to CSC ultimately delays evaluation and treatment of patients with ELVO.23 Treatment with tPA at the nearest primary stroke center becomes crucial in such situations, especially for patients who may otherwise be ineligible for MT by the time they reach the CSC.

    Several limitations of our study must be acknowledged. First, we presented self-reported data on safety and efficacy outcomes lacking central adjudication. However, the fact that the mRS scores were measured by vascular neurologists, who did not perform the procedure, helps to reduce bias with regard to the clinical outcome. Second, the specific devices and methods used for MT were heterogeneous and were selected according to the treating physician’s preference. Third, and most important, the majority of our patients treated with dMT had relative contraindications to IVT such as presentation in delayed time window, recent surgery or trauma, pretreatment with oral anticoagulants and, in rare situations, uncontrolled hypertension. This creates a substantial risk for confounding due to treatment allocation bias that cannot be fully eliminated even with multivariable logistic regression analyses that were used to control for residual confounding. The ongoing randomized clinical trials including SWIFT DIRECT (Bridging Thrombolysis Versus Direct Mechanical Thrombectomy in Acute Ischemic Stroke) may provide definite answers regarding the safety and efficacy of IVT pretreatment in patients with ELVO undergoing MT. Tenecteplase with more fibrin specificity and longer activity has been shown to be associated with a higher incidence of reperfusion and better functional outcome than alteplase when administered before MT in patients with ELVO.24 This makes the debate of pre-MT thrombolysis more interesting. Future trials comparing combination therapy with MT alone using tenecteplase pretreatment would potentially be required to resolve this equipoise completely.

    Conclusion

    IVT pretreatment shortens the duration of endovascular procedures by requiring fewer DP in patients with ELVO treated with MT. We need to wait for the results of ongoing randomized controlled clinical trials to get definitive answers on the utility of IVT pretreatment in patients with ELVO receiving MT. Until data from these trials are available, IVT should be offered in all tPA-eligible patients with ELVO treated with MT, as advocated by current international recommendations.

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    Footnotes

    • Contributors NG: study concept and design, acquisition of data, analysis and interpretation, critical revision of the manuscript for important intellectual content. GT, AHK: analysis and interpretation, critical revision of the manuscript for important intellectual content. AP, RK, MFI: acquisition of data, critical revision of the manuscript for important intellectual content. KM, BK, CN, VI-A, DH, LE, AA: critical revision of the manuscript for important intellectual content. ASA: study supervision, critical revision of the manuscript for important intellectual content.

    • 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.

    • Provenance and peer review Not commissioned; externally peer reviewed.

    • Patient consent for publication Not required.