Large-Vessel Occlusion Stroke: Effect of Recanalization on Outcome Depends on the National Institutes of Health Stroke Scale Score Karolina Skagen, MD,* Mona Skjelland, MD, PhD,* David Russell, MD, PhD,* and Eva A. Jacobsen, MD, PhD†
Background: Arterial recanalization is currently considered the main standard of successful early management of acute ischemic stroke. Intravenous (IV) thrombolysis with tissue plasminogen activator (tPa) is the only Food and Drug Administration–approved medical treatment. Large-vessel occlusion, estimated to account for up to 40% of all acute ischemic strokes, is often refractory to IV thrombolysis and is associated with a poor patient outcome. Mechanical recanalization procedures are therefore increasingly used in the treatment of large-vessel occlusion refractory to, or presenting outside the accepted time window for, IV thrombolysis. The aim of this study was to investigate the effect of early vessel recanalization on clinical outcome in patients with large-vessel occlusion stroke. Methods: This is a singlecenter cohort study, analyzing prospectively collected data on 152 patients with large-vessel occlusion and acute ischemic stroke. Seventy-one patients received endovascular treatment (of whom 57.7% also received IV tPA), and 81 (55.6% of whom also received IV tPa) were not treated with endovascular therapy. Clinical outcome was compared for 2 cohorts: patients who recanalized (n 5 46) and patients with persisting large-vessel occlusion (n 5 106). Results: Early recanalization was an independent predictor of a good clinical outcome in only those patients who presented with a severe ischemic stroke (National Institutes of Health Stroke Scale [NIHSS] score .15; P 5 .017). This was not the case for less severe strokes (NIHSS score #15) where recanalization did not lead to more patients with functional independence at 90-day follow-up (P 5 .21). Conclusions: In this study of acute large-vessel occlusion stroke, we found that clinical outcome following early recanalization was dependent on the patient’s pretreatment NIHSS score. A nonnegligible proportion of patients with milder strokes did well despite persistent large-vessel occlusion. These results may suggest that in patients who are able to maintain adequate collateral flow despite proximal arterial occlusion, effective adaptive mechanisms are present, which for some patients are long-lasting. This may influence the process of appropriate patient selection for endovascular therapy. Key Words: Large-vessel occlusion—ischemic stroke—recanalization— endovascular treatment—thrombectomy. Ó 2015 by National Stroke Association
From the *Department of Neurology, Oslo University Hospital, Oslo; and †Department of Neuroradiology, Oslo University Hospital, Oslo, Norway. Received August 23, 2014; revision received March 9, 2015; accepted March 14, 2015. Address correspondence to Karolina Skagen, MD, Department of Neurology, Oslo University Hospital, Rikshospitalet, Nevrologisk
poliklinikk, Postbox 4950 Nydalen, 0424 Oslo, Norway. E-mail: [email protected]. 1052-3057/$ - see front matter Ó 2015 by National Stroke Association http://dx.doi.org/10.1016/j.jstrokecerebrovasdis.2015.03.020
Journal of Stroke and Cerebrovascular Diseases, Vol. -, No. - (---), 2015: pp 1-8
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Arterial recanalization is currently considered the main standard of successful early management of acute ischemic stroke. Recanalization within 8 hours of symptom onset has been found to be associated with a 4- to 5-fold increase in odds for a good functional outcome and a 4- to 5-fold reduction in the odds of death.1 Large-vessel occlusions not responsive to intravenous (IV) thrombolysis have been shown to be associated with a poor prognosis. With persistent vessel occlusion (PVO), fewer patients achieve functional independence and mortality rates are higher.2 The concept that vessel recanalization improves outcome is termed the ‘‘recanalization-hypothesis.’’ This is the basis for thrombolytic stroke therapy and the development of new treatment options for acute large-vessel occlusion stroke. When assessing the approval of retriever devices for use in endovascular treatment, recanalization rates are used as the efficacy end point.3 However, ‘‘futile recanalization,’’ when recanalization is not followed by improved clinical outcome, is well recognized.4,5 Reperfusion injury is a well-known complication for patients improperly selected for both IV tissue plasminogen activator (tPa) and endovascular therapy. Furthermore, mechanical endovascular intervention is associated with a potential risk of harming the patient. Identifying the factors that translate angiographic recanalization into a favorable clinical outcome is therefore essential. In addition to vessel recanalization, several other factors including pretreatment stroke severity have been shown to predict clinical outcome after acute ischemic stroke.6 The National Institutes of Health Stroke Scale (NIHSS) is an accepted clinical tool for assessing stroke severity and clinical outcomes.7,8 Patients presenting with a pretreatment NIHSS score of more than 15, categorized as a moderateto-severe stroke, have been found to have a higher probability of a worse outcome and death compared with patients presenting with scores 15 or less (mild-to-moderate stroke).6 The Prolyse in Acute Cerebral Thromboembolism Trial (PROACT) trial showed a clinical effect of recanalization after intra-arterial thrombolysis only for patients with a pretreatment NIHSS score greater than 11.9 The Interventional Management of Stroke 3 study also showed a greater potential for endovascular treatment for patients presenting with an NIHSS score of more than 20 compared with patients presenting with a lower NIHSS score (8-19).10 Identifying the various factors associated with a good outcome after endovascular treatment with vessel recanalization is essential to enable better selection of patients to treatment. The aim of this study therefore was to investigate the effect of early recanalization on clinical outcome in patients with large-vessel occlusion stroke in a clinical setting.
Methods This is a single-center cohort study, analyzing prospectively collected data from 152 consecutive patients with
large-vessel occlusion stroke admitted to Oslo University Hospital (OUH), Rikshospitalet, between 2007 and 2012. OUH is a tertiary referral center providing endovascular service for regional and primary stroke units. After receiving approval from the Regional Ethics Committee for data collection and analysis, a database of consecutive patients with acute ischemic stroke referred to our hospital for endovascular treatment was established. Study inclusion criteria were acute stroke with clinical ischemic symptoms corresponding to an angiographically proven large intracranial vessel occlusion, absence of intracranial hemorrhage on computed tomography (CT) scan, and a clearly defined time of symptom onset within 6 hours of inclusion. Time of patient inclusion was time of CT angiogram confirming large-vessel occlusion. A limit of 8 hours from symptom onset to vessel recanalization was predefined because early recanalization is believed to have the greatest impact on clinical function.1 Following admission, all patients were re-examined clinically and if appropriate, new imaging was performed before deciding on further treatment with endovascular recanalization and/or IV thrombolysis, or general medical treatment. All patients without contraindications to IV thrombolytic therapy were given IV tPa. Contraindications were according to departmental guidelines and in agreement with international guidelines.11 IV tPa was administered at a dose of .9 mg per kg (maximum 90 mg), with 10% given as an initial bolus and the remaining 90% as a constant infusion over a period of 60 minutes. Patients who had an ischemic penumbra (mismatch between cerebral blood flow and cerebral blood volume on perfusion imaging) or clinical penumbra (mismatch between established infarct and clinical symptoms) with no contraindications to endovascular therapy were selected for intra-arterial recanalization therapy with intra-arterial thrombolysis alone or with mechanical device, or with mechanical device alone. Contraindications to endovascular therapy were the presence of a too large area of infarction on cerebral imaging defined as more than 50% of the territory supplied by the occluded artery (restricted diffusion on magnetic resonance imaging [MRI] or low attenuation on noncontrast CT), absence of mismatch between cerebral blood flow and cerebral blood volume on perfusion imaging (no ischemic penumbra), absence of clinical mismatch to established infarct on CT or cerebral MRI, technically impossible with lack of groin access (because of previous surgery or severe atherosclerosis), total occluded vessel from the arch of the aorta or extreme vessel tortuosity where catheterization carried increased risk of patient harm, spontaneous clinical improvement, open vessel on reimaging at our institution, and a too high burden of comorbidity with coexisting malignancy, other lifethreatening diseases, dementia, major organ-failure, or life expectancy less than 1 year. All patients included in
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this study were examined with CT and/or MRI within 6 hours of symptom debut. Patients with wake-up stroke were excluded. Patients were grouped according to vessel patency regardless of treatment and imaging modality into 2 groups: recanalization within 8 hours of symptom debut or PVO, which included unsuccessful endovascular recanalization, technically failed access, or not selected for interventional therapy. The dataset was analyzed with respect to patient age on admission, time from symptom onset to admission, and neurologic deficit on admission (quantified using the NIHSS score, ranging from 0 to 42 with higher scores indicating more severe cerebral infarction) by a trained clinician who was certified in the use of the scale, site of vessel occlusion, IV thrombolysis treatment with tPa, presence of atrial fibrillation, hypertension, diabetes mellitus, previous stroke, hypercholesterolemia, and blood sample analyses.12 All patients were examined with CT angiography or MR angiography with or without CT perfusion or MR perfusion. Time from symptom onset to imaging and time to angiographically proven recanalization on digital subtraction angiography, estimated size of cerebral infarction, and the degree of recanalization were registered. The degree of recanalization was assessed using the Thrombolysis in Cerebral Infarction (TICI) score, with a score of 2 or more considered to be recanalization success, 3 being a fully opened vessel, and 0-1 not recanalized.13 An experienced neurointerventionalist, blinded to clinical outcome, evaluated all DSA images. Clinical outcomes were assessed in all patients at 90 days using the modified Rankin scale (mRs, ranging from 0 to 6, with 0 indicating no symptoms and 6 indicating death) by a clinician with specific training in outcome assessment with the mRs. Relevant hospital records with clinical data were obtained from referring hospitals for patients unable to return to the OUH clinic. To assess the effect of recanalization for different stroke severities, we classified patients into 2 groups: those patients with an NIHSS score under or equal to 15 (mild-to-moderate stroke) and those with an NIHSS score greater than 15 (severe stroke). A threshold of NIHSS score of 15 was chosen as it is often used as a cutoff between mild and severe stroke, thereby allowing exploration of possible difference in effect of recanalization in relation to stroke severity.6 Mortality and good clinical outcomes (mRs,2) were then compared between the 2 groups.
Statistical Analysis SPSS for Windows statistical software (version 18.0; SPSS Inc., Chicago, IL) was used for all data analyses. Student t test or Mann–Whitney U test was used depending on the distribution of data. The chi-square test was used for analyzing contingency data. Coefficients of correlation were calculated by the Pearson correlation.
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The proportion of patients with mRs scores of 2 or less (good outcome) at 90 days and mRs 5 6 (death), was compared for patient groups using regression analysis. Biologically plausible baseline predictors of outcome (age, sex, NIHSS, and IV thrombolysis) were entered into the multivariable model and retained in the model if their P value was less than .05. Probability values (2-sided) were considered significant at P value less than .05.
Results One hundred fifty-two consecutive patients with acute ischemic stroke due to large -vessel occlusion stroke were included in the study. All patients without contraindications to IV thrombolytic therapy were given IV tPa, in total 86 patients (56.5%). Seventy-one (46.7%) of the 152 included patients received endovascular treatment (endovascular group) and 81 (53.3%) did not (nonendovascular group). In the endovascular group, 41 patients (57.7%) received IV tPA before endovascular treatment, and in the nonendovascular group, 45 patients (55.6%) received IV tPA. Five patients were excluded from the analyses because of incomplete follow-up data. Four patients experienced spontaneous vessel recanalization, who together with the 42 patients mechanically recanalized with endovascular intervention (TICI $2) made up the cohort of a total of 46 recanalized patients. The PVO cohort of patients consisted of 81 patients with confirmed largevessel occlusion who did not meet the inclusion criteria for endovascular treatment and 29 patients who did not recanalize (TICI ,2) after endovascular treatment (n 5 106). All further analyses performed were based on these 2 groups. The following are the most common reasons for not selecting patients for endovascular therapy: the presence of a too large infarcted area on imaging (restricted diffusion on MRI or low attenuation on CT) in more than 50% of the territory supplied by the occluded vessel area and/or absence of mismatch between cerebral blood flow and cerebral blood volume on perfusion imaging (no ischemic penumbra; 45 patients), technically impossible (16 patients), spontaneous clinical improvement (13 patients), open vessel on reimaging at our institution (4 patients) and a too high burden of comorbidity (3 patients). The 2 groups were comparable in terms of patient baseline characteristics (Table 1), with no statistically significant differences in age, sex, presenting NIHSS, or proportion of patients treated with IV thrombolysis. The mean age was 61.2 years in the recanalized group and 62.8 years in the PVO group (P 5 .54). Thirty-two (69%) patients in the recanalized group and 64 (60%) in the PVO group were men (P 5 .28). Median presenting NIHSS score was 15.8 (4-29) in the recanalized group and 16.2 (2-31) in the PVO group. The proportion of
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Table 1. Patient demographics. Baseline characteristics (n 5 152) Parameter
Recanalized (n 5 46)
Persistent vessel occlusion (n 5 106)
P value
Age* NIHSS* Male sex IV tPa Atrial fibrillation Hypertension Diabetes mellitus Previous stroke Hypercholesterolemia Site of occlusion Anterior circulation M1 M2/M3 ICA/T-occlusion Posterior circulation
61.2 6 12.8 15.8 6 6.2 (4-29) 32 (69.6) 27 (58.7) 19 (41.3) 20 (40.3) 2 (4.3) 6 (13) 13 (28.3)
62.8 6 15.6 16.2 6 8 (2-31) 64 (60.4) 59 (55.7) 40 (37.7) 56 (52.8) 12 (11.3) 10 (9.4) 37 (34.9)
.537 .788 .281 .666 .654 .242 .179 .442 .478 .196
44 (95.7) 34 (73.9) 6 (13) 4 (9) 2 (4.3)
95 (89.6) 49 (46.2) 20 (21.1) 26 (27.4) 11 (10.4)
Abbreviations: IV tPa, intravenous tissue plasminogen activator; NIHSS, National Institutes of Health Stroke Scale. Values are numbers (percentages) or * mean 6 SD.
patients receiving IV tPa was 58.7% in the recanalized group versus 55.7% in the PVO patient group (P 5 .66). Nineteen (41%) patients had atrial fibrillation in the recanalized group compared with 40 (38%) in the PVO group (P 5 .654). There were no statistical differences in cardiovascular risk factors (hypertension, diabetes, or hypercholesterolemia) between the 2 groups. Thirty-four (74%) patients who achieved vessel recanalization had a proximal middle cerebral artery (M1) occlusion compared with 49 (46%) in the PVO group. Univariate analysis comparing outcomes for the 2 patient cohorts are shown in Table 2. Twenty-eight (61%) patients with vessel recanalization achieved a good outcome (mRs#2) compared with 40 (38%) patients with PVO, which was a statistically significant difference in outcome between the groups (P 5 .017). Two patients (4.2%) died in the recanalized group compared with 29 (27.4%) in the PVO group (P 5 .012). Eighteen patients (39%) did not achieve a good functional outcome despite achieving vessel recanalization within 8 hours of symptom onset (futile recanalization). However, 23 (63%) patients who achieved a TICI score of 3 had a good clinical outcome at 90 days compared with seven (50%) patients with a TICI score of 2.
The results from multivariate analyses, which assessed factors important for outcome, are shown in Table 3. NIHSS was found to be a strong predictor of outcome with low NIHSS being an independent predictor of a good outcome in both study groups (P 5.014 in the recanalized group and P 5 .001 in the PVO group). Low NIHSS was also significantly associated with low mortality (P 5 .002) in the PVO group. Factors associated with a good clinical outcome at 3 months (mRs ,2) were lower NIHSS on admission and vessel recanalization. Age, history of hypertension, previous stroke, or bridging IV tPa treatment did not have a significant impact on outcome at 3 months. Figure 1 illustrates pretreatment NIHSS scores and outcomes at 90 days. NIHSS scores had a wide range in both the recanalized (4-29) and PVO (2-31) groups. For patients with a pretreatment NIHSS score of 15 or less, vessel recanalization did not have a significant effect on clinical outcome. Thirty-three (67%) of 49 patients with persistent large-vessel occlusion and a pretreatment NIHSS score of 15 or less achieved functional independence (mRs #2) at 3 months follow-up, compared with 20 (74%) of 27 patients in the recanalized group (P 5 .21). One of the patients with a pretreatment
Table 2. Clinical outcomes: a comparison of vessel recanalization with persistent vessel occlusion Outcome (mRs) at 90 days n (%) mRs 0-2 Mortality
Recanalization n 5 46
Persistent vessel occlusion n 5 106
P value
28 (60.9) 2 (4.3)
40 (37.7) 29 (27.4)
.017 (OR 5 .3 [.1-.8]) .012 (OR 5 .1 [.02-.6])
Abbreviations: mRs, modified Rankin scale; OR, odds ratio. Values are numbers (percentages).
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Table 3. Multivariable regression analyses of factors influencing a good clinical outcome (mRs #2) in the 2 groups: recanalization versus persistent vessel occlusion
Parameter
Recanalized Good outcome, n 5 28
Persistent vessel occlusion Good outcome, n 5 40
NIHSS Age Hypertension Atrial fibrillation IV thrombolysis
P 5 .014, OR 5 1.2 CI (1.0-1.4) P 5 .287, OR 5 1.0 (.97-1.1) P 5 .436, OR 5 .53 (.11-2.63) P 5 .745, OR 5 1.3 (.24-7.2) P 5 .935, OR 5 1.1 (.2-4.6)
P 5 .001, OR 5 1.3 (1.2-1.45) P 5 .561, OR 5 1.0 (.97-1.1) P 5 .970, OR 5 .98 (.29-3.26) P 5 .33, OR 5 1.8 (.5-6.0) P 5 .39, OR 5 1.7 (.5-5.6)
Abbreviations: IV, intravenous; NIHSS, National Institutes of Health Stroke Scale; OR, odds ratio.
NIHSS score of 15 or less (3.7%) died in the recanalized group compared with 6 patients (12%) in the PVO group (P 5 .10). However, for patients with a pretreatment NIHSS score of more than 15, achieving recanalization was of clear benefit to patient outcome. Eight (42%) of the 19 patients who recanalized and had a pretreatment NIHSS score of more than 15 achieved a good outcome at 90 days compared with 7 (12%) of 57 patients with PVO (P 5 .017). One patient (5.3%) with a pretreatment NIHSS score of more than 15 died in the recanalized group compared with 23 patients (40.4%) in the PVO group (P 5 .004). There was no significant difference in the site of the vessel occlusions between the 2 study groups. In the recanalized group, 44 (96%) occlusions were in the anterior circulation compared with 95 (90%) in the PVO group.
Discussion In this study of ischemic stroke patients with largevessel occlusion, we found that early recanalization was an independent predictor of a good clinical outcome in only those patients who presented with a severe ischemic stroke (NIHSS .15). This was not the case for less severe strokes (NIHSS #15) where recanalization did not lead to more patients with functional independence at 90-day follow-up. In fact, a non- negligible proportion of patients with milder strokes (NIHSS #15) had a good clinical outcome despite PVO. These results suggest that the recanalization hypothesis may require modification, as it may only be relevant for patients with severe strokes. In this study, 67% of patients presenting with less severe strokes (NIHSS #15) achieved functional independence at 90-day follow-up with persisting vessel
Figure 1. Effect of recanalization according to stroke severity. NIHSS score of 15 or less, mild-to-moderate stroke, and NIHSS score of more than 15, moderateto-severe stroke. Abbreviations: NIHSS, National Institutes of Health Stroke Scale.
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occlusion doing well despite not achieving vessel recanalization within 8 hours of symptom onset. However, for patients presenting with more severe strokes (NIHSS . 15), recanalization had a significant effect on outcome, and for these patients, achieving vessel recanalization was vital for both functional independence and survival. Forty-two percent of patients with severe strokes and vessel recanalization were functionally independent at 90 days, whereas this was the case for only 12% of patients with a persisting occlusion. Mortality was also significantly lower for patients with severe strokes who recanalized (5.3%) compared with those in whom the vessel remained occluded (40%). Previous reports have also suggested that the effect of recanalization on outcome is dependent on the pretreatment NIHSS score.8 The PROACT 2 study, investigating the effect of intra-arterial thrombolysis for M1 or M2 occlusions, demonstrated a beneficial treatment effect only for patients with an NIHSS score of greater than 11.14 The Interventional Management of Stroke 3 study also showed a greater potential for endovascular treatment for patients presenting with an NIHSS score above 20 compared with patients presenting with a lower NIHSS score (8-19).10 In developing the Multimodal Outcome Score for Stroke Thrombolysis scoring system (assessing pretreatment NIHSS, occlusion location, Alberta Stroke Program Early CT score, and blood pressure), an NIHSS score of more than 15was found to improve the predictive accuracy of vessel recanalization on stroke outcome.15 Patients with less severe strokes achieving a good outcome despite PVO can be explained by the presence of good collateral circulation, ischemic preconditioning, and other factors of microvascular cerebrovascular adaptation. Patients presenting with a low NIHSS score despite a proximal large-vessel occlusion are likely to have these effective adaptive mechanisms present, which for some patients are long-lasting, enabling maintained perfusion of threatened brain tissue and increasing the possibility of a good outcome independent of treatment. These patients may not be dependent on recanalization to achieve a good outcome. In this study, the patients with mild strokes (NIHSS #15) despite a persisting vessel occlusion were not selected for endovascular therapy because they presented to our hospital after the 6-hour time window or had a too large infarcted area on imaging. For these patients, a selection to endovascular therapy could have constituted an unnecessary risk. On the other hand, some of these patients after initial effective adaptation to the effect of arterial occlusion may experience clinical deterioration because of, for instance, delayed failure of collateral circulation, also once they are past the therapeutic window. This emphasizes the need for more information regarding the natural history of large-vessel occlusion stroke, especially in patients who present with mild strokes. Present knowledge is limited and mainly
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based on post hoc analyses of outcomes in patients in whom revascularization failed.2,16-18 Dedicated studies are therefore needed to increase our knowledge on mechanisms of microvascular cerebrovascular adaptation in the face of large-vessel occlusion. Knowledge derived from such studies could potentially lead to understanding of ways to offer neuroprotection. The futile recanalization rate in our study was 39% with 18 patients not achieving good function despite vessel recanalization. This stresses the need for better criteria, which may be of help in identifying those patients who may benefit from mechanical recanalization. A multicenter study from 2010 of 270 patients found a futile recanalization rate of 49% with an NIHSS score from 10 to 19 being an independent predictor of a poor clinical outcome.5 Different rates of futile recanalization have been reported with 26% in PROACT 2, 36% in the MERCI trial, and 52% of patients in the Penumbra trial not achieving good function despite successful vessel recanalization.18-20 The recently published study MR CLEAN randomized 500 patients to either intra-arterial treatment (233 patients) plus ‘‘usual care’’ (which for some patients included IV tPa) or ‘‘usual care alone’’ (267 patients).21 In this study, 233 patients received intra-arterial intervention, after which 141 recanalized. Seventy-six of these patients had good function (mRs, 0-2) at 90 days, making the futile recanalization rate 54%. The lack of clinical benefit, or worse, deterioration of the patient’s clinical condition after successful vessel recanalization comprises a paradoxically harmful effect of reperfusion that can be called reperfusion injury.22,23 Cerebral postischemic reperfusion injury has been defined as ‘‘the deterioration of ischemic brain tissue that parallels and antagonizes the benefits of restoring cerebral circulation after therapeutic thrombolysis for acute ischemic stroke.’’23-26 This cerebral injury is one of the major factors that impact outcome in patients after endovascular treatment and vessel recanalization causing malignant edema, hemorrhage, herniation, and death.27 Translation of angiographic recanalization into a favorable clinical outcome is dependent on several additional factors. Surveillance of blood pressure and its management after treatment is of great importance. Lack of blood pressure control may cause reperfusion injury and hemorrhage. The amount of collateral peripheral vessels and the completeness of circle of Willis28 vary among individuals and have a documented effect on both baseline variables (time course of ischemic injury and stroke severity), and the effect of treatment (recanalization rate, degree of reperfusion, and hemorrhagic transformation) as well as patient outcome after endovascular intervention.29 Riedel et al30 reported thrombus length to be another significant factor important for recanalization success. Lastly, the composition of the occluding thrombus can also influence the outcome of stroke after vessel recanalization. Boeckhberhens et al31 assessed the impact of thrombus
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composition on mechanical recanalization and reported findings suggesting that a more organized thrombi with a high white blood cell fraction are thought to be of cardioembolic origin and associated with a longer procedure time (thrombus is more difficult to retrieve), leading to incomplete vessel recanalization (lower TICI score) and a worse clinical outcome in acute ischemic anterior circulation stroke. This study has several limitations. It is a small cohort of consecutive patients in a clinical setting, and we therefore cannot rule out differences not detected because of underpowering. Furthermore, it is a referral cohort, and we cannot exclude inclusion bias with patients not deemed suitable for endovascular therapy not included. The infarct burden was evaluated visually by the neurointerventionalist on call, without automatic measurements and without standardized evaluation of collateral circulation before selection to endovascular treatment. The Diffusion and Perfusion Imaging evaluation for Understanding Stroke Evolution study calculated infarct volume using standardized computer software and concluded that the effect of recanalization on clinical outcome was dependent on infarct volume at presentation.32 In our study, visual assessments may have resulted in the underestimation of larger infarcts and interventional treatment in patients who should have been treated conservatively potentially, contributing to a higher futile recanalization rate. In this study, absence of ischemic penumbra from MRI or CT perfusion data was for some patient’s reason for excluding them from endovascular treatment. However, a number of pitfalls have been reported with CT perfusion: Cerebral Blood Volume data not being quantitative and CT perfusion data acquisition being flawed by major limitations of commercial reconstruction software, making CT data less reliable compared with MRI diffusion-weighted imaging with an assessment of core infarcts.33-37 Using MRI diffusion studies might therefore be more reliable for estimating core infarcts when selecting patients for endovascular therapy. To conclude, in this study we found that early recanalization was an independent predictor of a good clinical outcome only in patients who presented with a severe ischemic stroke (NIHSS .15). These results suggest that in patients who are able to maintain adequate collateral flow despite proximal arterial occlusion, effective adaptive mechanisms are present, which for some patients are long-lasting. This may influence the process of appropriate patient selection for endovascular therapy. Importantly, to reduce risk of harming the patients with futile recanalization and avoid reperfusion injury, criteria for better patient selection to endovascular revascularization therapy are needed. Developing such criteria is dependent on robust clinical and imaging methods that allow reliable assessment of cerebral ischemia, the area at risk, and reperfusion response, thereby allowing the assessment of the risk and benefit of endovascular treatment.
7 Acknowledgments: Are H. Pripp, Biostatistics Unit, Oslo University Hospital, Oslo, Norway.
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the use of endovascular stroke therapy. Stroke 2014; 45:467-472. Liebeskind DS. Collateral circulation. Stroke 2003; 34:2279-2284. Liebeskind DS. Collateral lessons from recent acute ischemic stroke trials. Neurol Res 2014;36:397-402. Riedel CH, Zimmermann P, Jensen-Kondering U, et al. The importance of size: successful recanalization by intravenous thrombolysis in acute anterior stroke depends on thrombus length. Stroke 2011;42:1775-1777. Boeckh-Behrens T, Schubert M, Forschler A, et al. The impact of histological clot composition in embolic stroke. Clin Neuroradiol 2014 [Epub ahead of print]. Olivot JM, Mlynash M, Thijs VN, et al. Relationships between infarct growth, clinical outcome, and early recanalization in diffusion and perfusion imaging for understanding stroke evolution (DEFUSE). Stroke 2008; 39:2257-2263. Schaefer PW, Mui K, Kamalian S, et al. Avoiding ‘‘pseudo-reversibility’’ of CT-CBV infarct core lesions in acute stroke patients after thrombolytic therapy: the need for algorithmically ‘‘delay-corrected’’ CT perfusion map postprocessing software. Stroke 2009;40:2875-2878. Konstas AA, Lev MH. CT perfusion imaging of acute stroke: the need for arrival time, delay insensitive, and standardized postprocessing algorithms? Radiology 2010;254:22-25. Kudo K, Sasaki M, Yamada K, et al. Differences in CT perfusion maps generated by different commercial software: quantitative analysis by using identical source data of acute stroke patients. Radiology 2010; 254:200-209. Kamalian S, Kamalian S, Maas MB, et al. CT cerebral blood flow maps optimally correlate with admission diffusion-weighted imaging in acute stroke but thresholds vary by postprocessing platform. Stroke 2011; 42:1923-1928. Kamalian S, Kamalian S, Konstas AA, et al. CT perfusion mean transit time maps optimally distinguish benign oligemia from true ‘‘at-risk’’ ischemic penumbra, but thresholds vary by postprocessing technique. AJNR Am J Neuroradiol 2012;33:545-549.
Background: Arterial recanalization is currently considered the main standard of successful early management of acute ischemic stroke. Intravenous (IV) thrombolysis with tissue plasminogen activator (tPa) is the only Food and Drug Administration–approved medical treatment. Large-vessel occlusion, estimated to account for up to 40% of all acute ischemic strokes, is often refractory to IV thrombolysis and is associated with a poor patient outcome. Mechanical recanalization procedures are therefore increasingly used in the treatment of large-vessel occlusion refractory to, or presenting outside the accepted time window for, IV thrombolysis. The aim of this study was to investigate the effect of early vessel recanalization on clinical outcome in patients with large-vessel occlusion stroke. Methods: This is a singlecenter cohort study, analyzing prospectively collected data on 152 patients with large-vessel occlusion and acute ischemic stroke. Seventy-one patients received endovascular treatment (of whom 57.7% also received IV tPA), and 81 (55.6% of whom also received IV tPa) were not treated with endovascular therapy. Clinical outcome was compared for 2 cohorts: patients who recanalized (n 5 46) and patients with persisting large-vessel occlusion (n 5 106). Results: Early recanalization was an independent predictor of a good clinical outcome in only those patients who presented with a severe ischemic stroke (National Institutes of Health Stroke Scale [NIHSS] score .15; P 5 .017). This was not the case for less severe strokes (NIHSS score #15) where recanalization did not lead to more patients with functional independence at 90-day follow-up (P 5 .21). Conclusions: In this study of acute large-vessel occlusion stroke, we found that clinical outcome following early recanalization was dependent on the patient’s pretreatment NIHSS score. A nonnegligible proportion of patients with milder strokes did well despite persistent large-vessel occlusion. These results may suggest that in patients who are able to maintain adequate collateral flow despite proximal arterial occlusion, effective adaptive mechanisms are present, which for some patients are long-lasting. This may influence the process of appropriate patient selection for endovascular therapy. Key Words: Large-vessel occlusion—ischemic stroke—recanalization— endovascular treatment—thrombectomy. Ó 2015 by National Stroke Association
From the *Department of Neurology, Oslo University Hospital, Oslo; and †Department of Neuroradiology, Oslo University Hospital, Oslo, Norway. Received August 23, 2014; revision received March 9, 2015; accepted March 14, 2015. Address correspondence to Karolina Skagen, MD, Department of Neurology, Oslo University Hospital, Rikshospitalet, Nevrologisk
poliklinikk, Postbox 4950 Nydalen, 0424 Oslo, Norway. E-mail: [email protected]. 1052-3057/$ - see front matter Ó 2015 by National Stroke Association http://dx.doi.org/10.1016/j.jstrokecerebrovasdis.2015.03.020
Journal of Stroke and Cerebrovascular Diseases, Vol. -, No. - (---), 2015: pp 1-8
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Arterial recanalization is currently considered the main standard of successful early management of acute ischemic stroke. Recanalization within 8 hours of symptom onset has been found to be associated with a 4- to 5-fold increase in odds for a good functional outcome and a 4- to 5-fold reduction in the odds of death.1 Large-vessel occlusions not responsive to intravenous (IV) thrombolysis have been shown to be associated with a poor prognosis. With persistent vessel occlusion (PVO), fewer patients achieve functional independence and mortality rates are higher.2 The concept that vessel recanalization improves outcome is termed the ‘‘recanalization-hypothesis.’’ This is the basis for thrombolytic stroke therapy and the development of new treatment options for acute large-vessel occlusion stroke. When assessing the approval of retriever devices for use in endovascular treatment, recanalization rates are used as the efficacy end point.3 However, ‘‘futile recanalization,’’ when recanalization is not followed by improved clinical outcome, is well recognized.4,5 Reperfusion injury is a well-known complication for patients improperly selected for both IV tissue plasminogen activator (tPa) and endovascular therapy. Furthermore, mechanical endovascular intervention is associated with a potential risk of harming the patient. Identifying the factors that translate angiographic recanalization into a favorable clinical outcome is therefore essential. In addition to vessel recanalization, several other factors including pretreatment stroke severity have been shown to predict clinical outcome after acute ischemic stroke.6 The National Institutes of Health Stroke Scale (NIHSS) is an accepted clinical tool for assessing stroke severity and clinical outcomes.7,8 Patients presenting with a pretreatment NIHSS score of more than 15, categorized as a moderateto-severe stroke, have been found to have a higher probability of a worse outcome and death compared with patients presenting with scores 15 or less (mild-to-moderate stroke).6 The Prolyse in Acute Cerebral Thromboembolism Trial (PROACT) trial showed a clinical effect of recanalization after intra-arterial thrombolysis only for patients with a pretreatment NIHSS score greater than 11.9 The Interventional Management of Stroke 3 study also showed a greater potential for endovascular treatment for patients presenting with an NIHSS score of more than 20 compared with patients presenting with a lower NIHSS score (8-19).10 Identifying the various factors associated with a good outcome after endovascular treatment with vessel recanalization is essential to enable better selection of patients to treatment. The aim of this study therefore was to investigate the effect of early recanalization on clinical outcome in patients with large-vessel occlusion stroke in a clinical setting.
Methods This is a single-center cohort study, analyzing prospectively collected data from 152 consecutive patients with
large-vessel occlusion stroke admitted to Oslo University Hospital (OUH), Rikshospitalet, between 2007 and 2012. OUH is a tertiary referral center providing endovascular service for regional and primary stroke units. After receiving approval from the Regional Ethics Committee for data collection and analysis, a database of consecutive patients with acute ischemic stroke referred to our hospital for endovascular treatment was established. Study inclusion criteria were acute stroke with clinical ischemic symptoms corresponding to an angiographically proven large intracranial vessel occlusion, absence of intracranial hemorrhage on computed tomography (CT) scan, and a clearly defined time of symptom onset within 6 hours of inclusion. Time of patient inclusion was time of CT angiogram confirming large-vessel occlusion. A limit of 8 hours from symptom onset to vessel recanalization was predefined because early recanalization is believed to have the greatest impact on clinical function.1 Following admission, all patients were re-examined clinically and if appropriate, new imaging was performed before deciding on further treatment with endovascular recanalization and/or IV thrombolysis, or general medical treatment. All patients without contraindications to IV thrombolytic therapy were given IV tPa. Contraindications were according to departmental guidelines and in agreement with international guidelines.11 IV tPa was administered at a dose of .9 mg per kg (maximum 90 mg), with 10% given as an initial bolus and the remaining 90% as a constant infusion over a period of 60 minutes. Patients who had an ischemic penumbra (mismatch between cerebral blood flow and cerebral blood volume on perfusion imaging) or clinical penumbra (mismatch between established infarct and clinical symptoms) with no contraindications to endovascular therapy were selected for intra-arterial recanalization therapy with intra-arterial thrombolysis alone or with mechanical device, or with mechanical device alone. Contraindications to endovascular therapy were the presence of a too large area of infarction on cerebral imaging defined as more than 50% of the territory supplied by the occluded artery (restricted diffusion on magnetic resonance imaging [MRI] or low attenuation on noncontrast CT), absence of mismatch between cerebral blood flow and cerebral blood volume on perfusion imaging (no ischemic penumbra), absence of clinical mismatch to established infarct on CT or cerebral MRI, technically impossible with lack of groin access (because of previous surgery or severe atherosclerosis), total occluded vessel from the arch of the aorta or extreme vessel tortuosity where catheterization carried increased risk of patient harm, spontaneous clinical improvement, open vessel on reimaging at our institution, and a too high burden of comorbidity with coexisting malignancy, other lifethreatening diseases, dementia, major organ-failure, or life expectancy less than 1 year. All patients included in
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this study were examined with CT and/or MRI within 6 hours of symptom debut. Patients with wake-up stroke were excluded. Patients were grouped according to vessel patency regardless of treatment and imaging modality into 2 groups: recanalization within 8 hours of symptom debut or PVO, which included unsuccessful endovascular recanalization, technically failed access, or not selected for interventional therapy. The dataset was analyzed with respect to patient age on admission, time from symptom onset to admission, and neurologic deficit on admission (quantified using the NIHSS score, ranging from 0 to 42 with higher scores indicating more severe cerebral infarction) by a trained clinician who was certified in the use of the scale, site of vessel occlusion, IV thrombolysis treatment with tPa, presence of atrial fibrillation, hypertension, diabetes mellitus, previous stroke, hypercholesterolemia, and blood sample analyses.12 All patients were examined with CT angiography or MR angiography with or without CT perfusion or MR perfusion. Time from symptom onset to imaging and time to angiographically proven recanalization on digital subtraction angiography, estimated size of cerebral infarction, and the degree of recanalization were registered. The degree of recanalization was assessed using the Thrombolysis in Cerebral Infarction (TICI) score, with a score of 2 or more considered to be recanalization success, 3 being a fully opened vessel, and 0-1 not recanalized.13 An experienced neurointerventionalist, blinded to clinical outcome, evaluated all DSA images. Clinical outcomes were assessed in all patients at 90 days using the modified Rankin scale (mRs, ranging from 0 to 6, with 0 indicating no symptoms and 6 indicating death) by a clinician with specific training in outcome assessment with the mRs. Relevant hospital records with clinical data were obtained from referring hospitals for patients unable to return to the OUH clinic. To assess the effect of recanalization for different stroke severities, we classified patients into 2 groups: those patients with an NIHSS score under or equal to 15 (mild-to-moderate stroke) and those with an NIHSS score greater than 15 (severe stroke). A threshold of NIHSS score of 15 was chosen as it is often used as a cutoff between mild and severe stroke, thereby allowing exploration of possible difference in effect of recanalization in relation to stroke severity.6 Mortality and good clinical outcomes (mRs,2) were then compared between the 2 groups.
Statistical Analysis SPSS for Windows statistical software (version 18.0; SPSS Inc., Chicago, IL) was used for all data analyses. Student t test or Mann–Whitney U test was used depending on the distribution of data. The chi-square test was used for analyzing contingency data. Coefficients of correlation were calculated by the Pearson correlation.
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The proportion of patients with mRs scores of 2 or less (good outcome) at 90 days and mRs 5 6 (death), was compared for patient groups using regression analysis. Biologically plausible baseline predictors of outcome (age, sex, NIHSS, and IV thrombolysis) were entered into the multivariable model and retained in the model if their P value was less than .05. Probability values (2-sided) were considered significant at P value less than .05.
Results One hundred fifty-two consecutive patients with acute ischemic stroke due to large -vessel occlusion stroke were included in the study. All patients without contraindications to IV thrombolytic therapy were given IV tPa, in total 86 patients (56.5%). Seventy-one (46.7%) of the 152 included patients received endovascular treatment (endovascular group) and 81 (53.3%) did not (nonendovascular group). In the endovascular group, 41 patients (57.7%) received IV tPA before endovascular treatment, and in the nonendovascular group, 45 patients (55.6%) received IV tPA. Five patients were excluded from the analyses because of incomplete follow-up data. Four patients experienced spontaneous vessel recanalization, who together with the 42 patients mechanically recanalized with endovascular intervention (TICI $2) made up the cohort of a total of 46 recanalized patients. The PVO cohort of patients consisted of 81 patients with confirmed largevessel occlusion who did not meet the inclusion criteria for endovascular treatment and 29 patients who did not recanalize (TICI ,2) after endovascular treatment (n 5 106). All further analyses performed were based on these 2 groups. The following are the most common reasons for not selecting patients for endovascular therapy: the presence of a too large infarcted area on imaging (restricted diffusion on MRI or low attenuation on CT) in more than 50% of the territory supplied by the occluded vessel area and/or absence of mismatch between cerebral blood flow and cerebral blood volume on perfusion imaging (no ischemic penumbra; 45 patients), technically impossible (16 patients), spontaneous clinical improvement (13 patients), open vessel on reimaging at our institution (4 patients) and a too high burden of comorbidity (3 patients). The 2 groups were comparable in terms of patient baseline characteristics (Table 1), with no statistically significant differences in age, sex, presenting NIHSS, or proportion of patients treated with IV thrombolysis. The mean age was 61.2 years in the recanalized group and 62.8 years in the PVO group (P 5 .54). Thirty-two (69%) patients in the recanalized group and 64 (60%) in the PVO group were men (P 5 .28). Median presenting NIHSS score was 15.8 (4-29) in the recanalized group and 16.2 (2-31) in the PVO group. The proportion of
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Table 1. Patient demographics. Baseline characteristics (n 5 152) Parameter
Recanalized (n 5 46)
Persistent vessel occlusion (n 5 106)
P value
Age* NIHSS* Male sex IV tPa Atrial fibrillation Hypertension Diabetes mellitus Previous stroke Hypercholesterolemia Site of occlusion Anterior circulation M1 M2/M3 ICA/T-occlusion Posterior circulation
61.2 6 12.8 15.8 6 6.2 (4-29) 32 (69.6) 27 (58.7) 19 (41.3) 20 (40.3) 2 (4.3) 6 (13) 13 (28.3)
62.8 6 15.6 16.2 6 8 (2-31) 64 (60.4) 59 (55.7) 40 (37.7) 56 (52.8) 12 (11.3) 10 (9.4) 37 (34.9)
.537 .788 .281 .666 .654 .242 .179 .442 .478 .196
44 (95.7) 34 (73.9) 6 (13) 4 (9) 2 (4.3)
95 (89.6) 49 (46.2) 20 (21.1) 26 (27.4) 11 (10.4)
Abbreviations: IV tPa, intravenous tissue plasminogen activator; NIHSS, National Institutes of Health Stroke Scale. Values are numbers (percentages) or * mean 6 SD.
patients receiving IV tPa was 58.7% in the recanalized group versus 55.7% in the PVO patient group (P 5 .66). Nineteen (41%) patients had atrial fibrillation in the recanalized group compared with 40 (38%) in the PVO group (P 5 .654). There were no statistical differences in cardiovascular risk factors (hypertension, diabetes, or hypercholesterolemia) between the 2 groups. Thirty-four (74%) patients who achieved vessel recanalization had a proximal middle cerebral artery (M1) occlusion compared with 49 (46%) in the PVO group. Univariate analysis comparing outcomes for the 2 patient cohorts are shown in Table 2. Twenty-eight (61%) patients with vessel recanalization achieved a good outcome (mRs#2) compared with 40 (38%) patients with PVO, which was a statistically significant difference in outcome between the groups (P 5 .017). Two patients (4.2%) died in the recanalized group compared with 29 (27.4%) in the PVO group (P 5 .012). Eighteen patients (39%) did not achieve a good functional outcome despite achieving vessel recanalization within 8 hours of symptom onset (futile recanalization). However, 23 (63%) patients who achieved a TICI score of 3 had a good clinical outcome at 90 days compared with seven (50%) patients with a TICI score of 2.
The results from multivariate analyses, which assessed factors important for outcome, are shown in Table 3. NIHSS was found to be a strong predictor of outcome with low NIHSS being an independent predictor of a good outcome in both study groups (P 5.014 in the recanalized group and P 5 .001 in the PVO group). Low NIHSS was also significantly associated with low mortality (P 5 .002) in the PVO group. Factors associated with a good clinical outcome at 3 months (mRs ,2) were lower NIHSS on admission and vessel recanalization. Age, history of hypertension, previous stroke, or bridging IV tPa treatment did not have a significant impact on outcome at 3 months. Figure 1 illustrates pretreatment NIHSS scores and outcomes at 90 days. NIHSS scores had a wide range in both the recanalized (4-29) and PVO (2-31) groups. For patients with a pretreatment NIHSS score of 15 or less, vessel recanalization did not have a significant effect on clinical outcome. Thirty-three (67%) of 49 patients with persistent large-vessel occlusion and a pretreatment NIHSS score of 15 or less achieved functional independence (mRs #2) at 3 months follow-up, compared with 20 (74%) of 27 patients in the recanalized group (P 5 .21). One of the patients with a pretreatment
Table 2. Clinical outcomes: a comparison of vessel recanalization with persistent vessel occlusion Outcome (mRs) at 90 days n (%) mRs 0-2 Mortality
Recanalization n 5 46
Persistent vessel occlusion n 5 106
P value
28 (60.9) 2 (4.3)
40 (37.7) 29 (27.4)
.017 (OR 5 .3 [.1-.8]) .012 (OR 5 .1 [.02-.6])
Abbreviations: mRs, modified Rankin scale; OR, odds ratio. Values are numbers (percentages).
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Table 3. Multivariable regression analyses of factors influencing a good clinical outcome (mRs #2) in the 2 groups: recanalization versus persistent vessel occlusion
Parameter
Recanalized Good outcome, n 5 28
Persistent vessel occlusion Good outcome, n 5 40
NIHSS Age Hypertension Atrial fibrillation IV thrombolysis
P 5 .014, OR 5 1.2 CI (1.0-1.4) P 5 .287, OR 5 1.0 (.97-1.1) P 5 .436, OR 5 .53 (.11-2.63) P 5 .745, OR 5 1.3 (.24-7.2) P 5 .935, OR 5 1.1 (.2-4.6)
P 5 .001, OR 5 1.3 (1.2-1.45) P 5 .561, OR 5 1.0 (.97-1.1) P 5 .970, OR 5 .98 (.29-3.26) P 5 .33, OR 5 1.8 (.5-6.0) P 5 .39, OR 5 1.7 (.5-5.6)
Abbreviations: IV, intravenous; NIHSS, National Institutes of Health Stroke Scale; OR, odds ratio.
NIHSS score of 15 or less (3.7%) died in the recanalized group compared with 6 patients (12%) in the PVO group (P 5 .10). However, for patients with a pretreatment NIHSS score of more than 15, achieving recanalization was of clear benefit to patient outcome. Eight (42%) of the 19 patients who recanalized and had a pretreatment NIHSS score of more than 15 achieved a good outcome at 90 days compared with 7 (12%) of 57 patients with PVO (P 5 .017). One patient (5.3%) with a pretreatment NIHSS score of more than 15 died in the recanalized group compared with 23 patients (40.4%) in the PVO group (P 5 .004). There was no significant difference in the site of the vessel occlusions between the 2 study groups. In the recanalized group, 44 (96%) occlusions were in the anterior circulation compared with 95 (90%) in the PVO group.
Discussion In this study of ischemic stroke patients with largevessel occlusion, we found that early recanalization was an independent predictor of a good clinical outcome in only those patients who presented with a severe ischemic stroke (NIHSS .15). This was not the case for less severe strokes (NIHSS #15) where recanalization did not lead to more patients with functional independence at 90-day follow-up. In fact, a non- negligible proportion of patients with milder strokes (NIHSS #15) had a good clinical outcome despite PVO. These results suggest that the recanalization hypothesis may require modification, as it may only be relevant for patients with severe strokes. In this study, 67% of patients presenting with less severe strokes (NIHSS #15) achieved functional independence at 90-day follow-up with persisting vessel
Figure 1. Effect of recanalization according to stroke severity. NIHSS score of 15 or less, mild-to-moderate stroke, and NIHSS score of more than 15, moderateto-severe stroke. Abbreviations: NIHSS, National Institutes of Health Stroke Scale.
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occlusion doing well despite not achieving vessel recanalization within 8 hours of symptom onset. However, for patients presenting with more severe strokes (NIHSS . 15), recanalization had a significant effect on outcome, and for these patients, achieving vessel recanalization was vital for both functional independence and survival. Forty-two percent of patients with severe strokes and vessel recanalization were functionally independent at 90 days, whereas this was the case for only 12% of patients with a persisting occlusion. Mortality was also significantly lower for patients with severe strokes who recanalized (5.3%) compared with those in whom the vessel remained occluded (40%). Previous reports have also suggested that the effect of recanalization on outcome is dependent on the pretreatment NIHSS score.8 The PROACT 2 study, investigating the effect of intra-arterial thrombolysis for M1 or M2 occlusions, demonstrated a beneficial treatment effect only for patients with an NIHSS score of greater than 11.14 The Interventional Management of Stroke 3 study also showed a greater potential for endovascular treatment for patients presenting with an NIHSS score above 20 compared with patients presenting with a lower NIHSS score (8-19).10 In developing the Multimodal Outcome Score for Stroke Thrombolysis scoring system (assessing pretreatment NIHSS, occlusion location, Alberta Stroke Program Early CT score, and blood pressure), an NIHSS score of more than 15was found to improve the predictive accuracy of vessel recanalization on stroke outcome.15 Patients with less severe strokes achieving a good outcome despite PVO can be explained by the presence of good collateral circulation, ischemic preconditioning, and other factors of microvascular cerebrovascular adaptation. Patients presenting with a low NIHSS score despite a proximal large-vessel occlusion are likely to have these effective adaptive mechanisms present, which for some patients are long-lasting, enabling maintained perfusion of threatened brain tissue and increasing the possibility of a good outcome independent of treatment. These patients may not be dependent on recanalization to achieve a good outcome. In this study, the patients with mild strokes (NIHSS #15) despite a persisting vessel occlusion were not selected for endovascular therapy because they presented to our hospital after the 6-hour time window or had a too large infarcted area on imaging. For these patients, a selection to endovascular therapy could have constituted an unnecessary risk. On the other hand, some of these patients after initial effective adaptation to the effect of arterial occlusion may experience clinical deterioration because of, for instance, delayed failure of collateral circulation, also once they are past the therapeutic window. This emphasizes the need for more information regarding the natural history of large-vessel occlusion stroke, especially in patients who present with mild strokes. Present knowledge is limited and mainly
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based on post hoc analyses of outcomes in patients in whom revascularization failed.2,16-18 Dedicated studies are therefore needed to increase our knowledge on mechanisms of microvascular cerebrovascular adaptation in the face of large-vessel occlusion. Knowledge derived from such studies could potentially lead to understanding of ways to offer neuroprotection. The futile recanalization rate in our study was 39% with 18 patients not achieving good function despite vessel recanalization. This stresses the need for better criteria, which may be of help in identifying those patients who may benefit from mechanical recanalization. A multicenter study from 2010 of 270 patients found a futile recanalization rate of 49% with an NIHSS score from 10 to 19 being an independent predictor of a poor clinical outcome.5 Different rates of futile recanalization have been reported with 26% in PROACT 2, 36% in the MERCI trial, and 52% of patients in the Penumbra trial not achieving good function despite successful vessel recanalization.18-20 The recently published study MR CLEAN randomized 500 patients to either intra-arterial treatment (233 patients) plus ‘‘usual care’’ (which for some patients included IV tPa) or ‘‘usual care alone’’ (267 patients).21 In this study, 233 patients received intra-arterial intervention, after which 141 recanalized. Seventy-six of these patients had good function (mRs, 0-2) at 90 days, making the futile recanalization rate 54%. The lack of clinical benefit, or worse, deterioration of the patient’s clinical condition after successful vessel recanalization comprises a paradoxically harmful effect of reperfusion that can be called reperfusion injury.22,23 Cerebral postischemic reperfusion injury has been defined as ‘‘the deterioration of ischemic brain tissue that parallels and antagonizes the benefits of restoring cerebral circulation after therapeutic thrombolysis for acute ischemic stroke.’’23-26 This cerebral injury is one of the major factors that impact outcome in patients after endovascular treatment and vessel recanalization causing malignant edema, hemorrhage, herniation, and death.27 Translation of angiographic recanalization into a favorable clinical outcome is dependent on several additional factors. Surveillance of blood pressure and its management after treatment is of great importance. Lack of blood pressure control may cause reperfusion injury and hemorrhage. The amount of collateral peripheral vessels and the completeness of circle of Willis28 vary among individuals and have a documented effect on both baseline variables (time course of ischemic injury and stroke severity), and the effect of treatment (recanalization rate, degree of reperfusion, and hemorrhagic transformation) as well as patient outcome after endovascular intervention.29 Riedel et al30 reported thrombus length to be another significant factor important for recanalization success. Lastly, the composition of the occluding thrombus can also influence the outcome of stroke after vessel recanalization. Boeckhberhens et al31 assessed the impact of thrombus
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composition on mechanical recanalization and reported findings suggesting that a more organized thrombi with a high white blood cell fraction are thought to be of cardioembolic origin and associated with a longer procedure time (thrombus is more difficult to retrieve), leading to incomplete vessel recanalization (lower TICI score) and a worse clinical outcome in acute ischemic anterior circulation stroke. This study has several limitations. It is a small cohort of consecutive patients in a clinical setting, and we therefore cannot rule out differences not detected because of underpowering. Furthermore, it is a referral cohort, and we cannot exclude inclusion bias with patients not deemed suitable for endovascular therapy not included. The infarct burden was evaluated visually by the neurointerventionalist on call, without automatic measurements and without standardized evaluation of collateral circulation before selection to endovascular treatment. The Diffusion and Perfusion Imaging evaluation for Understanding Stroke Evolution study calculated infarct volume using standardized computer software and concluded that the effect of recanalization on clinical outcome was dependent on infarct volume at presentation.32 In our study, visual assessments may have resulted in the underestimation of larger infarcts and interventional treatment in patients who should have been treated conservatively potentially, contributing to a higher futile recanalization rate. In this study, absence of ischemic penumbra from MRI or CT perfusion data was for some patient’s reason for excluding them from endovascular treatment. However, a number of pitfalls have been reported with CT perfusion: Cerebral Blood Volume data not being quantitative and CT perfusion data acquisition being flawed by major limitations of commercial reconstruction software, making CT data less reliable compared with MRI diffusion-weighted imaging with an assessment of core infarcts.33-37 Using MRI diffusion studies might therefore be more reliable for estimating core infarcts when selecting patients for endovascular therapy. To conclude, in this study we found that early recanalization was an independent predictor of a good clinical outcome only in patients who presented with a severe ischemic stroke (NIHSS .15). These results suggest that in patients who are able to maintain adequate collateral flow despite proximal arterial occlusion, effective adaptive mechanisms are present, which for some patients are long-lasting. This may influence the process of appropriate patient selection for endovascular therapy. Importantly, to reduce risk of harming the patients with futile recanalization and avoid reperfusion injury, criteria for better patient selection to endovascular revascularization therapy are needed. Developing such criteria is dependent on robust clinical and imaging methods that allow reliable assessment of cerebral ischemia, the area at risk, and reperfusion response, thereby allowing the assessment of the risk and benefit of endovascular treatment.
7 Acknowledgments: Are H. Pripp, Biostatistics Unit, Oslo University Hospital, Oslo, Norway.
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