DOI: https://doi.org/10.21203/rs.3.rs-2054098/v2
Purpose
To assess the clinical value of mechanical thrombectomy (MT) combined with intravenous thrombolysis (IVT) in acute ischemic stroke (AIS) by comparing it with the direct MT (dMT).
Method
We conducted a systematic review and meta-analysis involving studies from four databases including PubMed, Embase, WOS, and Cochrane Library. We collected observational studies and randomized controlled studies (RCTs) published from January 2011 to June 2022, providing data about outcomes in terms of functional independence (FI), excellent outcomes (mRS score:0-1), successful recanalization (SR), symptomatic intracerebral hemorrhage (sICH), any intracerebral hemorrhage (aICH), and mortality at three-month or discharge.
Results
A total of 55 eligible studies (nine RCTs and 46 observational studies) were included. For RCTs, the MT+IVT group was superior in FI (OR:1.27, 95%CI:1.11-1.46), excellent outcomes (OR:1.21, 95%CI:1.03-1.43), SR (OR:1.23, 95%CI:1.05-1.45), mortality (OR:0.72, 95%CI: 0.54-0.97) in crude analyses. In adjusted analyses, the MT+IVT group reduced the risk of mortality (OR:0.65, 95%CI: 0.49-0.88). For observational studies, the results of FI (OR:1.34, 95%CI:1.16-1.33), excellent outcomes (OR:1.30, 95%CI:1.09-1.54), SR (OR:1.23, 95%CI:1.05-1.44), mortality (OR:0.70, 95%CI:0.64-0.77) in the MT+IVT group were better. Additionally, the MT+IVT group increased the risk of hemorrhagic transformation (HT) including sICH (OR:1.16, 95%CI:1.11-1.21) and aICH (OR:1.24, 95%CI:1.05-1.46) in crude analyses. In crude analyses, significant better outcomes were seen in the MT+IVT group on FI (OR:1.36, 95%CI:1.21-1.52), excellent outcomes (OR:1.49, 95%CI:1.26-1.75), and mortality (OR:0.73, 95%CI: 0.56-0.94).
Conclusions
The MT+IVT therapy did improve the prognosis for AIS patients and did not increase the risk of HT compared with dMT therapy.
Stroke is the second greatest cause of mortality and the leading causes of disability worldwide. According to the Global Burden of Disease Study 2019, the burden of stroke is steadily rising, especially in low- and middle-income nations. Ischemic and hemorrhagic strokes are the two main subtypes, with ischemic strokes accounting for around 85% of instances[1]. Intravenous thrombolysis (IVT) and mechanical thrombectomy (MT) are routinely performed in acute ischemic stroke (AIS) patients with occlusion of anterior circulation. According to the latest guidelines, the treatment window for MT was expanded up to 16–24 hours, and IVT with alteplase was approved for patients within 4.5 hours[2].
The prognosis of AIS was greatly improved when comparing MT with routine medical care[3]. However, there has been controversy regarding the effectiveness of IVT before MT. Most studies indicated that bridging treatment can encourage successful recanalization (SR)[4–8]. IVT, however, raised potential complications, especially intracranial hemorrhage and distal embolization. IVT-induced thrombus fragmentation would make subsequent MT more difficult[9,10]. These conflicting results highlighted the challenges of clinical operation selection.
Currently, several systematic and meta-analysis have compared the direct MT (dMT) and bridging treatment (MT+IVT)[11–13]. Katsanos et al indicated that AIS patients with MT+IVT treatment, compared to dMT treatment, improved functional independence (FI), SR, and three-month mortality results[11]. In direct contrast, one study showed no statistically significant difference between the two treatment[12]. We also found either an assessment limited to observational studies or just randomized controlled trials (RCTs)[11–13]. Given the increasing number of clinical trials in this field, a comprehensive systematic review and meta-analysis should be conducted once more. The evaluations of therapeutic interventions would fall into two categories, observational studies and RCTs .
AIS, acute ischemic stroke; aICH, any intracerebral hemorrhage; CI, confidence interval; CS, cross-sectional study; dMT, direct mechanical thrombectomy; ECASS II, European Cooperative Acute Stroke Study 2 classification; ECASS III, European Cooperative Acute Stroke Study 3 classification; EVT, endovascular treatment; FI, functional independence; HBC, Heidelberg Bleeding Classification; IVT, Intravenous thrombolysis; I2, Higgin’s inconsistency index; LVO, large vessel occlusion; MT, mechanical thrombectomy; MeSH, Medical Subject Headings; mRS, modified Rankin Scale; mTICI, modified Thrombolysis in Cerebral Infarction; NOS, Newcastle-Ottawa Scales; PS, prospective study; PSM, propensity score method; RS, retrospective study; RCT, randomized controlled trials; SR: successful recanalization; sICH: symptomatic intracerebral hemorrhage; SITS-MOST, Safe Implementation of Thrombolysis in Stroke-Monitoring Study.
This study was carried out in compliance with the Preferred Reporting Items for Systematic Reviews and Meta-Analysis statement (PRISMA)[14]. This research has been registered via PROSPERO (CRD42022345385). Two investigators searched from four databases (PubMed, Embase, WOS, and Cochrane Library) published From January 2011 to June 2022. Our search strategy combined Medical Subject Headings (MeSH) and free words.
The selection criteria were based on the PICOS (population, intervention, comparison, outcomes, and study design) approach. The following criteria served as the basis for our study screening. Inclusion criteria: (1) The studies were observational studies and RCTs; (2) Data from adults (age≥18); (3) Studies provided the quantitative estimates and their 95% confidence interval (95%CI). Exclusion criteria: (1) Studies were literature reviews, protocols, case reports, comments, editorial articles, cell experiments, or animal experiments; (2) Patients of AIS with non-anterior circulation in large vessel occlusion (LVO).
We included AIS patients with LVO in the anterior circulation. Each participant received the dMT or IVT+MT therapy. Most of included studies primarily used the medication alteplase. It should be highlighted that we did not exclude some other IVT medications from our analysis even though they were not recommended by the guidelines.
In this study, FI for three months or hospital discharge, defined as a modified Rankin Scale (mRS) score (range,0 to 2), was selected as the primary efficacy outcome. The primary safety indicator was symptomatic intracerebral hemorrhage (sICH) at 24 or 36 hours according to Heidelberg Bleeding Classification (HBC)[15], or European Cooperative Acute Stroke Study 3 classification (ECASS III)[16], or ECASS II, or Safe Implementation of Thrombolysis in Stroke-Monitoring Study (SITS-MOST) criteria[17].
Thrombolysis in Cerebral Infarction (TICI score of 2B, 2C, or 3), modified TICI (mTICI) score (2B or 3), or eTICI score (2B, 2C, or 3)[18] was defined as SR with final cerebral angiography, and mRS score (range, 0 to 1) were adopted as secondary efficacy outcomes. Mortality at three months or discharge and any intracerebral hemorrhage (aICH) were analyzed as secondary safety outcomes.
Given that we had both RCTs, and observational studies included, we employed the Cochrane Risk of Bias tool (RoB) to assess RCTs, which included blinding, baseline comparison, allocation concealment, and randomization analysis. The modified Newcastle-Ottawa Scales (NOS) were used to assess the authenticity and quality of observational studies[19]. The NOS consisted of three sections: patient selection, study group comparability, and outcome assessment. The methodological quality of studies was assessed using a star system. The NOS can award up to nine points, with NOS≥7 indicating high-quality study. Beyond this, the study was considered “low quality”.
We performed sensitivity analyses to test the stability of our results by excluding each study one by one. Moreover, contour-enhanced funnel plots, Peter's test and Egger's test were conducted only when at least 10 studies were available to detect publication bias.
Two investigators reviewed each title, abstract, and full-text articles individually to select eligible studies. Any controversies were addressed in discussions with the third author. A Microsoft Excel file had the extracted data that was present. Study title, authors, publication date, study setting, study design, study period, participants, FI, SR, sICH, and mortality definitions, other important outcomes, and adjustment methods were among the extracted study characteristics. Crude data and effects estimate with their 95%CI of crude and adjusted were also included. For more details or unpublished data from conference abstracts, the corresponding authors would be contacted.
Considering the heterogenicity of the methodology, data source, and so on existed in the included studies. We evaluated the inter-study heterogeneity using I2 tests and the P-value. I2 values<25%, 25-50%, 50-75%, 75-100% indicated no, moderate, large, and high levels of heterogeneity, respectively. P-value<0.1 was considerately statistically significant. For RCTs, the Mantel-Haenszel fixed-effects model was used if I2<50%. Otherwise, the random-effects model was applied. For observational studies and subgroups analysis, wo chose the random-effects model to control the potential bias. After thoroughly reviewing each included study, we analyzed crude data and adjusted data separately to increase the credibility.
Also, we performed subgroup analysis by study design (prospective study and retrospective study), and study area (Asia, European, and America). All the analyses were conducted in the RevMan software version 5.3 and computer program R software version 4.1.1. Unless otherwise noted, all P-values were two-tailed and less than 0.05 was considered statistically significant.
Literature retrieval and study characteristics
The study process as shown in Fig. 1. There were 4,930 items in total (1,830 from PubMed, 1,428 from WOS, 501 from Embase, and 1,171 from Cochrane Library). 2,863 items were included in the abstract screening after eliminating duplicates. Then 2,774 pointless studies were excluded. A total of 88 full-text articles were assessed for eligibility. We excluded 33 studies, 22 of which used therapies other than MT or IVT, seven studies were reviews, and four pieces involved RCTs protocol. Finally, 55 studies met our protocol and were qualitatively synthesized and meta-analyzed.
The characteristics of eligible studies were displayed in Table 1. The study evaluated data from 17 nations, including 10 from Europe, four from Asia, two from The North American, and the one from Australia. Nine RCTs and 46 observational studies—29 retrospective (RS), 16 prospective (PS), and one cross-sectional (CS) were included in the analysis. almost all studies used an mRS score ≤ 2 to define FI. Methods to define SR included TICI 2b/3, mTICI 2b/3, and eTICI 2b/3. Additionally, several methods were adopted to assess sICH (ECASS II/III, HBC, and SITS-MOST). A portion of included studies adopted multivariate analysis, multivariate binary logistic regression, and propensity score method (PSM) to adjust the data.
According to RoB, most trials were of high quality and possessed a low overall risk of bias. Supplemental Fig. 11 showed the specific details. Due to randomization and blinding items, a trial had a high risk of bias[20]. Additionally, Supplemental Table 4 showed how detailed information from OS were evaluated using the NOS scale. Except for one study[21], which scored only 6 because controls for comparability between the two groups were omitted from the study. All other studies were rated as “high quality”.
The results would be reported separately by RCTs and observational studies. Regarding efficacy outcomes, data from the nine RCTs indicated that MT + IVT group had superior FI than the dMT group (OR:1.27, 95%CI:1.11–1.46, Fig. 2a), with large heterogeneity (I2 = 53%, P = 0.03). About safety outcomes, the results of sICH showed no significant difference between the two groups (OR:1.13, 95%CI:0.86–1.49, Fig. 2b), indicating no heterogeneity (I2 = 0, P = 0.82). Overall, 40 observational studies reported the results for FI, suggesting better results were seen in the MT + IVT group (OR:1.34, 95%CI:1.16–1.33, Fig. 2c), with large heterogeneity (I2 = 70%, P<0.01). Data on sICH was extracted from 36 observational studies and found a 16% higher risk of HT (OR:1.16, 95%CI: 1.11–1.21, Fig. 2d) in the MT + IVT group, with no heterogeneity (I2 = 0, P = 0.80).
On the secondary efficacy outcomes, in nine RCTs, the MT + IVT group outperformed the dMT group for excellent outcomes (mRS score: 0–1) (OR:1.21, 95%CI:1.03–1.43, Fig. 3a) with moderate heterogeneity (I2 = 43%, P = 0.09). Additionally, the MT + IVT group saw 23% more SR than the dMT group (OR:1.23, 95%CI:1.05–1.45, Fig. 3b) in eight RCTs, no heterogeneity accompanied (I2 = 0, P = 0.96). Regarding safety outcomes of aICH from seven RCTs, the MT + IVT group had a 25% higher risk of HT than the dMT group (OR:1.25, 95%CI:1.00–57, Fig. 3c), with low heterogeneity (I2 = 22%, P = 0.26). Mortality at 3-months or hospital discharge from eight RCTs in the MT + IVT group showed a lower mortality compared to the dMT group (OR:0.72, 95%CI:0.54–0.97, Fig. 3d), with large heterogeneity (I2 = 54%, P = 0.03).
For efficacy outcomes, a total of 16 OS reported the excellent outcomes (mRS score: 0–1). Better results were seen in the MT + IVT group (OR:1.30, 95%CI:1.09–1.54, Fig. 4a) with large heterogeneity (I2 = 61%, P<0.01). 38 OS showed SR outcomes, with the MT + IVT group increased the rate of SR (OR:1.23, 95%CI:1.05–1.44, Supplemental Fig. 4b), with large heterogeneity (I2 = 60%, P<0.01). For safety outcomes, the MT + IVT group had higher aICH by 19% than the dMT group (OR:1.24, 95%CI:1.05–1.46, Supplemental Fig. 4c) in 23 observational studies with moderate heterogeneity (I2 = 44%, P = 0.01). Additionally, in 34 investigations, mortality was 30% lower in the MT + IVT group compared to the dMT group (OR:0.70, 95%CI:0.64–0.77, Supplemental Fig. 4d), with moderate heterogeneity (I2 = 42%, P = 0.01).
Given the large heterogeneity of some outcomes, subgroup analysis by study design (RS vs PS) and area (Asia vs Europe vs America) was conducted. Regarding subgroup outcomes by study region in the RCTs, there was significant difference between Europe and Asia group in terms of FI (P = 0.05), Specifically, the MT + IVT group had better outcomes in Europe (OR:1.46, 95%CI:1.07–1.98), whereas there were no significant differences in Asia subgroup between the MT + IVT and the dMT therapy (OR:0.95, 95%CI:0.75–1.21). Moreover, stratifying studies according to mortality showed significant differences (P<0.01,). In Europe, the MT + IVT group reduced mortality risk by 45% (OR:0.55, 95%CI:0.45–0.68), while in Asia there was no significant difference (OR:1.07, 95%CI: 0.78–1.48). There were no significant differences regarding SR (P = 0.73), excellent outcomes (P = 0.14), sICH (P = 0.25), and aICH (P = 0.10). The above details were depicted in Supplemental Table 1. On the basis of the results of study area subgroup in OS, no statistically significant variations regarding FI (P = 0.28), excellent outcomes (P = 0.31), SR (P = 0.93), sICH (P = 0.63), aICH (P = 0.19), and mortality (P = 0.38), of which were detailed in Supplemental Table 2.
The results of the subgroup analysis for observational studies were described in more detail below. As shown in Supplemental Table 3, there was no difference in the outcomes of FI (P = 0.13), excellent outcomes (P = 0.14), SR (P = 0.37), sICH (P = 0.20), aICH (P = 0.70), and mortality (P = 0.92).
Results by assessing the adjusted ORs among RCTs between the MT + IVT group and the dMT group were non-significant for both FI (OR:1.17, 95%CI: 0.99–1.38, Fig. 3a) and sICH (OR:1.07, 95%CI:0.79–1.46, Fig. 3b), suggested no heterogeneity (I2 = 0, P = 0.54), and (I2 = 0, P = 0.40), respectively. However, significant better outcomes were seen in the MT + IVT group on FI in observational studies (OR:1.36, 95%CI: 1.21–1.52, Fig. 3c), with moderate heterogeneity (I2 = 48%, P = 0.02). We did not see the significant differences on sICH (OR:0.92, 95%CI:0.76–1.12, Fig. 3d) between groups with low heterogeneity (I2 = 13%, P = 0.32).
Results from RCTs indicated that the MT + IVT group significantly decreased the risk of mortality by 35% (OR:0.65, 95%CI:0.49–0.88, Supplemental Fig. 3d), with large heterogeneity (I2 = 52%, P = 0.07). All other results were non-significant differences between the two groups regarding excellent outcomes (OR:1.11, 95%CI:0.90–1.38, Supplemental Fig. 3a), SR (OR:0.92, 95%CI:0.75–1.13, Fig. 3b), and aICH (OR:0.93,95%CI: 0.75–1.15, Fig. 3c). The heterogeneities of above analyses were none (I2 = 0, P = 0.89), low (I2 = 24%, P = 0.24), and moderate (I2 = 63%, P = 0.04).
About observational studies, better results were seen in the MT + IVT group about the outcomes of excellent outcomes (OR:1.49, 95%CI:1.26–1.75, Supplemental Fig. 4a) with low heterogeneity (I2 = 4%, P = 0.40). We also observed the MT + IVT group reduced the risks of mortality by 27% (OR:0.73, 95%CI: 0.56–0.94, Supplemental Fig. 4d) with large heterogeneity (I2 = 67%, P = 0.40) between two groups. And no significant differences were seen in the outcomes of SR (OR:1.21, 95%CI:0.85–1.74, Supplemental Fig. 4b) with large heterogeneity (I2 = 74%, P<0.01), and aICH (OR:1.06, 95%CI:0.83–1.35, Supplemental Fig. 4c) by large heterogeneity (I2 = 28%, P = 0.22).
Due to the limited number of included RCTs, advanced subgroup analysis was performed solely in observational studies. Among the subgroup of study area, there were no distinguishable differences in the outcomes of FI (P = 0.25), excellent outcomes (P = 0.20), sICH (P = 0.31), and mortality (P = 0.53), except for SR (P = 0.04). Specifically, there was non-significance in Asia between two groups (OR:0.59, 95% CI:0.29–1.21). However, in contrast to the dMT therapy, the MT + IVT therapy raised the rate of SR by 51% in Europe (OR:1.51, 95%CI:1.23–1.86). All details were depicted in Supplemental Table 1.
No discernible differences were observable in outcomes of FI (P = 0.93), excellent outcomes (P = 0.22), SR (P = 0.57), sICH (P = 0.82) and aICH (P = 0.96) within the subgroup of study design between the two groups, except for mortality (P = 0.03). In prospective studies, MT + IVT therapy reduced the risk of mortality by 47% (OR:0.53, 95%CI: 0.43–0.78). Retrospective analyses, however, did not reveal significant differences in the findings (OR:0.95, 95%CI: 0.68–1.34). All details were displayed in Supplemental Table 3.
The sensitivity analysis of RCTs in crude data showed the effects of sICH (Supplemental Fig. 5b), SR (Supplemental Fig. 5d), and mortality (Supplemental Fig. 5f) were not substantially modified by exclusion of a certain study. The effect size of FI varied (OR:1.15, 95% CI:0.97–1.35, Supplemental Fig. 5a) when one study was excluded[22]. When the trial was eliminated[8], the total effect sizes showed no discernible improvement (OR:1.18, 95%CI: 0.99–1.40) in the excellent outcome of MT + IVT therapy. When this study was excluded[22], a similar outcome (OR:1.07, 95% CI:0.89–1.28) was observed. And the MT + IVT group did not increase the risk of aICH (Supplemental Fig. 5d) while removing the study[23] and the trial[24], the effect sizes were (OR:1.16, 95% CI:0.95–1.41) and (OR: 1.18, 95% CI: 0.98–1.44,), respectively. Similar outcomes were seen in the outcome of excellent outcomes (Supplemental Fig. 5c). As followed by the sensitivity analysis of RCTs in adjusted data, the direction of effect size did not change in the outcomes of our interest (Supplemental Fig. 6b-f) except for the FI. The MT + IVT therapy significantly increased FI (OR:1.23, 95%CI:1.03–1.48, Supplemental Fig. 6a) after eliminating the study[25].
As with the above analyses with observational studies, no significant differences were found in the outcomes of observational studies about crude data (Supplemental Fig. 7a, c-f), with the exception of the sICH (Supplemental Fig. 7b). When excluding the study[26], the effect of direction changed (OR:1.11, 95%CI: 0.96–1.29). Referring to observational studies of adjusted data, there were no discernible variations in the outcomes (Supplemental Fig. 8a-f).
For observational studies of crude data, the inspection of contour-enhanced funnel plots showed evidence of asymmetry of outcomes of FI (Fig. 4a), aICH (Supplemental Fig. 9c), and mortality (Supplemental Fig. 9d). No asymmetry was seen in the outcomes of excellent outcomes (Supplemental Fig. 9a), SR (Supplemental Fig. 9b), and sICH (Fig. 4b). However, there was no evidence in the corresponding Peter's statistical tests for funnel plot asymmetry in terms of the outcomes of FI (P = 0.06), excellent outcomes (P = 0.56), SR (P = 0.83), sICH (P = 0.89), aICH (P = 0.14), and mortality (P = 0.21).
The inspection of contour-enhanced funnel plots for observational studies with adjusted data revealed indications of asymmetries in outcomes of FI and sICH (Fig. 5a-b). There was no asymmetry in the mortality results (Supplemental Fig. 10). Additionally, except for sICH (P = 0.01), there was no indication of funnel plot asymmetry in the appropriate Egger's statistical tests for the outcomes of FI (P = 0.46) or mortality (P = 0.67). We did not run the funnel plot, Peter's, or Egger's statistical tests due to the numerous limitations of including RCTs and other observational studies.
In this systematic review and meta-analysis, a total of approximately 20,000 patients were included in the final analysis. Overall, MT + IVT treatment significantly improved FI, excellent outcomes, and mortality risk in the observational studies, both in raw and adjusted data. Furthermore, it is crucial to note that although in crude analysis we observed an increased risk of sICH and aICH with MT + IVT treatment, no significant difference was found in the adjusted analysis. In the RCTs, we found that MT + IVT treatment reduced the risk of mortality but did not increase the risk of sICH in either the crude or adjusted analyses. Similar effect size directions emerged in the raw and adjusted data in the FI, excellent outcome, and SR domains, implying that there was no significant difference between the two therapies. In addition, although MT + IVT treatment significantly increased the risk of aICH in the raw data, it was not present in the adjusted data. Clearly, the adjusted analysis was more plausible due to the controlled covariates. The use of IVT prior to MT was previously thought to enhance the likelihood of HT[27, 28]. However, our results provided further evidence that MT + IVT treatment did not significantly increase the risk of HT. Particularly, adjusted data from observational studies and RCTs, were used to draw conclusions.
The quality of life of impaired patients after stroke was significantly reduced, which caused mental and physical trauma to them and their families as well as a huge economic burden to the public health system. As such, improving the FI of stroke patients was a major rehabilitation object. In this meta-analysis, we found that the MT + IVT group significantly improved the FI in observational studies. although the outcome of FI was at the margin of significance in RCTs. This may be caused by the small number of included RCTs.
Considering the current inconsistency of large RCTs across different study areas, including Asia[23–25, 29] and the Europe[8, 20, 22, 30, 31], as well as a study pointing to regionally relevant differences in the safety of IVT treatment in patients with AIS[32]. We performed a subgroup analysis by study area in the meta-analysis. The results indicated that the race/ethnic-related differences appeared in the outcomes of FI and mortality in RCTs. Additionally, similar results were seen in observational studies (adjusted data) about SR. Overall, European outcomes were better than Asian. Specifically, European studies using MT + IVT therapy showed better FI, higher rates of SR, and lower mortality rates. The findings may suggest that in addition to taking racial factors into account when using MT + IVT therapy, larger clinical research will also be necessary in the future.
Supplemental Table 5 provided a detailed comparison of the prior meta-analysis and the current study. We conducted the most thorough research in this paper, utilizing the largest number of pertinent studies and populations. In addition, crude and adjusted analyses were conducted to further enhance the validity of our findings. Of particular note, although we conducted subgroup analyses by study design and area only, these analyses were based on extracting available data directly from the included studies with the aim of minimizing randomization and sampling error. The primary efficacy results derived from the analysis of observational studies in our study were consistent with previous studies[33]. Regarding the outcomes of the FI and sICH between two regimens by evaluating the raw data, non-significances were both seen when comparing the findings of synthesizing RCTs with the meta-analysis carried out by Vidale and colleagues[13]. Notably, our analysis of the adjusted data revealed that the MT + IVT therapy considerably outperformed the dMT therapy in terms of excellent outcomes, SR, and mortality.
Several strengths of this study should be noted, and the following were some of the benefits of this study. First, the breadth of the chosen research—observational studies and RCTs with sizable sample sizes—allowed us to perform joint and subgroup analyses and improve statistical analysis. Second, we conducted crude and adjusted data analyses, which increased the credibility of the findings by accounting for confounding factors. Third, except for the outcomes of FI, we also assessed the excellent outcomes (mRS score: 0–1).
However, some limitations must be remarked upon. First, we routinely followed current clinical guidelines so that we only included AIS patients with occlusion of anterior circulation. But there was a need to know whether the MT therapy would be effective for posterior circulation occlusion. However, few studies were seen in this field after searching for literature. Second, because most of the included studies did not provide adjusted data, we performed adjusted analysis by synthesizing only a portion of the included studies, suggesting that the adjusted data were insufficient. Moreover, the number of covariates varied across studies. Third, door-to-needle time (DNT) > 50 min, white blood cell counts ≥ 9000/mm3, and NIHSS scores ≥ 10 on admission were found to be independent risk factors for HT[34]. Also, HT may be associated with age, hyperlipidemia, and atrial fibrillation[35]. So, we took above confounding variables into account. However, the aforementioned statistics were challenging to directly record. We only conducted subgroup analyses of study design and area in order to minimize the bias. This may make it challenging for us to investigate additional potential confounders.
In summary, our findings showed that the MT + IVT therapy did, in fact, raise the rate of SR and lower the risk of mortality. Furthermore, we demonstrated that the MT + IVT therapy did not increase the risk of HT compared with the dMT therapy. Based on the findings of observational studies, we thought that the MT + IVT therapy was more beneficial in achieving the object of FI. Although the results of FI in RCTs showed the same trend, they formally failed to achieve statistical significance. This would obviously call for further RCTs and analysis, both of which are necessary for future work.
This article belonged to the category of systematic review and meta-analysis, and we have confirmed that no ethical approval is required.
All authors certify that they have no affiliations with or involvement in any organization or entity with any financial interest or non-financial interest in the subject matter or materials discussed in this manuscript.
Meiling Zheng: Conceptualization, Methodology, Software, Data curation, Original draft preparation; Li Li: Data curation, Writing- Reviewing and Editing; Lizhou Chen, Bin Li, and Cuiling Feng: Supervision,Validation.
This work was funded by the National Natural Science Foundation of China (Grant number: 82074303, 82174345).
All data generated or analyzed during this study are included in this published article and its supplementary information files.
Table 1 is available in the Supplementary Files section.