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Abstract

Background:

There is conflicting evidence as to whether intra-arterial thrombolysis (IAT) adds benefit in patients with acute stroke who undergo mechanical thrombectomy (MT).

Methods:

We conducted a systematic review to identify studies that evaluate IAT in patients with acute stroke who undergo MT. Data were extracted from relevant studies found through a search of PubMed, Scopus, and Web of Science until February 2023. Statistical pooling with random effects meta-analysis was undertaken to evaluate odds of functional independence, mortality, and near-complete or complete angiographic recanalization with IAT compared to no IAT.

Results:

A total of 18 studies were included (3 matched, 14 unmatched, and 1 randomized). The odds ratio (OR) for functional independence (modified Rankin Scale: 0–2) at 90 days was 1.14 (95% confidence interval (CI): 0.95–1.37, p = 0.17, 16 studies involving 7572 patients) with IAT with moderate between-study heterogeneity (I² = 38.1%). The OR for functional independence with IAT was 1.28 (95% CI: 0.92–1.78, p = 0.15) in studies that were either matched or randomized and 1.24 (95% CI: 0.97–1.58, p = 0.08) in studies with the highest quality score. IAT was associated with higher odds of near-complete or complete angiographic recanalization (OR: 1.65, 95% CI: 1.03–2.65, p = 0.04) in studies that were either matched or of randomized comparisons.

Conclusion:

Although the odds of functional independence appeared to be higher with IAT and MT compared with MT alone, none of the results were statistically significant. A prominent effect of the design and quality of the studies was observed on the association between IAT and functional independence at 90 days.

Keywords

Systematic review meta-analysis intra-arterial thrombolysis mechanical thrombectomy acute ischemic stroke

Introduction

In patients with acute ischemic stroke (AIS) who undergo endovascular treatment, intra-arterial thrombolysis (IAT) is recommended in the American Stroke Association/American Heart Association (ASA/AHA) guidelines since 2013,¹ with a preference for mechanical thrombectomy (MT) over IAT alone according to the ASA/AHA 2019 guidelines.² However, there is conflicting evidence as to whether concurrent IAT adds any additional benefit if MT is already being performed. Recent trials^3,4 have used MT alone without intra-arterial (IA) thrombolytics to reduce the occurrence of post-procedure intracranial hemorrhage (ICH). Although such trials^3,4 demonstrated that MT increased (compared with no MT) the rates of functional independence in AIS patients, almost one-third of patients did not achieve adequate tissue perfusion on magnetic resonance imaging (MRI) and/or functional independence despite recanalization following MT. Therefore, IAT is used concurrently with MT with considerable variation in practice between sites^5,6 to improve both the rates and time to achieve angiographic recanalization and distal arterial perfusion by acting on sites not amenable to MT.^7–9 There are two previous systematic reviews and meta-analyses by Chen et al.¹⁰ and Kaesmacher et al.,¹¹ which have provided conflicting results. A more conclusive analysis may be possible with the availability of additional studies^5,12–17 including results from the randomized Chemical Optimization of Cerebral Embolectomy (CHOICE)¹⁷ clinical trial. We performed an updated systematic review of the literature to evaluate the effect of IAT as an adjunct to MT.

Methods

Literature search strategy

This systematic review and meta-analysis were conducted and reported according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines.¹⁸ Three reviewers (A.L., I.N.A., and D.K.) searched the online databases of PubMed, Scopus, and Web of Science (from January 2012 until February 2023) to find all relevant observational studies, clinical trials, clinical studies, comparative studies, and multicenter studies. We also searched clinicaltrials.gov to identify any additional articles. We started the search from January 2012 to focus on contemporary MT devices that were initially approved in 2012¹⁹ (see Supplemental Material for detailed search strategy). Relevant studies identified during the screening process then entered full-text review, in which full-text manuscripts were evaluated independently by reviewers (A.L., I.N.A., and D.K.) for eligibility, as well as reference lists from these studies to identify additional eligible studies. Any uncertainties about the inclusion of a study in the review were discussed with the study’s supervisor (A.I.Q.) for resolution.

Eligibility criteria

Included studies involved AIS patients (>18 years) with large-vessel occlusion in the anterior or posterior circulation, with data available for two treatment arms: (1) IAT given as an adjunct to MT treatment and (2) MT treatment alone without IAT. MT included aspiration techniques, stent-retrievers, stenting, and balloon angioplasty. IA thrombolytics considered were plasminogen activators. We excluded studies that reported on IA use of other medications such as glycoprotein IIb/IIIa inhibitors. A recent meta-analysis by Kaesmacher et al.¹¹ included observational data derived from randomized controlled trials in the HERMES (Highly Effective Reperfusion Using Multiple Endovascular Devices) collaboration that had IAT in the MT arm. Randomized-controlled trials that had relevant data included the MR CLEAN (Multicenter Randomized Clinical trial of Endovascular treatment for Acute ischemic stroke in the Netherlands),²⁰ ESCAPE (Endovascular Treatment for Small Core and Anterior Circulation Proximal Occlusion with Emphasis on Minimizing CT to Recanalization Times),²¹ and THRACE (Trial and Cost Effectiveness Evaluation of Intra-arterial Thrombectomy in Acute Ischemic Stroke)²² trials. Outcome data from the IAT with MT versus MT alone groups were extracted from this meta-analysis.¹¹ We excluded studies with duplicate data or no specific data regarding patients receiving adjunct IAT. We also excluded studies with less than 10 patients undergoing endovascular treatment.²³ In addition, included studies had to report at least one of the primary or secondary outcomes. The primary outcome in our study was functional independence at 90 days (modified Rankin Scale: 0–2). Secondary outcomes were all-cause mortality within 90 days, occurrence of post-MT symptomatic intracranial hemorrhage (sICH) as defined by each study, and successful reperfusion on angiogram (Thrombolysis in Cerebral Infarction [TICI]/ Thrombolysis in Myocardial Infarction [TIMI] score of ⩾2b). If the sICH definition was not available, then other surrogates (i.e. parenchymal hematoma type 2 (PH2) according to ECASS (European Cooperative Acute Stroke Study) criteria) were considered, as was also done in the meta-analysis by Kaesmacher et al.,¹¹ as PH2 has been associated with a higher risk of early neurological deterioration.²⁴

Data extraction

Three reviewers (A.L., I.N.A., and D.K.) independently extracted study ID, author, year, characteristics, and quality data from included studies. The study characteristics that were extracted included (1) the proportion of the patient population receiving IAT, (2) the location of large-vessel occlusion in treated patients (anterior circulation (internal carotid artery (ICA), middle cerebral artery (MCA)) and/or basilar artery), (3) time to treatment (within 8 or 24 h of symptom onset), (4) type of comparison (matched, unmatched, or randomized), (5) type(s) of IAT used, (6) dosage of IAT given (if provided), and (7) timing of IAT (before or after MT). Primary and secondary outcome data and the sICH definitions applied in each study were also extracted.

Risk of bias assessment in studies

The quality of included observational studies^{5,6,12–16,20–22,25–31} was assessed by three independent reviewers (A.L., I.N.A., and D.K.) for risk of bias using the Newcastle–Ottawa Quality Scale (NOS) for Cohort Studies.³² The NOS evaluates three quality parameters (selection, comparability, and outcome), with a maximum of 4 points for selection, 2 points for comparability, and 3 points for outcomes, with a maximum total score of 9 for each study, representing a good quality study.³² Studies having a total score of less than five are identified as studies with a high risk of bias.^33,34 For assessing the quality of the single randomized trial in our study,¹⁷ we used a revised risk of bias (RoB-2) tool.³⁵ It evaluates the risk of bias as low, moderate, or high risk across different parameters (such as random sequence generation, allocation concealment, degree of blinding, attrition bias, or selective reporting) for an overall grading of low, moderate, or high risk of bias.

Statistical analysis

We calculated the odds ratio (OR) as effect size for each comparison for functional independence at 90 days, all-cause mortality within 90 days, post-MT sICH, and near-complete or complete recanalization. For each outcome, comparisons were analyzed using random effects models to account for heterogeneity, with a Mantel–Haenszel (MH) estimator for between-study heterogeneity statistic Q, and results displayed in forest plots. Heterogeneity was described using I² (the percentage of the residual variation that is attributable to between-study). We used meta-regression to identify any heterogeneity in effect due to study-level covariates including the location of occlusion in treated patients (middle cerebral artery only, middle cerebral or internal carotid arteries, any intracranial artery, or basilar artery only), time to treatment (⩽8 h and >8 h), comparator group (matched, unmatched, or randomized), and quality grade on the association between IAT and study outcomes. We tested for the presence and extent of publication bias using funnel plots. Adjusted effect sizes were then estimated by incorporating theoretically missing studies using the trim-and-fill approach.³⁶ We performed the following sensitivity analyses: (1) due to the presence of both funnel plot and between-study heterogeneity, we compared the fixed and random effects estimates of the intervention effect as recommended by Sterne et al.³⁷; (2) repeated the analysis after only including studies that used matched or randomized comparators; and (3) repeated the analysis after only including studies with the highest quality score (greater than 8). Statistical analyses were performed using R (version 4.2.0), R package dplyr (version 1.0.9), and meta (version 5.2-0). All estimates included a 95% confidence interval (CI) and p values <0.05 were considered statistically significant.

Results

Literature search and study characteristics

A flow diagram depicting the study selection for IAT in adjunct to MT is shown in Figure 1. A total of 1587 potentially relevant studies were found in the search. A total of 18 studies (17 nonrandomized observational studies and 1 randomized controlled trial) met the inclusion criteria. It is notable that two studies were excluded one of which had too small a sample size,²³ and the other study presented results that were not in a format that could be pooled along with the other studies.³⁸ A summary of study characteristics of included studies is shown in Table 1. Primary and secondary outcome data and definitions of sICH and successful reperfusion of included studies are shown in Supplemental Tables 1 and 2.

Figure 1.

Flow chart depicting identification of studies through literature search.

Table 1.

Study characteristics of the included studies.

Studies	Proportion of population receiving IAT (%)	Location of occlusion	Time interval between symptom onset to MT	Comparison	Type of IAT	Timing of IAT	Dose of IAT
Anadani et al.²⁵	50	ICA, MCA	Within 8 h	Matched	tPA	After MT (as a rescue therapy)	If IA-tPA is used, a single 3–5 mg dose is attempted first and can be repeated until recanalization is achieved or to a maximum of 15 mg is reached.
Baik et al.¹²	39.5	ICA, MCA	Within 24 h	Unmatched	Urokinase	After MT (as an adjunct therapy)	40,000 IU (20,000–60,000)
Berkhemer et al.²⁰	11.5	ICA, MCA	Within 8 h	Unmatched	Alteplase, urokinase	During MT	Alteplase maximum dose: 90 mg, maximum dose of urokinase: 1,200,000 IU
Bracard et al.²²	10.6	ICA, MCA	Within 8 h	Unmatched	Alteplase	After MT	7 (3–10) mg
Cappellari et al.¹³	21.6	MCA	Within 8 h	Unmatched	NA	Before or after MT	NA
Castonguay et al.²⁶	14	MCA	Within 8 h	Unmatched	rtPA	After MT (as a rescue therapy)	4 mg (IQR: 2–10)
Collette et al.¹⁴	4.2	ICA, MCA	Within 8 h	Unmatched	Urokinase, alteplase	During MT	Median doses were 250,000 IU; 20 mg (IQR: 12–20)
Fischer et al.²⁷	53.8	ICA, MCA	Within 8 h	Unmatched	Urokinase	Before MT	750,000 IU (range 0–1, 500, 000)
Goyal et al.²¹	4.2	ICA, MCA	Within 24 h	Unmatched	tPA	With MT	5 (1–7) mg
Heiferman et al.²⁸	70	ICA, MCA, posterior circulation	Within 8 h	Unmatched	tPA	Concomitant with MT	13 mg (IQR: 8–16)
Kaesmacher et al.²⁹	10.1	ICA, MCA	Within 8 h	Unmatched	Urokinase	After MT(as a rescue therapy)	300, 000 (IQR: 250, 000–500, 000) IU
Kohli et al.¹⁵	58.3	ICA, MCA, ACA	Within 8 h	Unmatched	tPA	Concomitant or after MT	Maximum dose of 10 mg
Qureshi et al.¹⁶	7.5	BA	Within 24 h	Unmatched	rtPA (alteplase), urokinase	NA	NA
Renú et al.¹⁷	54	ICA, MCA	Within 8 h	Unmatched	tPA (alteplase)	After MT	Maximum dose 22.5 mg
Singer et al.³⁰	20.3	ICA, MCA, VA, BA	NA	Unmatched	NA	Combined with MT	NA
Yi et al.³¹	39.8	ICA, MCA	Within 8 h	Unmatched	rtPA	Concomitant with MT	1 mg/min, total amount <5 mg
Zaidi et al.⁶	45.7	MCA	Within 8 h	Matched	rtPA	After MT(as a rescue therapy)	NA
Zaidi et al.⁵	60.8	ICA, MCA	Within 8 h	Matched	rtPA	After MT(as a rescue therapy)	4 (IQR: 2–12) mg

IAT: intra-arterial thrombolysis; MT: mechanical thrombectomy; ICA: internal carotid artery; MCA: middle cerebral artery; tPA: tissue plasminogen activator; IU: international units; rtPA: recombinant tissue plasminogen activator; IQR: interquartile range; mg: milligram; ACA: anterior cerebral artery; BA: basilar artery; VA: vertebral artery.

Study quality

The median quality grade was 8, with 11 studies having a quality grade of 8 or greater for risk of bias using the NOS scoring system^{5,6,12–16,20,25,29,31} (see Supplemental Tables 3 and 4). There was an overall low risk of bias using Rob-2 assessment tool for the randomized controlled trial.¹⁷ The only potential of bias that was classified as moderate risk was due to pre-mature terminated early during the corona virus disease 2019 pandemic due to difficulty in recruitment.

Effect of IAT on functional independence at 90 days

The OR for functional independence at 90 days was 1.14 (95% CI: 0.95–1.37, p = 0.17, 16 studies involving 7572 patients) with IAT with moderate between-study heterogeneity (I² = 38.1%; Figure 2(a)). A sizable asymmetry was detected in the funnel plot. After applying the trim and fill approach, the resulting adjusted OR for functional independence at 90 days slightly increased (OR: 1.16, 95% CI: 0.96–1.40, p = 0.13; Figure 2(b)). Similar results were observed in a fixed effect model (OR: 1.12, 95% CI: 0.97–1.30, p = 0.13). In the meta-regression, no relationship was identified between study-level covariates and effect size (p > 0.05). The OR for functional independence at 90 days with IAT was 1.28 (95% CI: 0.92–1.78, p = 0.15) in studies that were either matched or randomized comparisons, 1.24 (95% CI: 0.97–1.58, p = 0.08) in studies with the highest quality score, and 1.14 (95% CI: 0.94–1.38, p = 0.20) in observational studies.

Figure 2.

Plots of odds ratio for functional independence at 90 days (modified Rankin Scale score: 0–2) in patients undergoing MT with and without IAT. (a) Forest plot and hypothesis testing for heterogeneity, overall effect, and subgroup differences (b) Funnel plot for adjusting publication bias with published studies (filled circles) and trim-and-fill assigned studies (open circles). MT: mechanical thrombectomy; IAT: intra-arterial thrombolysis; MH: Mantel–Haenszel Test; CI: confidence interval.

Effect of IAT on all-cause mortality within 90 days

The OR for all-cause mortality within 90 days with IAT was 0.86 (95% CI: 0.71–1.05, p = 0.14, I² = 0%, 14 studies, 5197 subjects, Figure 3(a)). A sizable asymmetry was detected in the funnel plot. After applying the trim and fill approach, the resulting adjusted OR for all-cause mortality at 90 days was 0.88 (95% CI: 0.72–1.07, p = 0.18; Figure 3(b)). Similar results were observed in a fixed effect model (OR: 0.86, 95% CI: 0.70–1.04, p = 0.12). In the meta-regression, the location of occlusion (category of middle cerebral or internal carotid arteries) had a significant effect on the association between IAT and all-cause mortality within 90 days (p = 0.04). The ORs for all-cause mortality within 90 days with IAT were 0.76 (95% CI: 0.50–1.14, p = 0.18) in studies that were either matched or randomized comparisons, 0.85 (95% CI: 0.67–1.08, p = 0.19) in studies of highest quality grade, and 0.88 (95% CI: 0.72–1.07, p = 0.20) in observational studies.

Figure 3.

Plots of odds ratio for all-cause mortality within 90 days in patients undergoing MT with and without IAT. (a) Forest plot and hypothesis testing for heterogeneity, overall effect, and subgroup differences (b) Funnel plot for adjusting publication bias with published studies (filled circles) and trim-and-fill assigned studies (open circles). MT: mechanical thrombectomy; IAT: intra-arterial thrombolysis; MH: Mantel–Haenszel test; CI: confidence interval.

Effect of IAT on post-MT symptomatic intracerebral hemorrhage

The OR for post-MT sICH with IAT was 1.19 (95% CI: 0.89–1.58, p = 0.25, I² = 0%, 17 studies, 8231 subjects, Figure 4(a)). A sizable asymmetry was detected in the funnel plot. After applying the trim and fill approach, the adjusted OR for sICH was 1.25 (95% CI: 0.94–1.66, p = 0.12; see Figure 4(b)). The OR for post-MT sICH with IAT was 1.12 (95% CI: 0.84–1.49, p = 0.43) in a fixed effect model. In the meta-regression, no relationship was identified between study-level covariates and effect size (p > 0.05). The ORs for post-MT sICH with IAT were 1.39 (95% CI: 0.61–3.18, p = 0.43) in studies that were either matched or randomized comparisons, 1.04 (95% CI: 0.72–1.49, p = 0.85) in studies of highest quality grade, and 1.21 (95% CI: 0.90–1.61, p = 0.20) in observational studies.

Figure 4.

Plots of odds ratio for symptomatic intracranial hemorrhage in patients undergoing MT with and without IAT. (a) Forest plot and hypothesis testing for heterogeneity, overall effect, and subgroup differences (b) Funnel plot for adjusting publication bias with published studies (filled circles) and trim-and-fill assigned studies (open circles). MT: mechanical thrombectomy; IAT: intra-arterial thrombolysis; MH: Mantel–Haenszel test; CI: confidence interval.

Effect of IAT on near-complete or complete angiographic recanalization

The OR for near-complete or complete angiographic recanalization with IAT was 0.88 (95% CI: 0.63–1.23, p = 0.46, I² = 69.9%, 18 studies, 8403 subjects, Figure 5(a)). A sizable asymmetry was detected in the funnel plot. After applying the trim and fill approach, the adjusted OR for near-complete or complete angiographic recanalization was significantly lower with IAT (OR: 0.59, 95% CI: 0.39–0.88, p = 0.01; Figure 5(b)). IAT was associated with significantly lower odds of near-complete or complete angiographic recanalization in a fixed effect model (OR: 0.73, 95% CI: 0.62–0.85, p < 0.001). In the meta-regression, no relationship was identified between study-level covariates and effect size (p > 0.05). IAT was associated with higher odds (OR: 1.65, 95% CI: 1.03–2.65, p = 0.04) of near-complete or complete angiographic recanalization in studies that were either matched or randomized comparisons. The ORs for near-complete or complete angiographic recanalization with IAT were 0.85 (95% CI: 0.55–1.33, p = 0.48) in studies with the highest quality grade and 0.83 (95% CI: 0.59–1.15, p = 0.26) in observational studies.

Figure 5.

Plots of odds ratio for near-complete or complete recanalization in patients undergoing MT with and without IAT. (a) Forest plot and hypothesis testing for heterogeneity, overall effect, and subgroup differences (b) Funnel plot for adjusting publication bias with published studies (filled circles) and trim-and-fill assigned studies (open circles). MT: mechanical thrombectomy; IAT: intra-arterial thrombolysis; MH: Mantel–Haenszel test; CI: confidence interval.

Discussion

Salient findings

In the current systematic review and meta-analysis, we did not identify any significant association between IAT as an adjunct to MT and functional independence at 90 days, all-cause mortality within 90 days, or sICH. However, the direction of association suggested a possible increase in functional independence at 90 days (14% higher odds) and a reduction in all-cause mortality within 90 days with IAT. There was a trend toward higher odds of functional independence at 90 days among patients who received IAT in studies of the highest quality grade (24% higher odds) and in studies that were matched or randomized comparisons (28% higher odds). The direction of association suggested a possible increase in the odds of post-MT sICH with IAT although the increase was not detected when the analysis was restricted to studies of the highest quality grade. However, the odds increased from 19% higher (all studies) to 39% higher in studies that were matched or randomized comparisons. The association between IAT and near-complete or complete angiographic recanalization demonstrated inconsistent results. Overall, IAT was associated with lower rates of near-complete or complete angiographic recanalization in the fixed effect model but not in the random effects model. IAT was associated with higher odds of near-complete or complete angiographic recanalization in studies that were matched or randomized comparisons. A previous meta-analysis including 4581 patients by Chen et al.¹⁰ reported that IA treatment (thrombolytics or glycoprotein IIb/IIIa inhibitors) was associated with a higher rate of functional independence and another meta-analysis including 2797 patients by Kaesmacher et al.¹¹ reported that IAT was not associated with higher rates of functional independence as an adjunct to MT. Inclusion of additional studies^5,12–17 such as results from the randomized CHOICE¹⁷ trial in our analysis increased the sample size (7572 patients) by almost 2–4 folds compared with the previous analyses by Chen et al.¹⁰ and Kaesmacher et al.¹¹ Therefore, the precision of estimates of various outcomes was higher, and type 2 errors in comparisons were reduced. By increasing the design diversity among included studies, we also identified the prominent effect of design and quality of the studies on the association between IAT and functional independence at 90 days.

Current perception of IAT as adjunct to MT

IAT continues to be used frequently in an inconsistent manner as an adjunct to MT in AIS patients. Over 60% of respondents used IAT with MT without any clear consensus on its indications or therapeutic value in a survey of 104 neurointerventionalists.³⁹ Of those who used IAT, 60.4% indicated that they used IAT for: (1) treating a primary distal occlusion, (2) as rescue therapy, and/or (3) adjunctive therapy. Almost half (49.4%) of those surveyed believed that IAT may have a role with MT, but more evidence is needed, while 37.6% agreed that IAT has a role in MT. Only 12.9% felt there was no role for IAT in modern endovascular practice. A survey of 99 neurologists and neurointerventionalists from all German University hospitals, all participants of the German Stroke Registry—Endovascular Treatment (GSR), found that IAT was used in select cases by 39% and as a standard of care by 3% of the respondents.⁴⁰ We surveyed individuals who were part of the ACTION CVT (Direct Oral Anticoagulants Versus Warfarin in the Treatment of Cerebral Venous Thrombosis) group, Life journal authors of stroke-related publications, ASPIRE (Anticoagulation in ICH Survivors for Stroke Prevention and Recovery) clinical trial, COVID-19 stroke project, SVIN (Society of Vascular and Interventional Neurology) task force on trainee education, and Endovascular Stroke Treatment Optimization (ESTO)-2 investigators (unpublished data). A total of 92 (63%) of 146 respondents reported they followed no specific protocol on who received IAT, but 79% reported using IAT with MT. A total of 82 (56.1%) respondents stated that they would classify the importance of determining the therapeutic value of IAT during MT as very important or important. A total of 135 (92.5%) stated that they would definitely, very probably, or probably modify their practice if a randomized clinical trial demonstrated that IAT with MT reduced death or disability, and 121 (82.8%) respondents stated that they would be able to include IAT very easily or easily with MT in their practice.

Limitations of our analysis

The analysis is predominantly based on observational studies. Observational studies comprise approximately 80–90% of published clinical research^41,42 and 64% of systematic reviews include observational studies.⁴³ However, assessing the causal relationship between IAT and various outcomes is limited by both bias and confounding.⁴⁴ Particularly, IAT is preferentially used in patients who have incomplete or no recanalization after MT (rescue treatment). The inverse relationship between IAT and odds of near-complete or complete angiographic recanalization was probably reflective of the pattern of use rather than the lack of effect on recanalization. We think that methodological heterogeneity may also account for the lack of a significant association seen between IAT and various outcomes. We used the recommendations by Metelli and Chaimani⁴⁴ by using the random effects model accounts for heterogeneity, performing subgroup analysis or meta-regression by study design and characteristics, and performing a sensitivity analysis excluding studies of lower credibility. We used the NOS for cohort studies,⁴⁵ which is a commonly utilized method of grading the quality of observational studies.³³ We evaluated the effect of the quality of the study in the meta-regression and sensitivity analyses. Our analysis identified a prominent effect of the quality of the study and whether comparisons were made between groups that were either matched or assigned with random allocation. We also noticed funnel plot asymmetry in all the endpoints ascertained,^37,46 which can be a result of publication or other reporting biases, heterogeneity, and chance.³⁷ We acknowledge the limitations posed by performing meta-regression using a relatively small number of studies since a large ratio of studies to a covariate is required for a meaningful analysis. Usually, a ratio of 10 studies to 1 covariate is recommended in meta-regression.⁴⁷

Implications of our analysis

Our analysis points to the relative lack of evidence in existing reports that supports the relatively prevalent practice of administering IAT as an adjunct to MT in AIS patients. IAT was associated with higher rates of recanalization and functional independence when IAT was used as an adjunct to MT in some observational studies.^29,48 IAT may ameliorate microcirculatory compromise caused by a combination of capillary constriction followed by filling with entrapped erythrocytes, leukocytes, and fibrin-platelet deposits which prevents tissue perfusion after recanalization with MT.^49–51 Perfusion abnormalities can be seen in almost 80% of patients after near-complete or complete recanalization following MT.⁵² Our analysis suggested that the odds of functional independence at 90 days may be higher with IAT as an adjunct to MT (compared with MT alone) in studies of the highest quality grade, or in studies that were either matched or randomized comparisons. However, the odds of post-MT sICH may be higher with IAT, particularly in studies that were either matched or randomized comparisons. As none of the results were statistically significant and thus remain inconclusive, the risk–benefit ratio is not well known, and assuming a positive or null effect of IAT as an adjunct to MT may overlook a potentially negative effect of IAT. Randomized clinical trials are required to assess the risk–benefit ratio and identify AIS patient populations most likely to benefit from IAT as an adjunct to MT.

Supplemental Material

sj-docx-1-wso-10.1177_17474930231184369 – Supplemental material for Mechanical thrombectomy with intra-arterial thrombolysis versus mechanical thrombectomy alone in patients with acute ischemic stroke: A systematic review and meta-analysis

Supplemental material, sj-docx-1-wso-10.1177_17474930231184369 for Mechanical thrombectomy with intra-arterial thrombolysis versus mechanical thrombectomy alone in patients with acute ischemic stroke: A systematic review and meta-analysis by Adnan I Qureshi, Abdullah Lodhi, Iqra N Akhtar, Xiaoyu Ma, Danish Kherani, Chun Shing Kwok, Daniel E Ford, Daniel F Hanley, Ameer E Hassan, Thanh N Nguyen, Alejandro M Spiotta and Syed F Zaidi in International Journal of Stroke

Footnotes

Declaration of conflicting interests

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The author(s) received no financial support for the research, authorship, and/or publication of this article.

ORCID iDs

Adnan I Qureshi

Abdullah Lodhi

Danish Kherani

Chun Shing Kwok

Daniel F Hanley

Ameer E Hassan

Supplemental material

Supplemental material for this article is available online.

References

Jauch

Saver

Adams

, et al. Guidelines for the early management of patients with acute ischemic stroke: a guideline for healthcare professionals from the American Heart Association/American Stroke Association. Stroke 2013; 44: 870–947.

Powers

Rabinstein

Ackerson

, et al. Guidelines for the early management of patients with acute ischemic stroke: 2019 update to the 2018 guidelines for the early management of acute ischemic stroke: a guideline for healthcare professionals from the American Heart Association/American Stroke Association. Stroke 2019; 50: e344–e418.

Albers

Marks

Kemp

, et al. Thrombectomy for stroke at 6 to 16 hours with selection by perfusion imaging. N Engl J Med 2018; 378: 708–718.

Nogueira

Jadhav

Haussen

, et al. Thrombectomy 6 to 24 hours after stroke with a mismatch between deficit and infarct. N Engl J Med 2017; 378: 11–21.

Zaidi

Castonguay

Zaidat

, et al. Intra-arterial thrombolysis after unsuccessful mechanical thrombectomy in the STRATIS registry. AJNR Am J Neuroradiol 2021; 42: 708–712.

Zaidi

Castonguay

Jumaa

, et al. Intraarterial thrombolysis as rescue therapy for large vessel occlusions. Stroke 2019; 50: 1003–1006.

Noser

Shaltoni

Hall

, et al. Aggressive mechanical clot disruption. Stroke 2005; 36: 292–296.

Qureshi

Siddiqui

Suri

, et al. Aggressive mechanical clot disruption and low-dose intra-arterial third-generation thrombolytic agent for ischemic stroke: a prospective study. Neurosurgery 2002; 51: 1319–1327.

Sun

Huo

Raynald , et al. Intra-arterial thrombolysis vs. mechanical thrombectomy in acute minor ischemic stroke due to large vessel occlusion. Front Neurol 2022; 13: 860987.

10.

Chen

VHE

Lee

GKH

Tan

, et al. Intra-arterial adjunctive medications for acute ischemic stroke during mechanical thrombectomy: a meta-analysis. Stroke 2021; 52: 1192–1202.

11.

Kaesmacher

Meinel

Kurmann

, 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: 1073–1080.

12.

Baik

Jung

Kim

, et al. Local intra-arterial thrombolysis during mechanical thrombectomy for refractory large-vessel occlusion: adjunctive chemical enhancer of thrombectomy. AJNR Am J Neuroradiol 2021; 42: 1986–1992.

13.

Cappellari

Saia

Pracucci

, et al. Different endovascular procedures for stroke with isolated M2-segment MCA occlusion: a real-world experience. J Thromb Thrombolysis 2021; 51: 1157–1162.

14.

Collette

Bokkers

RPH

Mazuri

, et al. Intra-arterial thrombolytics during endovascular thrombectomy for acute ischaemic stroke in the MR CLEAN Registry. Stroke Vasc Neurol 2023; 8: 17–25.

15.

Kohli

Whyte

Schartz

, et al. Approaches to and outcomes of intra-arterial tPA in embolectomy for large vessel occlusion. J Stroke Cerebrovasc Dis 2022; 31: 106717.

16.

Qureshi

Lodhi

, et al. Intraarterial thrombolytics as an adjunct to mechanical thrombectomy in patients with basilar artery occlusion. J Neuroimaging 2023; 33: 415–421.

17.

Renú

Millán

San Román

, et al. Effect of intra-arterial alteplase vs placebo following successful thrombectomy on functional outcomes in patients with large vessel occlusion acute ischemic stroke: the CHOICE randomized clinical trial. JAMA 2022; 327: 826–835.

18.

Page

McKenzie

Bossuyt

, et al. The PRISMA 2020 statement: an updated guideline for reporting systematic reviews. BMJ 2021; 372: n71.

19.

Mokin

Dumont

Veznedaroglu

, et al. Solitaire flow restoration thrombectomy for acute ischemic stroke: retrospective multicenter analysis of early postmarket experience after FDA approval. Neurosurgery 2013; 73: 19–25.

20.

Berkhemer

Fransen

PSS

Beumer

, et al. A randomized trial of intraarterial treatment for acute ischemic stroke. N Engl J Med 2015; 372: 11–20.

21.

Goyal

Demchuk

Menon

, et al. Randomized assessment of rapid endovascular treatment of ischemic stroke. N Engl J Med 2015; 372: 1019–1030.

22.

Bracard

Ducrocq

Mas

, et al. Mechanical thrombectomy after intravenous alteplase versus alteplase alone after stroke (THRACE): a randomised controlled trial. Lancet Neurol 2016; 15: 1138–1147.

23.

Roa

Maud

Jabbour

, et al. Transcirculation approach for mechanical thrombectomy in acute ischemic stroke: a multicenter study and review of the literature. Front Neurol 2020; 11: 347.

24.

Fiorelli

Bastianello

von Kummer

, et al. Hemorrhagic transformation within 36 hours of a cerebral infarct: relationships with early clinical deterioration and 3-month outcome in the European Cooperative Acute Stroke Study I (ECASS I) cohort. Stroke 1999; 30: 2280–2284.

25.

Anadani

Ajinkya

Alawieh

, et al. Intra-arterial tissue plasminogen activator is a safe rescue therapy with mechanical thrombectomy. World Neurosurg 2019; 123: e604–e608.

26.

Castonguay

Zaidi

Jumaa

, et al. 8 intra-arterial thrombolysis as rescue therapy in MCA occlusions: subanalysis from the STRATIS registry. J Neurointerv Surg 2019; 11: A133.

27.

Fischer

Mono

Schroth

, et al. Endovascular therapy in 201 patients with acute symptomatic occlusion of the internal carotid artery. Eur J Neurol 2013; 20: 1017–1024, e87.

28.

Heiferman

Pecoraro

Smolenski

Tsimpas

Ashley

Jr.

Intra-arterial alteplase thrombolysis during mechanical thrombectomy for acute ischemic stroke. J Stroke Cerebrovasc Dis 2017; 26: 3004–3008.

29.

Kaesmacher

Bellwald

Dobrocky

, et al. Safety and efficacy of intra-arterial urokinase after failed, unsuccessful, or incomplete mechanical thrombectomy in anterior circulation large-vessel occlusion stroke. JAMA Neurol 2020; 77: 318–326.

30.

Singer

Haring

Trenkler

, et al. Periprocedural aspects in mechanical recanalization for acute stroke: data from the ENDOSTROKE registry. Neuroradiology 2013; 55: 1143–1151.

31.

Chen

, et al. Adjuvant intra-arterial rt-PA injection at the initially deployed solitaire stent enhances the efficacy of mechanical thrombectomy in acute ischemic stroke. J Neurol Sci 2018; 386: 69–73.

32.

Wells

Shea

O’Connell

, et al. The Newcastle-Ottawa Scale (NOS) for assessing the quality of nonrandomised studies in meta-analyses, 2000, https://www.ohri.ca/programs/clinical_epidemiology/oxford.asp

33.

Luchini

Stubbs

Solmi

, et al. Assessing the quality of studies in meta-analyses: advantages and limitations of the Newcastle Ottawa Scale. World J Meta-Anal 2017; 5: 80–84.

34.

Veronese

Cereda

Solmi

, et al. Inverse relationship between body mass index and mortality in older nursing home residents: a meta-analysis of 19,538 elderly subjects. Obes Rev 2015; 16: 1001–1015.

35.

Sterne

Savović

Page

, et al. RoB 2: a revised tool for assessing risk of bias in randomised trials. BMJ 2019; 366: l4898.

36.

Duval

Tweedie

. A nonparametric “trim and fill” method of accounting for publication bias in meta-analysis. J Am Stat Assoc 2000; 95: 89–98.

37.

Sterne

Sutton

Ioannidis

, et al. Recommendations for examining and interpreting funnel plot asymmetry in meta-analyses of randomised controlled trials. BMJ 2011; 343: d4002.

38.

Laredo

Rodríguez

Oleaga

, et al. Adjunct thrombolysis enhances brain reperfusion following successful thrombectomy. Ann Neurol 2022; 92: 860–870.

39.

Castonguay

Jumaa

Zaidat

, et al. Insights into intra-arterial thrombolysis in the modern era of mechanical thrombectomy. Front Neurol 2019; 10: 1195.

40.

Kellert

Wollenweber

Thomalla

, et al. Thrombolysis management in thrombectomy patients: real-life data from German stroke centres. Eur Stroke J 2017; 2: 356–360.

41.

Funai

Rosenbush

Lee

Del Priore

. Distribution of study designs in four major US journals of obstetrics and gynecology. Gynecol Obstet Invest 2001; 51: 8–11.

42.

Mueller

D’Addario

Egger

, et al. Methods to systematically review and meta-analyse observational studies: a systematic scoping review of recommendations. BMC Med Res Methodol 2018; 18: 44.

43.

Page

Shamseer

Altman

, et al. Epidemiology and reporting characteristics of systematic reviews of biomedical research: a cross-sectional study. PLoS Med 2016; 13: e1002028.

44.

Metelli

Chaimani

. Challenges in meta-analyses with observational studies. Evid Based Ment Health 2020; 23: 83–87.

45.

Stang

. Critical evaluation of the Newcastle-Ottawa scale for the assessment of the quality of nonrandomized studies in meta-analyses. Eur J Epidemiol 2010; 25: 603–605.

46.

Sterne

Gavaghan

Egger

. Publication and related bias in meta-analysis: power of statistical tests and prevalence in the literature. J Clin Epidemiol 2000; 53: 1119–1129.

47.

Meta-regression, https://www.meta-analysis.com/downloads/Meta-analysis%20Meta%20regression.pdf (accessed May 20 2023).

48.

Kaesmacher

Abdullayev

Maamari

, et al. Safety and angiographic efficacy of intra-arterial fibrinolytics as adjunct to mechanical thrombectomy: results from the INFINITY registry. J Stroke 2021; 23: 91–102.

49.

Belayev

Pinard

Nallet

, et al. Albumin therapy of transient focal cerebral ischemia: in vivo analysis of dynamic microvascular responses. Stroke 2002; 33: 1077–1084.

50.

Morris

Davies

Zhang

, et al. Measurement of cerebral microvessel diameters after embolic stroke in rat using quantitative laser scanning confocal microscopy. Brain Res 2000; 876: 31–36.

51.

Yemisci

Gursoy-Ozdemir

Vural

Can

Topalkara

Dalkara

. Pericyte contraction induced by oxidative-nitrative stress impairs capillary reflow despite successful opening of an occluded cerebral artery. Nat Med 2009; 15: 1031–1037.

52.

Rubiera

Garcia-Tornel

Olivé-Gadea

, et al. Computed tomography perfusion after thrombectomy. Stroke 2020; 51: 1736–1742.

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