DSA-based grading scales

The most widely recognised grading system is the American Society of Interventional and Therapeutic Neuroradiology/Society of Interventional Radiology (ASITN/SIR) collateral scale based on DSA, classifying the cerebral collateral status to grades 0–4 as follows: grade 0, no collaterals visible to the ischaemic site; grade 1, slow collaterals to the periphery of the ischaemic site with persistence of some of the defect; grade 2, rapid collaterals to the periphery of ischaemic site with persistence of some of the defect and to only a portion of the ischaemic territory; grade 3, collaterals with slow but complete angiographic blood flow of the ischaemic bed by the late venous phase; and grade 4, collaterals with slow but complete angiographic blood flow of the ischaemic bed by the late venous phase.28 Grades 0–1, 2 and 3–4 are usually regarded as poor, moderate and good collateral flow. The ASITN/SIR collateral grading system has been demonstrated to be reliable in assessing the collateral status in patients with stroke in a number of multicentre studies.

The Endovascular Stroke Treatment (ENDOSTROKE) registry was an international, multicentre study recruiting adult patients with acute ischaemic stroke and intracranial large artery occlusion for whom mechanical revascularisation procedure was attempted.29 Among the 160 patients with acute proximal MCA occlusion in the ENDOSTROKE registry, the ASITN/SIR collateral scale was used to gauge the collateral status to correlate with the imaging and clinical outcomes after acute endovascular treatment. The investigators found a positive correlation between a better collateral status and a higher reperfusion rate, leading to a smaller infarct volume and a better clinical outcome. The rates of achieving successful reperfusion by the Thrombolysis in Cerebral Infarction Scale 2b or 3 among those with ASITN/SIR collateral grades of 0–1, 2 or 3–4 were, respectively, 21%, 48% and 77% (p<0.001). The proportion of the infarcts smaller than one-third of the MCA territory (32%, 48% and 69% for collateral grades 0–1, 2 or 3–4; p<0.001), and more importantly the proportion of patients with a good functional outcome at least 3 months after the intervention (11%, 35% and 49% for collateral grades 0–1, 2 or 3–4; p=0.007), were both significantly higher in those with better collaterals. Multivariate analysis reinforced the role of collateral status as an independent predictor for reperfusion, infarct size and long-term functional outcomes in patients receiving endovascular treatment for acute proximal MCA occlusion.29 Another subgroup analysis of the ENDOSTROKE registry of 148 patients with acute basilar artery occlusion also indicated the predictive value of collateral status by the ASITN/SIR collateral scale for reperfusion and clinical outcomes.30 In addition, post-hoc analysis of the Interventional Management of Stroke III (IMS III)31 and Solitaire FR With the Intention for Thrombectomy32 trials’ data showed similar results.

Christoforidis et al33 proposed another collateral grading system based on DSA that is less frequently used, which classifies the collateral status to five grades: grade 1, collaterals reconstituted the entire distal portion of the occluded vessel segment; grade 2, collaterals reconstituted vessels in the proximal portion of the segment adjacent to the occluded vessel; grade 3, collaterals reconstituted vessels in the distal portion of the segment adjacent to the occluded vessel; grade 4, collaterals reconstituted vessels two segments distal to the occluded vessel; and grade 5, little or no significant reconstitution of the territory of the occluded vessel. Good collateral status by this grading system (grades 1 or 2) has been correlated with smaller infarct volume, lower risk of haemorrhagic transformation and lower modified Rankin Scale (mRS) at discharge, in patients with ischaemic stroke receiving intra-arterial thrombolysis in relatively small-scale studies.33 34 This collateral grading method is not commonly used in clinical practice.

CTA-based grading scales

The Endovascular Treatment for Small Core and Proximal Occlusion Ischemic Stroke (ESCAPE) study2 is an international multicentre RCT study evaluating thrombectomy, with a primary prognostic indicator of functional outcome at 90 days after onset. The results showed that for patients with acute ischaemic stroke with favourable collateral circulation, based on multiphase CTA ASPECTS collateral circulation score (5–4 points), prompt administration of endovascular treatment improved functional outcome (mRS score at 90 days) and reduced mortality.

Table 1 shows examples of other collateral grading methods based on CTA, including the methods proposed by Miteff et al35 (grading collateral flow distal to MCA occlusion), Maas et al36 (assessing collaterals at the Sylvian sulcus and cerebral convexity, as well as collateral pathways via the circle of Willis), Tan et al37 (grading collaterals in the MCA territory), the regional leptomeningeal collateral (rLMC) score38 (assessing collaterals in MCA cortical regions, parasagittal ACA territory, the basal ganglia and the Sylvian sulcus), and the ACA-MCA and PCA-MCA regional collateral score.39 40 There are also modified versions of originally DSA-based collateral grading methods for CTA, such as the ASITN/SIR collateral scale28 for CTA and the Christoforidis collateral grading system33 for CTA, which are not listed in table 1. There have been studies comparing the clinical relevance of these grading methods, but the findings were heterogeneous and none of the collateral grading systems have been well validated in large-scale studies. Further investigation is needed to establish an optimal method to non-invasively assess collateral circulation in patients with stroke.

The predictive values of the ACA-MCA and PCA-MCA regional collateral score,39 40and the Maas et al36 and Tan et al37 collateral grading methods for a favourable 3-month functional outcome after intravenous thrombolysis and/or endovascular treatment, among patients with acute stroke with M1 MCA occlusion±intracranial internal carotid artery (ICA) occlusion, were tested in 185 patients from the IMS III cohort. In multivariate analyses, collateral status by each of the collateral scales was significantly, independently correlated with an mRS of 0–2 at 3 months after treatment.40

Another study compared the abilities of the Miteff et al,35 Maas et al36 and Tan et al37 collateral grading methods and the rLMC score to predict the 3-month functional outcomes in acute anterior circulation stroke treated with intravenous thrombolysis. Among 200 patients, only good collateral status by the Miteff collateral grading method was found to be an independent predictor for a favourable functional outcome (mRS 0–1) at 3 months (OR, 3.34; 95% CI 1.24 to 9.00; p=0.01). In addition, poor collateral status by the Miteff method, the Maas method and the rLMC score were all independently related to an extremely poor functional outcome (mRS 5–6) at 3 months.41

A more recent study has compared four different CTA-based collateral scales in predicting the volume of infarct core and the perfusion:diffusion mismatch ratio within the first few hours after an ischaemic stroke among 30 patients with acute M1 MCA or terminal carotid artery occlusion. The ACA-MCA and PCA-MCA regional collateral score39 40 and a modified version of the ASITN/SIR collateral scale28 for dynamic CTA both showed good correlations with early infarct core volume (Spearman’s correlation coefficients both around –0.7; p<0.001) and the mismatch ratio (Spearman’s correlation coefficients both around 0.6; p<0.001). However, the Miteff collateral grades, or a modified version of the Christoforidis collateral grading system33 for dynamic CTA, were not significantly linearly correlated with the infarct core volume and the mismatch ratio.42

Collateral circulation and intravenous thrombolysis in stroke

Intravenous thrombolysis is the first-line treatment for patients with acute ischaemic stroke presenting within 4.5 hours without contraindications.43 45 By far, there have been few prospective studies investigating the role of collateral circulation in determining outcomes of patients receiving intravenous thrombolytic therapy. Yet post-hoc analysis of several RCTs indicated that a better collateral status prior to intravenous thrombolysis was associated with less severe clinical symptoms (the Combined Lysis of Thrombus in Brain Ischemia Using transcranial Ultrasound and Systemic TPA trial, CLOTBUST),47 a smaller infarct core in diffusion-weighted MRI and a larger diffusion–perfusion mismatch (Echoplanar Imaging Thrombolytic Evaluation Trial).48 More importantly, better collaterals at baseline were associated with a higher incidence of achieving a favourable functional outcome at 3 months after the treatment (CLOTBUST and IMS III trials).40 47

A recent systematic review and meta-analysis synthesised evidence regarding the impact of pretreatment collateral circulation on the outcomes of patients with stroke treated with intravenous thrombolysis.49 Overall, 28 primary studies of 3057 patients were included in the analysis, including 25 cohort studies (mostly retrospective) and 3 post-hoc analyses of RCTs. Meta-analysis based on these data has demonstrated a favourable role of better collateral circulation in this subset of patients, including a lower risk of symptomatic intracranial haemorrhage (risk ratio (RR) 0.38; 95% CI 0.16 to 0.90; p=0.03), a higher incidence of early neurological improvement (RR 4.21; 95% CI 1.57 to 11.28; p=0.004) and a higher frequency of a favourable functional outcome (mRS 0–2 or 0–1 as defined in different primary studies) at 3–6 months after the thrombolytic treatment (RR 2.45; 95% CI 1.94 to 3.09; p<0.001).49 Such findings may be attributed to a lower National Institutes of Health Stroke Scale score (NIHSS; mean difference 6.6; 95% CI 4.4 to 8.7; p<0.001) and a smaller infarct volume in patients with better collateral circulation. However, no significant correlation was identified between the baseline collateral status and successful reperfusion or recanalisation after intravenous thrombolytic therapy (RR 1.34; 95% CI 0.87 to 2.07; p=0.19). Unfortunately, data are limited to allow quantitative synthesis of the correlations between baseline collateral status and the overall risk of haemorrhagic transformation (symptomatic or asymptomatic), the final infarct volume and death risk at 3 months after treatment.49

In summary, previous studies show that pretreatment collateral status plays an important role in determining short-term and long-term outcomes of patients with stroke receiving intravenous thrombolytic therapy, while further prospective investigations are needed before more confirmative conclusions could be drawn.

Collateral circulation and endovascular treatment in stroke

A number of previous trials failed to prove the superiority of endovascular treatment over routine medical treatment with or without intravenous thrombolysis in acute ischaemic stroke. In 2015, several pivotal RCTs demonstrated the safety and efficacy of endovascular treatment in ischaemic stroke with cervical or intracranial arterial occlusion, when the American and Chinese guidelines on early management of ischaemic stroke were updated, recommending endovascular treatment for eligible patients presenting within 6 hours of symptom onset with or without prior intravenous thrombolytic therapy.44 46 Except for the application of newer generation thrombectomy devices, adding imaging eligibility criteria for patient selection, for example, a moderate-to-good collateral circulation, a smaller infarct core or evidence of salvageable brain tissue, may have contributed to the positive findings in these more recent RCTs.2 25 50–53 In 2017, encouraging evidence has emerged that patients with ischaemic stroke with cervicocerebral artery occlusion may benefit from endovascular treatment up to 24 hours after stroke onset. For instance, the Diffusion-Weighted Imaging or Computerized Tomography Perfusion Assessment with Clinical Mismatch in the Triage of Wake Up and Late Presenting Strokes Undergoing Neurointervention (DAWN) trial enrolled patients with occlusion of the ICA and/or the first segment of the MCA in 6–24 hours, and had a mismatch between the severity of the clinical deficit and the infarct volume, which was assessed with the use of diffusion-weighted MRI or perfusion CT. The DAWN trial witnessed a significant increase (an absolute increase of 35%) in the incidence of a 90-day favourable functional outcome (mRS 0–2) in patients with intracranial ICA or M1 MCA occlusion, yet a small infarct core treated with mechanical thrombectomy 6–24 hours after the stroke onset as compared with routine medical treatment.52 53 Moreover, the CT Perfusion to Predict Response to Recanalization in Ischemic Stroke trial revealed that baseline CTP ‘target mismatch’, which had a small ischaemic core and a large penumbra, indicated a significant improvement in the NIHSS score even in those treated up to 18 hours after symptom onset.26 The DEFUSE 3 trial indicates that endovascular thrombectomy for patients with ischaemic stroke 6–16 hours with proximal MCA or internal carotid artery occlusion, an initial infarct size of less than 70 mL, and a ratio of the volume of ischaemic tissue on perfusion imaging to infarct volume of 1.8 or more had a significant favourable functional outcomes on the mRS at 90 days compared with the medical therapy-alone group (OR, 2.77; p<0.001).27

To enlarge the benefit of endovascular treatment within or beyond the 6-hour time window as recommended by current guidelines, it is also essential to find the ‘right’ patients to treat, while good pretreatment collaterals may play an important role in preserving salvageable tissue. Two recent systematic reviews and meta-analyses investigated the effects of pretreatment collateral circulation in governing clinical and imaging outcomes of patients with stroke receiving endovascular treatment.54 55 Based on data from over 20 studies of >2000 patients with stroke treated with intra-arterial thrombolysis and/or mechanical thrombectomy, with or without prior intravenous thrombolysis, better pretreatment collateral circulation is associated with slightly higher rates of successful recanalisation (RR 1.23; 95% CI 1.06 to 1.42; p=0.006) and reperfusion (RR 1.28; 95% CI 1.17 to 1.40; p<0.001),55 a significantly lower risk of symptomatic intracranial haemorrhage within 7 days or before discharge (RR 0.59; 95% CI 0.43 to 0.81; p=0.001), a doubled chance of achieving a favourable functional outcome at 3 months (RR 1.98; 95% CI 1.64 to 2.38; p<0.001), and a halved risk of death at 3 months (RR 0.49; 95% CI 0.38 to 0.63; p<0.001).54 Although the mechanisms underlying the protective effects of collateral circulation in such patients have not been well illustrated, inferences are that collateral circulation via the circle of Willis or pial arteries compensates cerebral blood flow adjacent to the ischaemic area, which provides better access of the clot to intrinsic and extrinsic thrombolytic agents and possibly a back pressure that facilitates dislodgement of the clot. It may also mitigate the ischaemia-reperfusion injuries.56 57

Collaterals via the circle of Willis and outcomes of patients with symptomatic ICAS

There is no confirmative conclusion regarding the effect of collaterals via the circle of Willis on the risk of recurrence and the functional outcomes of patients with symptomatic ICAS. The largest study by far reporting the correlation between the completeness of the circle of Willis and the recurrence risk in patients with ischaemic stroke or TIA was CICAS.60 Patients with stroke or TIA with a complete circle of Willis had a higher risk of recurrence within 1 year, as compared with those without (adjusted HR 2.36; 95% CI 1.19 to 4.69; p=0.015). However, such findings were generated from an overall analysis of CICAS, including 1335 patients with and 1529 patients without ICAS. Thus, no conclusion could be drawn from such analysis concerning the protective or harmful effect of collateral flow through the circle of Willis in patients with ICAS.60 There has been another small-scale study reporting that a complete circle of Willis reduced the risk of recurrence within 3 years among patients with 70%–99% symptomatic ICAS who received medical treatment, which did not affect the recurrent risk among 43 patients who received angioplasty with/without stenting therapy.69

Leptomeningeal and other collateral pathways and outcomes of patients with symptomatic ICAS

Among 569 patients recruited to the WASID trial with 50%–99% symptomatic atherosclerotic stenosis of a major intracranial artery, who were treated with antiplatelet or anticoagulant therapies, adequate angiographic data to assess the leptomeningeal collaterals were available in 287 patients. The angiogram-based collateral extent independently predicted recurrent ischaemic stroke in the symptomatic arterial territory (HR for none vs good collaterals, 1.14;  95% CI 0.39 to 3.30; HR for poor vs good collaterals, 4.36;  95% CI 1.46 to 13.07; p<0.0001). Subgroup analyses by the severity of arterial stenosis indicated that more robust leptomeningeal collaterals were associated with a lower risk of recurrence among patients with 70%–99% symptomatic ICAS (HR none vs good, 4.60;  95% CI 1.03 to 20.56; HR poor vs good, 5.90; 95% CI 1.25 to 27.81; p=0.0427), which, however, were associated with an increased risk of recurrence in those with 50%–69% symptomatic ICAS (HR none vs good, 0.18;  95% CI 0.04 to 0.82; HR poor vs good, 1.78; 95% CI 0.37 to 8.57; p<0.0001).4

A small-scale, single-centre study of 69 patients with 50%–100% symptomatic ICAS found that those with better leptomeningeal collateral compensations (ASITN/SIR collateral flow grades 2–4 vs 0–1) had a better chance to achieve a favourable functional outcome at 3 months (adjusted OR 7.50; 95% CI 1.11 to 50.7; p=0.04) and a lower risk of recurrent ischaemic stroke or TIA within 1 year (OR 0.18;  95% CI 0.04 to 0.96; p=0.04).64

Another small study of 88 patients with symptomatic MCA occlusion implied that better collaterals as defined by the presence of hyperintensities in the Sylvian fissure on fluid-attenuated inversion recovery sequence were independently correlated with a lower risk of poor functional outcome (mRS 3–6) at 3 months (adjusted OR 0.272; 95% CI 0.101 to 0.733; p=0.010). However, MCA occlusions in this study were attributed to various aetiologies, among which only 40% were of atherosclerotic origin.66

Lee et al⁶⁸ modified the ASITN/SIR collateral flow grades to assess the extent of vessel filling in the superior cerebellar artery territory (scores 0–4) and the anterior/posterior inferior cerebellar artery territory (scores 0–4), with a total score of 0–8, among 98 patients with symptomatic, atherosclerotic basilar artery stenosis (70%–99%). Better collateral status by such method was associated with a reduced incidence of poor functional outcome (mRS 3–6) at 3 months (OR of 1-score increment in the collateral score, 0.21; 95% CI 0.08 to 0.58; p=0.003).68

Except for the collateral pathways as mentioned above, the effect of the presence of the anterior temporal artery in patients with symptomatic MCA occlusion was investigated in 98 patients, which was significantly correlated with a favourable functional outcome (mRS 0–2) at 3 months (adjusted OR 4.45; 95% CI 1.52 to 13.03; p=0.007), independent of the baseline NIHSS score, the infarct size and pattern.65

Extracranial-intracranial bypass surgery

Extracranial-intracranial (EC-IC) bypass surgery may improve haemodynamic parameters in patients with symptomatic cervicocerebral artery stenosis or occlusion.70 A large RCT (1377 patients) conducted over 30 years ago, the EC/IC Bypass Study, indicated the inferiority of direct EC-IC bypass surgery over medical treatment among patients with steno-occlusive disease of the extracranial and/or intracranial arteries.71 From 2002 to 2010, the Carotid Occlusion Surgery Study (COSS) trial compared direct EC-IC bypass surgery plus medical treatment versus medical treatment alone among patients with symptomatic atherosclerotic internal carotid artery occlusion, who had haemodynamic cerebral ischaemia as defined by an increased ipsilateral:contralateral oxygen extraction fraction ratio on PET.72 The COSS trial was prematurely terminated due to futility—the rates of stroke or death within 30 days and ipsilateral ischaemic stroke within 2 years were not significantly different between the surgical and non-surgical groups (21.0% vs 22.7%; p=0.78).72 The Japanese EC-IC Bypass Trial (JET), recruiting patients between 1998 and 2002, had a similar study design with that of COSS, but the JET trial defined the cerebral haemodynamic compromise by decreased cerebral blood flow and deceased cerebrovascular reactivity to vasodilation in PET or SPECT.73 The JET trial reported a lower rate of the primary endpoint in the surgical than in the non-surgical groups among 196 patients (p=0.046). However, there have been concerns over the results of JET, since there was zero primary endpoint in the surgical group within the first month after the EC-IC bypass surgery in JET, which was 15% in the surgical group of the COSS trial.72 73 Overall, based on currently available evidence, direct EC-IC bypass surgery is not recommended for patients with ischaemic stroke or TIA and ipsilateral, atherosclerotic ICA or MCA stenosis or occlusion in the 2014 American Heart Association/American Stroke Association guidelines for secondary stroke prevention.74

Encephaloduroarteriosynangiosis (EDAS), an indirect EC-IC bypass surgical method, has recently been reported safe and possibly effective in improving collateral circulation and reducing risk of recurrence, among small groups of patients with symptomatic ICAS with refractory stroke despite the best medical treatment.75 76 A prospective, single-arm clinical trial, the EDAS (Surgical) Revascularization for Symptomatic Intracranial Arterial Stenosis trial (ClinicalTrials.gov identifier: NCT01819597), is investigating the safety and efficacy of EDAS in these patients.

Partial aortic occlusion by the NeuroFlo technology

The NeuroFlo Catheter has two balloons which when mounted and inflated in the aorta could partially occlude the aortic lumen above and below the renal arteries, to increase cerebral blood flow. The Safety and Efficacy of NeuroFlo in Acute Ischemic Stroke (SENTIS) trial is the largest trial comparing the NeuroFlo technique with standard medical treatment among patients with acute cortical ischaemic stroke.77 It demonstrated in 515 patients that partial aortic occlusion by NeuroFlo Catheter to increase cerebral blood flow is safe among patients with stroke (p value for comparison of serious adverse events between the two groups=0.923). There was no significant difference between the two groups in the primary efficacy outcome, a favourable function outcome (OR 1.17; 95% CI 0.81 to 1.67; p=0.407), but there was a trend of decreased all-cause mortality in the NeuroFlo-treated group (11.2% vs 16.3%; OR 1.60; 95% CI 0.91 to 2.83; p=0.086).77 Subsequent subgroup analysis of the SENTIS data showed that patients aged over 70 years, patients who were treated with NeuroFlo within 5 hours of stroke onset and patients with moderate stroke severity (NIHSS scores of 8–14) may benefit more from the NeuroFlo treatment than medical treatment.77 78 Selecting appropriate patients is important for the NeuroFlo treatment to benefit, while relevant findings need further verification.

External counterpulsation

External counterpulsation (ECP) is a non-invasive method that enhances cardiac output and blood flow to vital organs including the brain, by inflating pressure cuffs around the lower extremities and the buttocks during the diastole and deflating the cuffs during the systole. ECP treatment is safe and feasible in patients with ischaemic stroke.79–81 It could augment cerebral blood flow in the ipsilateral and contralateral hemispheres among patients with stroke with large artery occlusive disease, which may imply enhanced collateral flow to the ischaemic territories.82 A single session of ECP (1 hour) may be associated with transient improvement in the neurological symptoms of patients with stroke, according to the Counterpulsation to Upgrade Forward Flow in Stroke trial (23 patients).81 Another pilot study of 50 patients with ischaemic stroke with large artery occlusive disease showed a slightly more significant decrease in the NIHSS score (2.1 vs 1.3; p=0.061) after 35 daily sessions of ECP treatment (1 hour per session) than no ECP treatment.80 Therefore, ECP is a safe and possibly effective method to enhance cerebral blood flow and improve outcomes of patients with stroke, which warrants further investigation.

Lying-flat head positioning

Cerebral autoregulation may be impaired in patients with ischaemic stroke, especially in the affected cerebral hemisphere. Thus, a lying-flat head positioning may increase cerebral blood flow through collateral circulation or gravity, as compared with an upright head positioning.83 A systematic review and meta-analysis of four small studies (57 patients in total) indicated that ipsilesional but not contralesional MCA flow velocities were significantly higher when patients were in a lying-flat head position at 0° or 15° as compared with an upright head position of 30°.84 The mean flow velocity of ipsilesional MCA increased by 8.3 cm/s on average with a head position from 30° to 0° (95% CI 5.3 to 11.3 cm/s; p<0.001) and 4.6 cm/s from 30° to 15° (95% CI 2.9 to 6.2 cm/s; p<0.001).84 The Head Position in Acute Stroke Trial (HeadPoST) investigated the effects of different head positions in altering outcomes of over 11 000 patients with acute ischaemic or haemorrhagic stroke who were nursed to a lying-flat or sitting-up (≥30°) head positions and remaining in the position for 24 hours.85 Unfortunately, the HeadPoST study did not show any difference in the lying-flat and sitting-up head positions in affecting the 3-month function outcome, in the overall analysis or in subgroup analyses according to stroke subtypes, initial stroke severity, age and others.86 Of note, HeadPoST did not assess arterial occlusion status in patients with stroke, which reduced power to detect a benefit of lying flat. Therefore, no conclusion could be drawn based on current evidence regarding the effects of different head positions on clinical outcomes of patients with ischaemic stroke.

Other non-pharmacological interventions

Remote limb ischaemic preconditioning (RIPC) may condition remote vital organs including the brain for subsequent ischaemic events, by inducing transient episodes of mild ischaemia in the limbs. There have been preliminary studies indicating that long-term, repeated RIPC of bilateral arms is safe and feasible in patients with stroke aged under or above 80 years who had symptomatic ICAS. Compared with standard medical treatment alone, RIPC plus standard medical treatment may reduce the risk of recurrent stroke or TIA in such patients by improving cerebral perfusion and relieving the inflammation stress.87 88 Large prospective studies are needed to further explore the efficacy of RIPC in patients with stroke, for instance, the Remote Ischemic Conditioning for Avoiding Recurrence of Ischemic Stroke in Patients with Symptomatic Intracranial Atherosclerotic Stenosis trial (ClinicalTrials.gov identifier: NCT02534545), which is currently under way.

In addition, there are novel methods that have shown promising effects in enhancing cerebral collateral circulation and cerebral blood flow in experimental stroke models, such as inhaling nitric oxide,89 stimulating the sphenopalatine ganglion90 and others. But more evidence is needed before testing these methods in patients with stroke.

Statins

Statin therapy has been demonstrated to have a protective effect in preventing stroke in patients with stroke, TIA or coronary artery disease. The relative risk reduction of statins versus placebo for a stroke event during follow-up in previous RCTs ranged from below 5% to over 30%.91 A recent systematic review and meta-analysis has demonstrated that prestroke statin use is associated with milder initial stroke severity (OR 1.24; 95% CI 1.05 to 1.48; p=0.013), better functional outcome (OR 1.50; 95% CI 1.29 to 1.75; p<0.001) and lower mortality (OR 0.42; 95% CI 0.21 to 0.82; p=0.011). In-hospital statin use is also associated with better functional outcome and lower mortality. Among patients with stroke treated with thrombolytic therapy, statin use also leads to a higher rate of a favourable functional outcome (OR 1.44; 95% CI 1.10 to 1.89; p=0.001), despite a higher risk of symptomatic haemorrhagic transformation with statin use (OR 1.63; 95% CI 1.04 to 2.56; p=0.035).92 The protective effect of statins towards a better functional outcome and against stroke recurrence may lie in their pleiotropic effects, for instance, reducing the concentration of low-density lipoprotein cholesterol, mild effect in lowering the blood pressure and anti-inflammatory effects.91 Moreover, it has been indicated in small studies that prestroke use of statins might be independently associated with better collateral circulation in cardioembolic, large artery atherosclerotic strokes or strokes of unknown aetiologies, possibly through increasing nitric oxide synthesis and promoting ischaemia-induced neovascularisation.93 94 The pleiotropic effects of statins in patients with stroke, including that in boosting collateral flow, warrant further investigation.

Urinary kallidinogenase and dl-3-n-butylphthalide

Urinary kallidinogenase increases cerebral blood flow velocity and reduces the infarct size in an experimental stroke model by thread occlusion of MCA in rats.95 A small, open-label, controlled, prospective study implied that short-term application of human urinary kallidinogenase could upregulate vascular endothelial growth factor and apelin expression, shorten the MTT in MR perfusion, and improve the 3-month functional outcome, as compared with control, among patients with acute stroke.96 According to a systematic review and meta-analysis of 24 trials with 2433 patients published in 2012, human urinary kallidinogenase injection reduced death or dependency in two trials (RR 0.69; 95% CI 0.55 to 0.86) and increased the rate of neurological improvement after treatment based on data from 20 trials (2117 patients) (RR 1.56; 95% CI 1.44 to 1.70) as compared with control, while the risks of non-fatal intracranial haemorrhage or death were not significantly different between those treated with human urinary kallidinogenase or controls.97

Administration of dl-3n-butylphthalidehas has been indicated to increase the number of perfused microvessels, enhance cerebral blood flow, and reduce the incidence and infarct size in rat stroke models.98 99 A systematic review and meta-analysis published in 2010 reported more significant neurological improvement in patients treated with dl-3n-butylphthalide than controls (21 studies of 2123 patients), while there was no report on the rates of death of dependency in these studies.100 A recent RCT of 170 patients reported that dl-3n-butylphthalide plus standard medical treatment had a mild effect in enhancing neurological recovery in patients with acute ischaemic stroke as compared with standard medical treatment alone, which was correlated with a significantly higher level of circulating endothelial progenitor cells that may promote angiogenesis and neovascularisation in those treated with dl-3n-butylphthalide.101 Another RCT compared the efficacies of 14-day infusion of dl-3n-butylphthalide followed by a dl-3n-butylphthalide capsule, 14-day infusion of dl-3n-butylphthalide followed by aspirin, or a 14-day infusion of ozagrel followed by aspirin, among 573 patients with acute ischaemic stroke treated starting within 48 hours of onset. The study found a significant better functional outcome at 90 days in patients treated with dl-3n-butylphthalide for 90 days than those treated with ozagrel (p<0.001).102 However, there are doubts in the study findings, since none of the treatment assignments in this study were standard medical treatment in clinical practice.

Overall, although urinary kallidinogenase and dl-3n-butylphthalide have shown promising effects in promoting collateral circulation, increasing cerebral blood flow and improving the functional outcome after ischaemic stroke in animal models and in preliminary clinical studies, flawed study design of previous relevant studies urges further investigation on the effects and pharmaceutical mechanisms of the two novel medications in patients with stroke.

Drug-induced hypertension

Results of animal studies hinted that drug-induced mild hypertension could increase cerebral blood flow and cerebral oxygen metabolism in the infarct core and penumbra, which might lead to a smaller infarct size.103 By far, data are limited regarding the safety and efficacy of induced hypertension therapy in patients with ischaemic stroke. A couple of small studies showed a possible favourable effect of induced hypertension (using phenylephrine to increase the systolic blood pressure to a target of 160–200 mm Hg or increase the mean blood pressure by 10%–20%) over early neurological improvement in patients with acute ischaemic stroke with large artery occlusion or significant perfusion–diffusion mismatch.104 Findings of a currently ongoing multicentre, randomised, open-label trial, the Therapeutic INduced HYPERTENSION in acute non-cardioembolic ischaemic stroke (SETIN-HYPERTENSION; ClinicalTrials.gov identifier: NCT01600235) trial, may yield valuable data for this topic.

Hypervolaemic treatment

Preclinical studies and pilot clinical studies showed possible neuroprotective effect of hypervolaemic treatment using albumin in acute ischaemic stroke, which improved cerebral perfusion in regions with critically reduced cerebral blood flow that might lead to a better functional outcome.105 However, early initiation of albumin treatment has been shown to have no additional clinical benefit versus isotonic saline in adult patients with ischaemic stroke with a baseline NIHSS score of 6 or higher who were treated within 5 hours of symptoms onset, in a multicentre, double-blinded RCT, the Albumin in Acute Ischemic Stroke Trial (ALIAS) trial. The ALIAS trial was stopped early at 841 patients since no difference was identified in the albumin and saline treatment groups in the primary outcome (mRS 0–1 or NIHSS scores 0–1 at 90 days; 44% vs 44%; RR 0.96; 95% CI 0.84 to 1.10), while there were more events of pulmonary oedema or congestive heart failure within 48 hours (13% vs 1%; RR 10.8; 95% CI 4.37 to 26.72) and symptomatic intracranial haemorrhage within 24 hours (4% vs 2%; RR 2.42; 95% CI 1.02 to 5.78) in those treated with albumin than isotonic saline.106