Mothership versus Drip-and-Ship Model for Mechanical Thrombectomy in Acute Stroke: A Systematic Review and Meta-Analysis for Clinical and Radiological Outcomes

Article information

J Stroke. 2020;22(3):317-323

Publication date (electronic) : 2020 September 29

doi : https://doi.org/10.5853/jos.2020.01767

Michele Romoli^a,b, Maurizio Paciaroni^c, Georgios Tsivgoulis^d,e, Elio Clemente Agostoni^f, Simone Vidale^,a

^aNeurology Unit, Rimini “Infermi” Hospital, AUSL Romagna, Rimini, Italy

^bNeurology Clinic, Santa Maria della Misericordia Hospital, University of Perugia, Perugia, Italy

^cStroke Unit and Division of Cardiovascular Medicine, Santa Maria della Misericordia Hospital, University of Perugia, Perugia, Italy

^dSecond Department of Neurology, “Attikon” Hospital School of Medicine, National and Kapodistrian University of Athens, Athens, Greece

^eDepartment of Neurology, University of Tennessee Health Science Center, Memphis, TN, USA

^fDepartment of Neurology, Niguarda Ca’ Granda Hospital, Milan, Italy

Correspondence: Simone Vidale Department of Neurology, Infermi Hospital, Viale Luigi Settembrini 2, 47923 Rimini, Italy Tel: +39-0541705600 E-mail: simone.vidale@auslromagna.it

Received 2020 May 14; Revised 2020 August 7; Accepted 2020 August 25.

Abstract

Introduction

Previous randomized-controlled clinical trials (RCTs) showed that the combination of intravenous thrombolysis (IVT) and endovascular thrombectomy (EVT) is effective in patients with ischemic stroke due to a large vessel occlusion [1-3]. Current international guidelines have been updated accordingly [4]. However, EVT is only available at Comprehensive Stroke Centers (CSC), which are fewer than Primary Stroke Centers (PSC), the latter being only able to administer IVT. Therefore, two main organizational paradigms have been developed: the mothership (MS), in which the patient is directly brought to the CSC, and the drip and ship (DS) model, where initially assessment and eventual IVT at the PSC are followed by “shipping” to the CSC. The choice of a model over another implies clinical consequences for treated patients as well as for local health policies, including the distribution of hospital facilities over the region of interest.

Previous systematic reviews comparing MS versus DS models were limited to few studies and provided conflicting results [5,6]. Computational modeling provided potential insights on time of transport, although with consistent limitations due to assumptions of treatment efficacy and patient eligibility [7]. Therefore, no conclusive evidence is available to date concerning the superiority of one model over the other by clinical and economic results.

We conducted a systematic review and pooled data meta-analysis of studies comparing MS versus DS model, including subgroup analysis by type of treatment, clinical severity and timing of treatments.

Methods

Results

Systematic search retrieved 18 studies including 7,017 patients (PRISMA flowchart) (Figure 1) [10-27]. Most of the included studies were observational and prospective, only one study was a RCT [15] (Table 1). As a result, quality of studies ranged fair to good, with only one RCT achieving optimal score on risk of bias assessment. Funnel plot showed low levels of visual asymmetry (Supplementary Figure 1 for complete bias assessment). No significant differences emerged comparing patients treated in the two organizational paradigms for sex, age, and NIHSS score at admission. On the contrary, DS patients had longer onset-to-treatment timing (Table 2).

Figure 1.

Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) flow-chart for selection of studies included in the meta-analysis.

Table 1.

Summary of included studies

Table 2.

Differences between groups

Considering the primary endpoint of functional independence at 90 days, MS paradigm was superior to DS model (OR, 1.34; 95% CI, 1.16 to 1.55; I²=30%) (Figure 2). More specifically, the rates of functional independence were 53% and 47% in the MS and DS organizational paradigms respectively, with a NNT of 29 in favor of MS model (Figure 2). Results from DerSimonian & Laird model were also confirmed applying the Hartung-Knapp-Sidik-Jonkman model (OR, 1.38; 95% CI, 1.20 to 1.59; P_{heterogeneity}=0.11). In the subgroup analysis restricted to studies exploring bridging therapy, the MS model provided marginally higher rate of functional independence (OR, 1.26; 95% CI, 0.98 to 1.63; I²=34%) (Figure 3).

Figure 2.

Forest plot showing the association of organizational paradigms with functional independence (modified Rankin Scale 0–2) at 3 months. M-H, Mantel-Haenszel; CI, confidence interval.

Figure 3.

Forest plot showing the association of organizational paradigms with functional independence (modified Rankin Scale 0–2) at 3 months in subgroup of patients treated with bridging therapy (combination of intravenous thrombolysis and endovascular thrombectomy). M-H, Mantel-Haenszel; CI, confidence interval.

Meta-regression analysis revealed a significant association between ONT and good functional outcome, with longer ONT being detrimental for recovery (Supplementary Figure 2). Differences of age, clinical severity at presentation, and OGT between study groups did not have significant correlation with functional outcome (Supplementary Figures 3-5).

MS and DS had similar rates of mortality at 90 days (OR, 0.94; 95% CI, 0.78 to 1.13; I²=28%) and successful recanalization (OR, 0.81; 95% CI, 0.54 to 1.21; I²=80%) (Supplementary Figures 6 and 7). Sensitivity analysis through leave-one out paradigm confirmed results (Supplementary Table 1). Pooling data from all observational studies, excluding RCT, MS was still superior to DS paradigm 1.33 (95% CI, 1.16 to 1.53) (Supplementary Table 1). Combinatorial analysis further confirmed clustering of possible pooled estimates in favor of MS for primary outcome (Supplementary Figure 8).

Overall, no significant difference was noted in terms of sICH depending on organizational paradigm, with a 6.3% and 6.7% in MS and DS models respectively (OR, 0.87; 95% CI, 0.70 to 1.10; I²=15%) (Supplementary Figure 9). There was substantial heterogeneity for the endpoint of successful recanalization across the included studies (P for Cochran Q <0.00001, I²=80%). There was little or no heterogeneity regarding all the other endpoints.

Discussion

In this systematic review and meta-analysis including patients with acute ischemic stroke eligible for reperfusion strategies, MS organizational paradigm was associated with a higher rates of functional independence at 3 months compared to DS. Our findings add and put into context previous studies and systematic reviews [5,6,28], particularly regarding the role of treatment timing on plausible benefit. MS provided better 90-day outcome compared to DS in a previous meta-analysis, which however was limited to eight studies (n=2,068) and provided no meta-regression for timing of treatment [5]. MS superiority failed to be replicated in a meta-analysis integrating 9 studies (n=4,127), which showed similar performance of the two paradigms [6]. Reviews put into question MS superiority [28], and previous conditional modeling providing suggestions for network organization was consistently limited by assumptions on eligibility, door-to-needle time at PSCs, and standardized rates of recanalization [7,29]. Our results, deriving from 18 studies (n>7,000), provide substantial insights in the overall net benefit of MS compared to DS, and detail effects on both good functional outcome, sICH and mortality. Specific, patients treated under MS paradigm had approximately 40% higher odds of being functionally independent at 3 months, with no increase in the risk of sICH, or mortality. The benefit of MS on functional outcome was further confirmed across sensitivity analysis. Therefore, MS might be preferred to DS whenever local facilities allow the application of this organizational paradigm.

A marginal and non-significant benefit of MS over DS was also found taking into account studies investigating bridging. This finding needs to be looked at with caution. First, the analysis was consistently limited by the sample size and heterogeneity, with large-sample studies clustering towards MS benefit versus small-sample ones distributing in the opposite direction. Second, the fact that such trend emerges together with the lack of relationship between OGT and functional outcome might suggest that what happens before EVT translates on outcome. To this extent, ONT was correlated with functional outcome, and was significantly shorter in MS group, suggesting that the rapid access to reperfusion strategies still represents the principal target to achieve good outcome. Results from this meta-analysis highlight that longer ONT negatively impacted 3-month functional outcome, suggesting that logistics should be appropriately addressed when configuring a stroke network. The fact that age and clinical severity did not impact on the benefit of paradigm choice on functional outcomes argues in favor of common pathways for all stroke patients, independently from age and clinical severity at stroke onset.

Regarding recanalization, a marginal, although not significant, increase in rates of recanalization with DS was found compared to MS with substantial heterogeneity detected across included studies. These findings support similar efficacy of the two organizational paradigms, although it might also prompt speculations on possible higher rates of futile recanalization in patients managed via DS, which might be attributable to long transportation-time between primary and comprehensive centers, treatment in late time-windows, and lack of eligibility rechecking at arrival.

Limitations to this meta-analysis might be related to the design of included studies, as well as in the use of tabular data, which precluded further adjustment for confounding factors. Second, our results might not be fully representative of stroke care in the near future, when expansion of tissue-based windows for treatment might consistently refine the advantages of one paradigm over the other. To this extent, implementation of simulation modeling might represent a useful resource to orientate logistics, with appropriate continuous audit/feedback [7]. Third, meta-regression analysis was performed with the caveat of low number of studies, and therefore results regarding ONT timing should be considered with caution. Finally, meta-analysis did not include geographical factors and different centers performance, which might indeed represent critical details to organize the stroke network. However, given MS associates with improved functional outcome, policies might be implemented to support such paradigm in areas with transportation time to CSC below 45 minutes. The ongoing Transfer to the Local Stroke Center versus Direct Transfer to Endovascular Center of Acute Stroke Patients with Suspected Large Vessel Occlusion in the Catalan Territory (RACECAT; NCT02795962) and PREhospital Routage of Acute STroke Patients With Suspected Large Vessel Occlusion: Mothership Versus Drip and Ship (PRESTO-F; NCT04121013) trials will provide more answers to the open questions comparing MS and DS.

Conclusions

Patients with acute ischemic stroke eligible for reperfusion strategies might benefit from MS paradigm compared to DS. RCTs are needed to further refine best management taking into account logistics, facilities and resources.

Supplementary materials

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