Bridging Thrombolysis Achieved Better Outcomes Than Direct Thrombectomy After Large Vessel Occlusion: An Updated Meta-Analysis
Abstract
The utility and necessity of pretreatment with intravenous thrombolysis (IVT) before mechanical thrombectomy (MT) remains an issue of strong debate. This study aims to compare the outcomes of bridging thrombolysis (BT, IVT+MT) with direct MT (d-MT) after large vessel ischemic stroke based on the most up-to-date evidence. MEDLINE, EMBASE, Scopus, and the Cochrane Library from January 2017 to June 2020 were searched for studies that directly compared the outcomes of the 2 strategies. Methodological quality was assessed using the Quality in Prognostic Studies tool. Combined estimates of odds ratios (ORs) of BT versus d-MT were derived. Multiple subgroup analyses were performed, especially for IVT-eligible patients. Thirty studies involving 7191 patients in the BT group and 4891 patients in the d-MT group were included. Methodological quality was generally high. Compared with patients in the d-MT group, patients in the BT group showed significantly better functional independence (modified Rankin Scale score 0–2) at 90 days (OR=1.43 [95% CI, 1.28–1.61]), had lower mortality at 90 days (OR=0.67 [95% CI, 0.60–0.75]), and achieved higher successful recanalization (modified Thrombolysis in Cerebral Ischemia score 2b-3) rate (OR=1.23 [95% CI, 1.07–1.42]). No significant difference was detected in the occurrence of symptomatic intracranial hemorrhage between 2 groups (OR=1.01 [95% CI, 0.86–1.19]). Subgroup analysis showed that functional independence frequency remained significantly higher in BT group regardless of IVT eligibility or study design. Compared with d-MT, bridging with IVT led to better clinical outcomes, lower mortality at 90 days, and higher successful recanalization rates, without increasing the risk of near-term hemorrhagic complications. The benefits of BT based on this most recent literature evidence support the current guidelines of using BT.
Mechanical thrombectomy (MT) has become the widely accepted care for acute ischemic stroke patients with large vessel occlusion. The current American and European guidelines recommend use of intravenous thrombolysis (IVT) for all eligible patients with large vessel occlusion before MT (class of recommendation-I).1,2 However, the efficacy and benefit of routine IVT in eligible patients before thrombectomy has been a topic of contention lately.3 Pretreatment with systemic thrombolysis in patients with large vessel occlusion may result in successful reperfusion in 11% to 33% cases, negating the need for additional endovascular reperfusion.4,5 However, recanalization may not occur early enough to obviate subsequent MT in clinical practice.3 Also, lower efficacy of IVT is seen with tandem occlusions, long or totally occlusive thrombus and poor collateral circulation.4,5 There is considerable between-study variance whether IVT facilitates successful and faster reperfusion in subsequent MT.3 Bridging thrombolysis (BT, indicating IVT+MT) is possible to be associated with complications including increased risk of distal emboli or intracranial hemorrhage rates.6 Administration of IVT may also lead to delay in MT, with adverse impact on patient outcome.7
Direct MT (d-MT) has been shown to be an effective therapy and improves outcomes among patients ineligible for IVT.8 Multiple meta-analyses which included studies published before 2017 have been published, but even the pooled results from these meta-analyses were contradictory.9–12 A considerable amount of studies have been published to address this issue since reflecting the most up-to-date standard of practice. The purpose of this study was to conduct a meta-analysis of studies published in 2017 and beyond to compare outcomes after thrombectomy with and without prior IVT in comparable patient populations.
Methods
The data that support the findings of this study are available from the first authors upon reasonable request.
Search Strategy and Study Selection
This meta-analysis strictly followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Institutional review board approval was not required as data was derived from the published literature.
A medical librarian (A. Brackett) performed a comprehensive search of multiple databases: Ovid Embase (January 1, 2010, to May 31, 2019) and Ovid MEDLINE (January 1, 2010, to June 10, 2020). The detailed search strategy, inclusion and exclusion criteria are listed in the Data Supplement.
Data Extraction
The comparative outcomes were measured by odds ratio (OR) between the BT group and d-MT group. The data were extracted by 2 evaluators (Drs Wang and Zhu) and cross-checked by a third evaluator (Dr Wu) according to a standardized data extraction approach. Data collected are listed in the Data Supplement.
Data Analysis and Statistical Methods
Individual ORs with 95% CIs from each study were used to calculate the combined ORs with 95% CIs by meta-analysis with a Mantel-Haenszel model, performed using Stata (version 12.0). The ORs extracted were calculated as BT versus d-MT. I2 was calculated as a measure of statistical heterogeneity, with I2 values of 0% to 40%, 30% to 60%, 50% to 90%, and 75% to 100% representing not important, moderate, substantial, and considerable inconsistency, respectively.13 A random-effects model was generally used, while analysis using fixed-effects model was additionally performed when an I2 value was <50%.14
The methodology of subgroup analysis based on IVT eligibility, study design, in studies including anterior circulation only, and in studies using propensity score (PS) matched data is shown in the Data Supplement.
Meta-regression was performed for the OR of the proportions of good outcome and mortality against difference in time from symptom onset to groin puncture.
The effect of bridging strategies was considered as statistically significant if the 95% CI for the combined OR did not overlap 1.0. Statistical significance for hypothesis testing was set at the 0.05 two-tailed level.
Quality Assessment and Publication Bias
To evaluate the methodological quality of included studies, 2 reviewers (Drs Wang and Zhu) independently assessed each study using the Quality in Prognostic Studies tool, a validated method for assessing the risk of bias in prognostic factor studies.15 The following checklist consisting of 6 domains were evaluated for each study: study participation, study attrition, prognostic factor measurement, confounding measurement, outcome measurement, and analysis and reporting. The risk of bias of each domain was rated as high, moderate, or low according to the detailed listed standards. Disagreements were resolved by consensus between the 2 reviewers.
Publication bias was assessed with (1) plots of ORs against error/variance of the study (funnel plots) and (2) Begg rank correlation test and Egger regression test. An asymmetrical funnel plot or a 2-tailed P<0.05 with the latter 2 tests would suggest potential bias.
Results
Study Selection and Characteristics
As the detailed study selection flowchart showed in Figure 1, the initial search yielded 5912 articles. During the study selection, there were 2 pairs of studies that were very likely to have partial overlap of patient cohorts but could not have the overlapped data sorted, so both were included.16–19 On the contrary, 2 studies had almost complete overlap of patient cohorts (based on institutions and enrollment time interval) after careful examination, and the one with smaller sample size was excluded.16,20 Finally, 30 studies met the inclusion criteria and were included in the meta-analysis.
The main characteristics of the 30 studies are summarized in Table I in the Data Supplement. A total of 7191 patients in the BT group and 4891 patients in the d-MT group were included. Median sample size was 280 (range, 46–1507), and mean age ranged from 61.8 to 73.6 years old. A total of 28/30 studies reported outcomes at 90 days, whereas 2 studies also reported outcomes at discharge.21,22 The median baseline National Institutes of Health Stroke Scale was above 10 in all studies. The median Alberta Stroke Program Early CT Score was above 6 in 17 studies and not described in 13 studies. Six studies reported PS matching and separate subgroup analysis was performed for the PS matched data.16,18,23–26
A total of 5/30 included studies had IVT eligible patients with 1209 patients in the BT and 1035 patients in the d-MT arm. One study provided clear details of randomization of patients between the subgroups.27 The treatment decision was at the discretion of the neurologist and neurointerventionalist on duty.23,26,28 The predominant reason to not treat eligible patients with IVT were exclusionary criteria recommended by previous guidelines and no longer reported in current ones, or due to concerns about IVT use (patients were too close to the 4.5-hour time window, borderline international normalized ratio, advanced age, high clot burden, or proximal clot location).
Eight studies mentioned that either a drip-and-ship or mothership system was used, but only 2 studies reported the outcomes of each treatment arm.16,17,24,28–32 Higher recanalization rates were reported after IVT in drip-and-ship patients compared with mothership patients, likely because of longer exposure time to IVT.33 However, in the study by Di Maria et al,16 neither mothership (OR=1.19 [95% CI, 0.67–2.12]) nor drip-and-ship (OR=1.25 [95% CI, 0.86–1.82]) approaches had significant impact on clinically favorable outcomes in the PS matched model.
Six studies included wake-up strokes or uncertain time frame since symptom onset, but the separately reported data was too scarce for subgroup analysis.28–31,34,35 Usually, the clinical management relied on imaging (magnetic resonance imaging or computed tomography) based evaluation with evidence of penumbra. Two of the 3 studies that reported the data separately reported no significant difference of wake-up stroke prevalence between the BT and d-MT groups.29,30
Clinical Outcomes at 90 Days
Pooled OR showed that patients in the BT group achieved significantly better clinical outcomes at 90 days than those in the d-MT group, measured either by functional independence as defined as modified Rankin Scale score 0-2 (OR=1.43 [95% CI, 1.28–1.61]) or by excellent clinical outcome as defined as modified Rankin Scale score 0-1 (OR=1.42 [95% CI, 1.21–1.67]). The benefit of bridging approach remained robust after adopting PS matched data and also in the subset of studies investigating anterior circulation strokes only (Table). Subgroup analysis showed that functional independence frequency remained significantly higher in BT group regardless of IVT eligibility (5 IVT eligible and 23 IVT ineligible) or study design (7 prospective and 21 retrospective), but the difference in excellent clinical outcome frequency became borderline in IVT-eligible patients (OR=1.11 [95% CI, 0.93–1.33]; Figure 2A and 2B). The only randomized trial (DIRECT-MT) showed functional independence in 36.4% in the d-MT group compared with 36.8 in the BT group.27
Outcome | No. of studies | No. of patients | Pooled OR* | 95% CI | I2 |
---|---|---|---|---|---|
mRS score 0–2 at 90 d† | |||||
Overall | 28 | 6837 vs 4680 | 1.43 | 1.28–1.61 | 43.8% |
PS matched when available | 28 | 5239 vs 4306 | 1.40 | 1.24–1.57 | 36.6% |
Anterior circulation only | 19 | 5080 vs 3398 | 1.39 | 1.20–1.60 | 46.4% |
mRS score 0–1 at 90 d† | |||||
Overall | 14 | 5087 vs 3070 | 1.42 | 1.21–1.67 | 50.3% |
PS matched when available | 14 | 4266 vs 2700 | 1.39 | 1.19–1.64 | 44.1% |
Anterior circulation only | 10 | 3971 vs 2339 | 1.43 | 1.15–1.77 | 62.8% |
Mortality at 90 d† | |||||
Overall | 28 | 6941 vs 4708 | 0.67 | 0.60–0.75 | 23.5% |
PS matched when available | 28 | 6099 vs 4328 | 0.69 | 0.60–0.79 | 33.9% |
Anterior circulation only | 21 | 5378 vs 3632 | 0.69 | 0.59–0.79 | 30.4% |
Symptomatic intracranial hemorrhage | |||||
Overall | 26 | 6925 vs 4683 | 1.01 | 0.86–1.19 | 0.0% |
PS matched when available | 26 | 6107 vs 4314 | 1.03 | 0.87–1.22 | 0.0% |
Anterior circulation only | 18 | 5181 vs 3412 | 1.08 | 0.89–1.31 | 0.0% |
mTICI score 2b-3 after procedure† | |||||
Overall | 30 | 7152 vs 4861 | 1.23 | 1.07–1.42 | 45.2% |
PS matched when available | 30 | 6310 vs 4481 | 1.26 | 1.10–1.44 | 34.6% |
Anterior circulation only | 21 | 4626 vs 3357 | 1.24 | 1.05–1.46 | 37.9% |
mTICI 3 after procedure | |||||
Overall | 13 | 3240 vs 2198 | 1.02 | 0.84–1.23 | 56.3% |
PS matched when available | 13 | 2671 vs 2074 | 1.00 | 0.82–1.23 | 55.9% |
Anterior circulation only | 10 | 2670 vs 1758 | 1.11 | 0.97–1.26 | 48.9% |
mRS indicates modified Rankin Scale; mTICI, modified Thrombolysis in Cerebral Ischemia; OR, odds ratio; and PS, propensity score.
*
Present results from random-effect model.
†
Statistically significant.
Mortality at 90 Days
Pooled OR showed that patients in the BT group had significantly lower mortality at 90 days than those in the d-MT group (OR=0.67 [95% CI, 0.60–0.75]). The benefit of bridging approach remained robust after adopting PS matched data and also in the subset of studies investigating anterior circulation only (Table). Subgroup analysis indicated that the mortality at 90 days was significantly lower in the BT group in 23 studies with IVT-ineligible patients, but the difference became borderline in 5 studies with IVT eligible patients (OR=0.84 [95% CI, 0.69–1.02]; Figure 2C). The mortality at 90 days was still significantly lower in the BT group regardless of study design.
Hemorrhagic Complication
Pooled OR showed no significant difference in the occurrence of symptomatic intracerebral hemorrhage between the 2 groups (OR=1.01 [95% CI, 0.86–1.19], I2=0%, P=0.70). The results remain similar after adopting PS matched data and also in the subset of studies investigating anterior circulation strokes only (Table). No significant difference was found in the subgroup analysis by IVT eligibility or study design (Figure 2D).
Recanalization
Patients in the BT group achieved higher rates of successful recanalization (defined as modified Thrombolysis in Cerebral Ischemia score 2b-3) compared with patients in the d-MT group (OR=1.23 [95% CI, 1.07–1.42]). The benefit of bridging approach remained robust after adopting PS matched data and also in the subset of studies investigating strokes in anterior circulation only (Table). However, the difference became not significant in IVT eligible patients or in prospectively designed studies (Figure 2E). However, complete recanalization (defined as modified Thrombolysis in Cerebral Ischemia score 3) rate did not differ between 2 groups (OR=1.02 [95% CI, 0.84–1.23]), and the results remained similar in subgroup analysis by IVT eligibility or study design (Figure 2F).
Meta-Regression Based on Differences in Time From Symptom Onset to Groin Puncture
Bubble plot of the OR of good outcome (BT against d-MT) showed a trend of a larger difference in time to groin puncture with a higher OR. However, the correlation is not statistically significant in our meta-regression analysis (P=0.6). The correlation between time difference and mortality was not statistically significant either (Figure 3, html format are available at https://rpubs.com/xiaowu/649086 and https://rpubs.com/xiaowu/649087).
Quality and Publication Bias Assessment
Table II in the Data Supplement summarized the results of methodology assessment by Quality in Prognostic Studies tool of 6 domains. All studies except one showed low risk of bias in at least 4 domains, indicating relatively high methodological quality in general. Common reasons for moderate risk of bias included unclear selection criteria regarding administration of IVT (N=6),18,25,34,36,37 MT techniques unclear or not specified (N=7),18,19,30,32,34,38,39 mixed MT techniques especially in multicenter studies without statistical adjustment (N=5),17,21,24,40,41 and significant difference in baseline demographic characteristics between 2 groups without statistical adjustment (N=5).17,23,31,34,42
There was no substantial visual asymmetry in the funnel plots in any of the investigated outcomes, as shown in Figure 4. All P values yielded by the Begg test and Egger test were >0.05, indicating no significant publication bias detected (Table III in the Data Supplement).
Discussion
This updated meta-analysis based on 30 clinical studies, including 7191 patients in the BT group and 4891 patients in the d-MT group, shows that the bridging approach has better functional outcomes and lower mortality at 90 days without increasing the risk of near-term hemorrhagic complications. The BT group had a higher rate of successful recanalization (modified Thrombolysis in Cerebral Ischemia score 2b-3) than did the d-MT group. The better outcomes after bridging approach remained robust after adopting PS matched data and also in the subset of studies investigating anterior circulation strokes only. Functional independence frequency remained significantly higher in BT group regardless of IVT eligibility or study design.
The utility and necessity of pretreatment with IVT before MT remain an issue of strong debate with major implications for stroke systems of care, and if patients should get transferred to endovascular capable centers immediately versus receive IVT at the closest center first. The studies proposing BT argued that preceding IVT could facilitate the endovascular procedure by partially lysing and fragmentating the clot, and enable recanalization of distal thrombi that are inaccessible to endovascular devices.16,17,28,36 However, the studies advocating for d-MT cited the number of exclusion criteria for IVT, its cost, the time required for its mixing and infusion, and safety considerations as reasons to bypass IVT.9,23,40 Decline in benefit because of delays from stroke onset to treatment are reported with both IVT and MT, although it may be 2.5-fold less for IVT in patients with large vessel occlusion.43 Better selection of patients for IVT using perfusion imaging for collateral flow may further increase utility of bridging treatment.44
Although the current guideline recommended the use of BT, a recent multicenter randomized clinical trial (DIRECT-MT) among IVT eligible patients from China reported d-MT as noninferior compared with BT.27 However, the margin used to declare noninferiority was generous (CI did not exclude a benefit of ≈20% in the combination-therapy group).45 Overall good outcomes were significantly lower compared with those reported in previous trials. The futile recanalization rates were 48.7% and 52.3% in the control and intervention groups, respectively, which are much higher than the range of 15% to 28% reported by the randomized trials in HERMES.8 All these factors limit the generalizability of the results.45 We have included this study in our meta-analysis to assess the effect, and the pooled results still indicate BT was associated with better outcomes. Possible underlying reasons might be that the beneficial effect of prior IVT before MT (the potential early reperfusion, possible reopening of distal occluded branches and enhanced efficacy of MT16, 29, 36) exceeds its disadvantages (delay of MT and possible hemorrhagic risk9).
It has been argued that a literature comparison of BT and d-MT patient groups in a nonrandomized setting would be biased, since a considerable portion of patients in the d-MT group were ineligible for IVT due to reasons, such as delayed presentation outside the IVT window, long onset to groin puncture time, and increased international normalized ratio, which could be associated with worse clinical outcome and increased risk of hemorrhagic complications.12,31 Therefore, we did subgroup analysis of IVT-eligible patients only. This analysis showed the benefit of IVT before MT remained significant in terms of better functional independence at 90 days and was borderline in terms of lower mortality at 90 days.
Comparison With Previous Meta-Analyses
Multiple previous meta-analyses have been published with contradictory results regarding the utility of BT. A study-level meta-analysis found no significant difference in outcome between patients with and without pretreatment with IVT, but it included studies evaluating posterior circulation strokes without subgroup analysis and a few studies which used first-generation MT devices.10 Mistry et al11 reported better functional outcomes, lower mortality, and higher rates of successful recanalization in BT patients compared with d-MT patients.11 However, these studies did not distinguish between patient eligibility for IVT and outcomes. Kaesmacher et al12 reported comparable safety and efficacy with or without IVT even in IVT-eligible patients. One of the 3 included studies in their analysis that assessed IVT eligible patients by Weber et al7 had outsized effect and its exclusion would result in significant association between d-MT and lower rates of good outcomes.7 All these meta-analyses included studies up to early 2017, and several studies have been published in the past 3 years. More recent meta-analysis included all relevant studies before early 2019; one study did not discriminate IVT eligibility and another one did not report data about PS matching.46,47 We exclusively included and analyzed studies from 2017 January till 2020 June, aiming to reflect the pooled results of the most up-to-date practice and advances in recanalization techniques. Our study included 30 more recent studies with over 12 000 patients in total, including 9 studies with 3831 patients after 2019. We also included the just published (May 21, 2020) DIRECT-MT study, the only RCT published between d-MT and BT.27 Previous studies were smaller and reported more significant heterogeneity for certain outcome measures. Our analysis showed that despite some of the included studies being observational in nature, their quality as assessed by the Quality in Prognostic Studies tool was generally high. Subgroup analysis about IVT eligibility, study design, PS matching, anterior strokes have been performed, and meta-regression about onset to groin puncture time have also been explored.
Limitations
The current work experienced several limitations. First, there existed some overlap of patient cohorts. When we identified a multicenter study with a shorter period of enrollment time and a study from one of those centers with a longer period of enrollment time, attempts were made to contact the corresponding authors to request specific data, but the failure to respond resulted in inclusion of both studies leading to selection bias. Another limitation was the presence of missing data in some covariates of included studies. Although the design of meta-analysis was to gain greater statistical power by increasing the effective sample size, we could not exclude that missing data could introduce a bias in estimates. Third, many of the included studies lacked a random allocation of patients to either treatment group despite PS adjustment in some studies. Only one of the included 30 studies was randomized and although we did subgroup analysis for PS matched data and inverse probability weighting, residual unmeasured confounders may exist. Furthermore, there are many more studies investigating IVT-ineligible patients than those investigating IVT-eligible patients due to various practical reasons in the clinical setting. Patients ineligible for IVT may be more likely to have thrombi of cardiogenic origin, with a high fibrin content and associated lower rates of successful reperfusion, emphasizing the importance of comparison of the 2 treatments only among IVT eligible patients in future study designs.48 Fourth, the data of the patients who reperfused or clinically improved after receiving IVT, and therefore, did not proceed to MT was not included in any of these studies. As a result, this potentially important advantage of the BT was not incorporated in the current analysis. Finally, although the included studies were published after January 1, 2017, many patients included underwent thrombectomy in previous years.
Conclusions
The updated literature from the past 3 years shows that compared with d-MT, BT led to better clinical outcomes, lower mortality at 90 days, and higher successful recanalization rates, without increasing the risk of near-term hemorrhagic complications. However, further formal testing in randomized-controlled trials is warranted to draw strong conclusions. Several trials are currently underway (SWIFT DIRECT [Solitaire With the Intention for Thrombectomy Plus Intravenous t-PA Versus DIRECT Solitaire Stent-Retriever Thrombectomy in Acute Anterior Circulation Stroke], MR CLEAN-NO IV [Multicenter Randomised Controlled Trial of Endovascular Treatment for Acute Ischemic Stroke in the Netherlands], and RACECAT [Direct Transfer to an Endovascular Center Compared to Transfer to the Closest Stroke Center in Acute Stroke Patients With Suspected Large Vessel Occlusion] trials) to compare d-MT with BT.
Acknowledgments
We thank the librarian Alexandria Brackett for the help of literature search.
Supplemental Material
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Published online: 11 December 2020
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This work is supported by the Scientific Research Fund of Sichuan Provincial People’s Hospital, 2020LY05.
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- Bridging the Gap: Improving Acute Ischemic Stroke Outcomes with Intravenous Thrombolysis Prior to Mechanical Thrombectomy, Neurology International, 16, 6, (1189-1202), (2024).https://doi.org/10.3390/neurolint16060090
- Endovascular thrombectomy without versus with different pre-intravenous thrombolysis in acute ischemic stroke: a network meta-analysis of randomized controlled trials, Frontiers in Neurology, 15, (2024).https://doi.org/10.3389/fneur.2024.1344961
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- Meta-analysis of direct endovascular thrombectomy vs bridging therapy in the management of acute ischemic stroke with large vessel occlusion, Clinical Neurology and Neurosurgery, 236, (108070), (2024).https://doi.org/10.1016/j.clineuro.2023.108070
- Safety and efficacy of bridging intravenous thrombolysis plus mechanical thrombectomy versus direct mechanical thrombectomy in different age groups of acute ischemic stroke patients, Acta Neurologica Belgica, (2024).https://doi.org/10.1007/s13760-024-02672-0
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