Background: Futile reperfusion (FR) is becoming an urgent issue for acute ischemic stroke patients who underwent endovascular treatment (EVT). Although the recanalization rate has improved after EVT, it is far from translating to increased tissue reperfusion and functional independence. Summary: Many underlying mechanisms including the “no-reflow” phenomenon, poor collateral flow, venous dysfunction, and inflammation were proposed, but the pathophysiology of FR is still unclear. Clinically, reliable predictors are still yet to be identified, and ongoing trials on shortening the time delay and cytoprotection may provide novel ideas for interventions of FR. Key Messages: This review will summarize the latest advances in FR and hopefully shed light on potential interventions.

© 2023 S. Karger AG, Basel

Introduction

Stroke remains the second leading cause of death globally [1], and acute ischemic stroke (AIS) due to large vessel occlusion (LVO) is a devastating disease with high mortality and morbidity if not treated. In 2015, endovascular thrombectomy (EVT) within 6 h from symptom onset was proven to be the pivotal treatment for early recanalization and favorable 90-day functional outcome in AIS patients due to LVO [2-6]. The subsequent new evidence of an extended time window of 6–24 h was achieved by clinical diffusion-weighted magnetic resonance imaging mismatch or computed tomographic perfusion mismatch [7, 8].

Although the rates of successful recanalization have reached up to 85–90% [9-11], a substantial proportion of patients treated with EVT still have unfavorable functional outcome at 3 months despite angiographically successful recanalization, which is called futile reperfusion (FR). FR is a mismatch between successful recanalization and favorable functional outcome. There is still a notable paucity of its mechanism, predictive factors, and potential management. In this review, we aimed to summarize the current advances of FR after EVT in AIS due to LVO.

Definition of FR

In 2010, FR was initially defined as “the modified Rankin scale (mRS) score of ≥3 at 1–3 months (unfavorable outcomes) despite complete angiographic recanalization” in a pooled analysis of 6 studies of AIS patients treated with mainly intra-arterial thrombolysis, and complete angiographic recanalization referred to Qureshi grade 0 or the thrombolysis in myocardial infarction (TIMI) score grade 3 [12]. As the recanalization grading system was updated (shown in online suppl. Table S1; see www.karger.com/doi/10.1159/000528922 for all online suppl. material), the modified thrombolysis in cerebral infarction (mTICI) scale became the most widely used reperfusion score, and it was used in most of the recent intra-arterial treatment landmark trials to assess the recanalization of mechanical thrombectomy [13]. In 2013, Consensus Meeting on Revascularization Grading Following Endovascular Therapy recommended mTICI as the primary revascularization grading scale and that the target angiographic endpoint for technical success should be defined as mTICI 2b [14]. Subsequently, FR was commonly described as poor functional outcome assessed by mRS score at 3 months (mRS ≥3) despite complete or near-complete recanalization which was defined as mTICI 2b–3 [15-17].

In 2005, an additional 2c grade was introduced to the TICI scale [18], and in 2019, the HERMES (Highly Effective Reperfusion Evaluated in Multiple Endovascular Stroke Trials) collaborators further divided the TICI 2 into 2a, 2b50, 2b67, and 2c. It was suggested that within the >50% reperfusion category, subjects in finer subdivisions of 50–66%, 67–89%, and 90–99% identified meaningful differences with regard to clinical outcomes [19].

Regarding poor functional outcomes, mRS 4–6 [20] or 5–6 [16] were proposed. Generally, the definition of FR is still controversial due to the uncertainty of the target of revascularization and the optimal primary outcome endpoint. A consistent definition of the FR is critical for clinical trial design and cross-comparison between varying studies. Currently, as addressed before, FR was most frequently described as mRS ≥3 at 3 months despite successful recanalization with mTICI 2b–3. However, the mortality rates between FR patients and those without recanalization are lacking.

Prevalence of FR

The prevalence of FR varies from each other by different definitions. We summarized the FR rates in observational studies (Table 1) and post hoc analyses of randomized controlled trials (Table 2) and found that FR occurred in 32.4–69.6% of subjects with AIS due to LVO after EVT. The highest prevalence of 80.6% (25/31) was observed in a retrospective study that was conducted at a single center but with small sample size; therefore, the results should be interpreted with caution [23]. The overall high FR rate implies that FR is a common phenomenon, and the underlying mechanism, clinical predictors, and potential management strategies for FR are warranted to be investigated.

Table 1.

Proportions of FR after EVT in observational studies

Table 2.

Proportions of FR after EVT in randomized controlled trials

Underlying Mechanisms of FR

Although FR is such a common phenomenon, there is a notable paucity of further research focusing specifically on the underlying pathophysiological mechanisms. “No-reflow” phenomenon, poor collateral status, unfavorable venous drainage, and inflammatory response are proposed underlying mechanisms.

“No-Reflow” Phenomenon

The “no-reflow” phenomenon refers to microvascular reperfusion failure and tissue damage despite successful recanalization of the larger occluded artery [39]. During the arterial occlusion, lactic acid and other vasoactive mediators accumulated, leading to the microcirculation loss of the cerebral blood flow autoregulation. Thus, after the recanalization, hyperemia occurred but failed to provide significant perfusion and then hypoxia was envisioned. Subsequently, reperfusion initiated a dampened pathophysiological cascade involving a delayed oxyhemoglobin concentration decline, activated microglia, and interleukin-1α after the first 6 h within the ipsilateral hemisphere, which eventually caused blood-brain barrier (BBB) breakdown and microvascular “no-reflow” [40].

The “no-reflow” phenomenon was believed to reflect the microvascular resistance secondary to endothelial dysfunction and thromboinflammation. It seemed that cerebral ischemia/reperfusion triggered interactions among the vessel wall, platelets, leukocytes, and coagulation which could impair reperfusion and destabilize the BBB (shown in Fig. 1). The interactions were initiated immediately after occlusion instead of the consequence of reperfusion as the dominant paradigm. Consistently, the latest translational stroke research found that neutrophil extracellular traps (NETs) were present in the brains of stroke patients and plasma NET levels predicted clinical outcomes, implying a pathological role in the interaction between coagulation, platelets, and the innate immune system (referred to as immunothrombosis), which culminated in the formation of NETs and mediated microthrombosis and neurotoxicity, in the acute setting of ischemic stroke [41].

Fig. 1.

A dampened pathophysiological cascade initiated within the ipsilateral hemisphere after the first 6 h of reperfusion.

Clinically, in a prospective cohort of 31 enrolled patients with proximal anterior circulation stroke, the proportion of FR was 1/31 and the patient had an excellent outcome (mRS = 0), which suggested that no-reflow might be infrequent in humans and thus might not substantially account for FR. [42] However, the “no-reflow” was defined as hypoperfusion ≥40% in cerebral blood flow, affecting anatomical regions of the affected hemisphere on 24 h arterial spin labeling perfusion mapping [42]. The subjective criteria and small sample size limited the generalizability of the results. It was noted that the study set a strict inclusion criterion as patients having TICI 2c–3 recanalization as successful recanalization.

Poor Collateral Status

After arterial occlusion, there can be temporal growth of the ischemic core into the penumbral area that is modulated by collateral blood flow [43]. Fast progressors whose infarct growth is most sensitive to the duration of ischemia may have rapidly failing collaterals and large ischemic cores. These patients will benefit from the fastest possible reperfusion in the early time window [44].

Unfavorable Venous Drainage

Cerebral venous drainage may be as critical as arterial infusion for infarct evolution and clinical sequelae in the pathological stroke content [45]. First, in animal studies, ischemia-reperfusion injury-related activation of inflammatory cells and platelets tended to accumulate mainly in venules rather than in arterioles [46]. Besides, the higher intramural pressure caused by early edema after ischemia was likely to result in that blood flow from collateral or successful recanalization would diverge to the penumbra rather than to the core. Thus, FR emerged due to the insufficiency of venous drainage and “venous stealing” despite arterial recanalization. Second, it is the venule side that tended to suffer hemorrhagic changes due to BBB abruption and luxury perfusion [45].

Inflammatory Response

Neutrophil aggregation and neutrophil stalling of brain capillaries contributed to reperfusion failure using a model where a fibrin rich clot was induced in the middle cerebral artery occlusion, which was later dissolved by intravenous tissue plasminogen activator infusion at 30 min after ischemia onset, closely mimicking the clinical scenario of ischemic stroke and early intravenous thrombolysis [39].

Generally, the phenomenon of FR suffers from certain ambiguities at the mechanistic level, and research in the real world is particularly subjected to paucity. Research investigating the mechanism of FR is of great significance to better understand the nature of such a phenomenon, reveal more promising markers, and provide candidate targets for interventions.

Predictors of FR

Various studies have explored the predictive factors for FR, including clinical, interventional, image, and laboratory variables (Table 3). DIRECT-MT (Direct Intra-arterial Thrombectomy in Order to Revascularize Acute Ischemic Stroke Patients with Large Vessel Occlusion Efficiently in Chinese Tertiary Hospitals: a Multicenter Randomized Clinical Trial) registry investigators [46] concluded that older age (odds ratio [OR] 1.120; 95% confidence interval [CI] 1.055–1.189), higher baseline systolic blood pressure (OR 1.026; 95% CI 1.002–1.051), incomplete reperfusion (defined as a grade below 3 with expanded TICI grades) (OR 0.510; 95% CI 0.290–0.898), and larger final infarct volume (OR 1.018; 95% CI 1.008–1.029) were independent predictors of FR. The latest pooled analysis including 12 studies enrolled 2,138 patients reported that age (mean difference [MD] 5.81; 95% CI 4.16–7.46), female sex (OR 1.40; 95% CI 1.16–1.68), National Institutes of Health Stroke Scale (NIHSS) (MD 4.22; 95% CI 3.38–5.07), Alberta Stroke Program Early Computed Tomography Score (ASPECTS) (MD −0.71; 95% CI −1.23 to −0.19), hypertension (OR 1.73; 95% CI 1.43–2.09), diabetes (OR 1.78; 95% CI 1.41–2.24), atrial fibrillation (OR 1.24; 95% CI 1.01–1.51), admission systolic blood pressure (MD 4.98; 95% CI 1.87–8.09), serum glucose (MD 0.59; 95% CI 0.37–0.81), internal carotid artery occlusion (OR 1.85; 95% CI 1.17–2.95), pretreatment intravenous thrombolysis (OR 0.67; 95% CI 0.55–0.83), onset-to-puncture time (MD 16.92; 95% CI 6.52–27.31), puncture-to-recanalization time (MD 12.37; 95% CI 7.96–16.79), and posttreatment symptomatic intracerebral hemorrhage (OR 6.09; 95% CI 3.18–11.68) were significantly associated with FR [27]. Wang et al. [56] studied retrospectively 332 patients selected from the ACTUAL (Multicenter Endovascular Treatment for Acute Anterior Circulation) ischemic stroke registry and yielded 5 early items: prior intravenous thrombolysis (aOR 0.42; 95% CI 0.19–0.91), poor collateral status (ASITN/SIR 2–3 vs. 0–1, aOR 0.36; 95% CI 0.17–0.79), high blood glucose (aOR 1.16; 95% CI 1.00–1.35), large blood neutrophil to lymphocyte ratio (aOR 1.08; 95% CI 1.01–1.15), and high baseline NIHSS (aOR 1.07; 95% CI 1.01–1.14) which independently associated with FR. Consequently, PREDICT (poor outcome of endovascular treatment with successful recanalization) scale with a top score of 19 consisting of these factors was developed to predict FR, and compared with those with a score of ≤5, patients with a score of ≥12 had an 18.33-fold (95% CI 6.36–52.89) increased risk of poor outcome [56]. Based on the specificity of 0.95, the cutoff point was set as 12 in the derivation group, with a sensitivity of 0.26, positive predictive value of 0.32, and negative predictive value of 0.92; meanwhile, the cutoff showed a sensitivity of 0.29, specificity of 0.93, positive predictive value of 0.33, and negative predictive value of 0.92 in the validation group [56]. Other studies also found that door-to-angiographic reperfusion [47], passes of stent retriever device [49], and brain atrophy [53] independently predicted FR. The abovementioned possible predictors with great heterogeneity might be due to the nature of retrospective studies, small sample size, and different inclusion criteria. However, previous FR prediction-related research works mainly laid emphasis on demographics and clinical characteristics of patients instead of imaging and laboratory markers, and older age, higher initial NIHSS score, hypertension, and longer delay of intervention were the most frequent predictors in these studies.

Table 3.

Predictors of FR after EVT

Potential InterventionsNeuroprotection with Nerinetide

The mysteries about the mechanism make it difficult to develop an efficient therapy to rescue the brain tissues before or after FR occurs. However, on the microcosmic and cytological scope, FR is related to the injury and death of neurons after ischemia-reperfusion; thus, neuroprotection has been investigated as a potential therapy. Postsynaptic density protein 95 (PSD-95) inhibitor NA1 (nerinetide or Tat-NR2B9c) uncouples N-methyl-D-aspartate glutamate receptors from downstream neurotoxic signaling pathways without affecting normal glutamate receptor function and thus attenuates N-methyl-D-aspartate receptor-mediated neuronal cell death after stroke in rats, [58], mice [59], and primate ischemia models [60, 61]. The ESCAPE-NA1 (Efficacy and Safety of Nerinetide for The Treatment of Acute Ischaemic Stroke) trial in 1,105 patients with LVO within a 12-h treatment window failed to show overall benefit of nerinetide over placebo; however, in thrombectomy patients without tissue plasminogen activator, the treatment arm has significantly better functional outcome than the placebo arm [62]. It suggested that neuroprotection in human stroke might be possible. and the ongoing ESCAPE-NEXT (Efficacy and Safety of Nerinetide in Participants With Acute Ischemic Stroke Undergoing Endovascular Thrombectomy Excluding Thrombolysis, NCT04462536) trial will further confirm the neuroprotective role of nerinetide. In addition, the REPERFUSE-NA1 (Recanalization following Endovascular Treatment and Imaging of Perfusion, Regional Infarction and Atrophy to Understand Stroke Evolution – NA1) trial, as a substudy of the ESCAPE-NA1 trial, will determine if administration of the neuroprotectant NA1 prior to endovascular therapy can significantly reduce early and delayed secondary infarct growth and it remains to see the expected results [63].

Alternative Neuroprotectant Agents

Neuroprotectant agents including magnesium sulfate [64], uric acid [65], glyburide [66], argatroban [67], and activated protein C [68] have recently been found to yield signals of potential benefit in phase 2 clinical studies and edaravone dexborneol in phase 3 [69] with no associated major safety concerns. Besides, small case series attesting to the safety and feasibility of autologous and allogeneic stem cell therapy and hypothermia have been published, but data from humans are absent or just in phase 1/2 human studies and randomized controlled trials are expected. It is reasonable that most cytoprotective drugs will be developed acting on multiple targets and as an adjunct in conjunction with reperfusion therapy which is also in conformity with the principles set by the Stroke Therapy Academic Industry Roundtable (STAIR) [70].

Other Management Targets

Actually, the 2015 STAIR IX meeting proposed more adjuvant approaches to EVT apart from neuroprotection including collateral therapeutics, periprocedural management (i.e., blood pressure management before and after reperfusion, the use of general anesthesia, optimal postprocedural antithrombotic regimen, optimal blood glucose management, and optimal collateral augmentation strategies such as body position, blood pressure, and fluid status) and improvement of microcirculation [70]. Angiographic and microvascular reperfusion amelioration using glycoprotein IIb/IIIa receptor inhibitors such as eptifibatide has been proven safe and effective when combined with MT for patients with AIS due to LVO [71]. More recently, the CHOICE (Chemical Optimization of Cerebral Embolectomy) trial demonstrated the preliminary efficacy of adjunct intra-arterial alteplase compared with placebo to improve functional independence (a score of 0 or 1 on the mRS) at 90 days among AIS patients with post-thrombectomy eTICI score of 2b50 or greater (adjusted risk difference, 18.4%; 95% CI 0.3–36.4%; p = 0.047), thus suggesting another promising preventive strategy for FR [72]. The ongoing prospective, single-arm, pilot study INSIST-CT (Improving Neuroprotective Strategy for Ischemic Stroke With Sufficient Recanalization After Thrombectomy by Intra-arterial Cocktail Therapy, NCT04202549) trial will explore the safety, feasibility, and efficacy of thrombectomy with sufficient recanalization (TICI 2b–3) bridged by intra-arterial cocktail therapy of a combination of argatroban, dexamethasone, and edaravone in AIS patients to prevent artery re-occlusion, hemorrhagic transformation, and no-reflow phenomenon.

Apart from the above interventions, the workflow of EVT may be another important target. The benefit of MT on functional recovery is highly time sensitive. The HERMES analysis found that each 1 h delay to reperfusion was associated with less functional independence (OR, 0.81; 95% CI 0.71–0.92). The probability of FR (mRS 3–6 at 3 months) increased from 35.9% with symptom onset-to-reperfusion time of 180 min to 53.9% with onset-to-reperfusion time of 480 min [36]. These results encourage considering the out-of-hospital transfer paradigm. The mothership and the drip and ship models were recently found comparable with each other for functional outcomes at 90 days in the RACECAT (Transfer to the Closest Local Stroke Center vs. Direct Transfer to Endovascular Stroke Center of Acute Stroke Patients With Suspected Large Vessel Occlusion in the Catalan Territory) trial [73]. Similar conclusion could be drawn between deployment of a flying intervention team for EVT versus patient interhospital transfer in an observational study, although the flying intervention team reduced more than half of the median time from the decision to pursue thrombectomy to the start of the procedure [74]. The optimal strategy to address the mismatch between patient location and time-critical access to stroke expert resources remains unknown [75]. In addition, mobile stroke units, an emerging new technology, consisting of an ambulance equipped with a CT scanner, point-of-care laboratory, and specialized prehospital stroke team, have been shown superior over emergency medical services in terms of the shorter time to treatment, higher thrombosis rates, and more favorable functional outcomes [76, 77]. However, the geomorphologic differences and economic efficacy need to be taken into consideration. Integrating other innovative approaches such as telestroke service is expected to refine the workflow and provide strategic opportunities to improve stroke systems of care as well [78].

Conclusion

FR is a relatively new field in endovascular therapy for patients with AIS and has attracted more and more attention from clinical neurointerventionists and scientific researchers. However, our understanding of such a phenomenon is subjected to the paucity of high-quality evidence from well-designed and controlled clinical trials. Completed work posed a challenge to the traditional definition of FR and suggested a trend of eTICI 2c/3 as an alternative to mTICI 2b/3 to assess successful recanalization and mRS 4–6 or even 5–6 at 3 months as poor functional outcome. Most common predictors are clinical markers in the current research works such as older age, higher initial NIHSS score, hypertension, and longer delay of intervention. The concept of “tissue reperfusion” instead of just “vessel recanalization” after EVT needs to be recommended, and the pathophysiological mechanisms and potential management strategies of FR need further investigation. The neuroprotection poses a promising direction and several trials are ongoing. Hopefully, it may provide new evidence for reducing the rate of FR.

Conflict of Interest Statement

The authors have no conflicts of interest to declare.

Funding Sources

This work was supported by the National Natural Science Foundation (Grant No. 82171272). The funders had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

Author Contributions

Liyuan Wang contributed to the conceptualization and design of this article, including literature review and interpretation, and original draft preparation and Yunyun Xiong contributed to the conceptualization and critically revising the manuscript for important intellectual content.

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