was safe and well-received by the patients. In the inter-
vention group, vigorous physical activity initially
increased more than in the control group; however, the
difference was not sustained over time. Regarding the pri-
mary outcome, no significant difference in cardiorespira-
tory fitness was found between the groups after the
treatment or in 12-month follow-up. Secondary outcomes
improved in a similar way in both study groups. A possi-
ble interpretation of the findings is that adherence to phys-
ical activity programmes post-stroke is poor in the long
term. Both groups – even the control group – might have
enhanced their physical activity or increased their aware-
ness of the importance of physical activity, which could
explain the improved outcomes of both study groups. The
study was discussed to be limited by the small sample
size, and possibly insufficient intensity of exercise or a
bias in selection of patients.

*Dietary interventions.* A substudy of the VITATOPS trial reported data on a subgroup of patients with recent lacunar stroke and cognitive impairment but no dementia.²¹⁷ The trial was a randomised, double-blind, placebo-controlled trial of a daily administration of B-vitamins (2 mg folic acid, 25 mg vitamin B6 and 0.5 mg vitamin B12) versus placebo (baseline *n* = 118 + 112). The outcome of the study was defined as the change in cognitive test scores over 5 years. Overall, the trial failed to demonstrate any significant effect of the vitamin B complex on cognitive outcomes. The results do not support a routine administration of vitamin B to reduce cognitive decline in patients with lacunar stroke and cognitive impairment no dementia.

*Other lifestyle interventions.* The literature search found no RCTs on the effect of other lifestyle interventions such as smoking cessation, weight reduction, cognitive/behavioural or social interventions or sleep disorder/sleep apnoea interventions in reducing adverse outcomes in patients with lacunar stroke.

Additional information

Given the small number of trials providing direct evidence
for the effectiveness of lifestyle interventions in preventing
adverse clinical outcomes in patients with lacunar stroke,
we also reviewed indirect evidence from relevant observa-
tional studies and RCTs with related patient groups.

A secondary analysis of the SPS3 trial assessed the asso-
ciation of smoking status on major cardiovascular outcomes
in patients with MRI-confirmed symptomatic lacunar
stroke.²¹⁸ The patients were classified as never smokers,
prior smokers, current smokers who quit within 3 months of
the index event, and persistent smokers. Persistent smokers
had an increased risk of composite outcome of death, stroke
and myocardial infarction, compared with never smokers.
Notably, there was no difference between never smokers,
former smokers and those who quit smoking suggesting that

smoking cessation after stroke may have beneficial effects
in reducing the risk of death and cardiovascular events.

The Impact of physical activity in vascular cognitive impairment (AFIVASC) study is an ongoing trial including community dwellers with either probable mild vascular cognitive impairment (VCI) or previous stroke (>6 months before) or TIA (>1 month before), who have no dementia or significant functional impairment.²¹⁹ Patients are randomised to usual care or a structured physical activity intervention (three sessions a week). The primary outcome is decline in cognitive status, whereas secondary outcomes include changes in cognitive measures, quality of life, functional and motor status as well as radiological markers of SVD progression on brain MRI. The trial has not planned subgroup analyses for patients with lacunar strokes. The first cross-sectional observational data (prior to randomisation) have suggested that objective measurement (accelerometry) is more realiable indicator of physical activity as compared to self-reports, and that physical exercise as performed at least according to WHO recommendations is significantly associated with higher global cognition, attention and processing speed.²²⁰

Excessive salt intake is as an important risk factor for cardiovascular disease and stroke. It has been estimated that even a modest reduction in salt consumption (by 1 g/day) would result in a considerable decrease in adverse outcomes.²²¹ In patients with minor stroke (lacunar or cortical), dietary salt intake has been cross-sectionally associated with lacunar stroke type as well as more severe WMH and other SVD brain changes.²²²,²²³ Both animal and human studies have demonstrated several adverse effects of high salt intake on small and large arteries beyond increased blood pressure, including impaired endothelial function and increased arterial stiffness.²²⁴ Besides the effects of high Na⁺ on cerebral vascular dysfunction via excess inflammation²²⁵ and oxidative stress,²²⁶ there is also evidence of sensitisation of central sympathetic circuits by central Na⁺ sensing, which occurs in the circumventricular organs leading to excessive sympathetic outflow.²²⁷ In addition, this augmented sympathetic vascular transduction can be enhanced with an increase of potent circulating vasoconstrictors, such as endothelin-1 and arginine vasopressin, associated with dietary salt.²²⁴

In recent years, increasing interest has focused on multi-
domain interventions to target several life-style factors
simultaneously in the attempt of preventing cognitive
impairment and dementia (reviewed in²²⁸). The FINGER
study was among the first trials to demonstrate beneficial
effects of a 2-year multidomain intervention (diet, physical
exercise, cognitive training and vascular risk monitoring)
on cognitive functions in older individuals with existing
dementia-related risk factors.²²⁹ The intervention was effec-
tive in reducing incident cerebrovascular events and also
total cardiovascular events (coronary event, stroke, TIA)
among those with a history of cardiovascular disease.²³⁰ As
the aetiology of dementia is multifactorial and the
was safe and well-received by the patients. In the inter-
vention group, vigorous physical activity initially
increased more than in the control group; however, the
difference was not sustained over time. Regarding the pri-
mary outcome, no significant difference in cardiorespira-
tory fitness was found between the groups after the
treatment or in 12-month follow-up. Secondary outcomes
improved in a similar way in both study groups. A possi-
ble interpretation of the findings is that adherence to phys-
ical activity programmes post-stroke is poor in the long
term. Both groups – even the control group – might have
enhanced their physical activity or increased their aware-
ness of the importance of physical activity, which could
explain the improved outcomes of both study groups. The
study was discussed to be limited by the small sample
size, and possibly insufficient intensity of exercise or a
bias in selection of patients.

*Dietary interventions.* A substudy of the VITATOPS trial reported data on a subgroup of patients with recent lacunar stroke and cognitive impairment but no dementia.²¹⁷ The trial was a randomised, double-blind, placebo-controlled trial of a daily administration of B-vitamins (2 mg folic acid, 25 mg vitamin B6 and 0.5 mg vitamin B12) versus placebo (baseline *n* = 118 + 112). The outcome of the study was defined as the change in cognitive test scores over 5 years. Overall, the trial failed to demonstrate any significant effect of the vitamin B complex on cognitive outcomes. The results do not support a routine administration of vitamin B to reduce cognitive decline in patients with lacunar stroke and cognitive impairment no dementia.

*Other lifestyle interventions.* The literature search found no RCTs on the effect of other lifestyle interventions such as smoking cessation, weight reduction, cognitive/behavioural or social interventions or sleep disorder/sleep apnoea interventions in reducing adverse outcomes in patients with lacunar stroke.

Additional information

Given the small number of trials providing direct evidence
for the effectiveness of lifestyle interventions in preventing
adverse clinical outcomes in patients with lacunar stroke,
we also reviewed indirect evidence from relevant observa-
tional studies and RCTs with related patient groups.

A secondary analysis of the SPS3 trial assessed the asso-
ciation of smoking status on major cardiovascular outcomes
in patients with MRI-confirmed symptomatic lacunar
stroke.²¹⁸ The patients were classified as never smokers,
prior smokers, current smokers who quit within 3 months of
the index event, and persistent smokers. Persistent smokers
had an increased risk of composite outcome of death, stroke
and myocardial infarction, compared with never smokers.
Notably, there was no difference between never smokers,
former smokers and those who quit smoking suggesting that

smoking cessation after stroke may have beneficial effects
in reducing the risk of death and cardiovascular events.

The Impact of physical activity in vascular cognitive impairment (AFIVASC) study is an ongoing trial including community dwellers with either probable mild vascular cognitive impairment (VCI) or previous stroke (>6 months before) or TIA (>1 month before), who have no dementia or significant functional impairment.²¹⁹ Patients are randomised to usual care or a structured physical activity intervention (three sessions a week). The primary outcome is decline in cognitive status, whereas secondary outcomes include changes in cognitive measures, quality of life, functional and motor status as well as radiological markers of SVD progression on brain MRI. The trial has not planned subgroup analyses for patients with lacunar strokes. The first cross-sectional observational data (prior to randomisation) have suggested that objective measurement (accelerometry) is more realiable indicator of physical activity as compared to self-reports, and that physical exercise as performed at least according to WHO recommendations is significantly associated with higher global cognition, attention and processing speed.²²⁰

Excessive salt intake is as an important risk factor for cardiovascular disease and stroke. It has been estimated that even a modest reduction in salt consumption (by 1 g/day) would result in a considerable decrease in adverse outcomes.²²¹ In patients with minor stroke (lacunar or cortical), dietary salt intake has been cross-sectionally associated with lacunar stroke type as well as more severe WMH and other SVD brain changes.²²²,²²³ Both animal and human studies have demonstrated several adverse effects of high salt intake on small and large arteries beyond increased blood pressure, including impaired endothelial function and increased arterial stiffness.²²⁴ Besides the effects of high Na⁺ on cerebral vascular dysfunction via excess inflammation²²⁵ and oxidative stress,²²⁶ there is also evidence of sensitisation of central sympathetic circuits by central Na⁺ sensing, which occurs in the circumventricular organs leading to excessive sympathetic outflow.²²⁷ In addition, this augmented sympathetic vascular transduction can be enhanced with an increase of potent circulating vasoconstrictors, such as endothelin-1 and arginine vasopressin, associated with dietary salt.²²⁴

In recent years, increasing interest has focused on multi-
domain interventions to target several life-style factors
simultaneously in the attempt of preventing cognitive
impairment and dementia (reviewed in²²⁸). The FINGER
study was among the first trials to demonstrate beneficial
effects of a 2-year multidomain intervention (diet, physical
exercise, cognitive training and vascular risk monitoring)
on cognitive functions in older individuals with existing
dementia-related risk factors.²²⁹ The intervention was effec-
tive in reducing incident cerebrovascular events and also
total cardiovascular events (coronary event, stroke, TIA)
among those with a history of cardiovascular disease.²³⁰ As
the aetiology of dementia is multifactorial and the
risk factor profiles differ between individuals, preventive interventions are likely enhanced by personalised multidomain approaches and could be facilitated by digital health solutions.²²⁸

In regard to secondary stroke prevention, most current guidelines and recommendations address lifestyle modifications but not in the light of specific stroke subtypes (Table 1).

The AHA/ASA 2021 Guideline for the Prevention of Stroke in Patients With Stroke and Transient Ischaemic Attack identifies medication adherence and a healthy lifestyle as key components of secondary stroke prevention, with the highest class of recommendation for smoking cessation (Class 1; Level of Evidence A, B-nonrandomised) and substance use (Class 1; Levels of Evidence B-nonrandomised, C-expert opinion), followed by physical activity (Class 1–2b; Levels of Evidence C-limited data, B-randomised, C-expert opinion, B-nonrandomised) and nutrition (Class 2a; Level of Evidence B-randomised).²¹ AHA/ASA published 2014 a scientific statement on Physical Activity and Exercise Recommendations for Stroke Survivors, recognising that physical inactivity after stroke is highly prevalent and listing evidence supporting the use of exercise training, both aerobic and strength training, for stroke survivors that need to be customised for the individual to maximise long-term adherence.²¹³

Canadian Stroke Best Practice Recommendations: Secondary Prevention of Stroke Update 2020 gives recommendations on preferable lifestyle behaviours for reducing the risk of an initial stroke and the risk of a subsequent stroke for patients with a prior history of stroke, which include a healthy balanced diet, low sodium intake, physical activity, weight management, moderate alcohol consumption, avoiding recreational drug use, smoking cessation including the use of e-cigarettes as well as controlling emerging risk factors such as air pollution.²⁴

Chinese Stroke Association guidelines for clinical management of cerebrovascular disorders from 2020 comprise a section on Cerebral small vessel disease management, which did not address lifestyle modifications.²⁸

Australian and New Zealand Clinical Guidelines for Stroke Management published in 2021 emphasised that lifestyle modifications require multimodal interventions, including education, a counselling approach and supervised/active exercise, commenced early after hospital discharge through organised processes and considering the patient's living circumstances.²⁷

Recommendations of the Spanish Society of Neurology for the prevention of stroke. Interventions on lifestyle and air pollution specifically addressed lifestyle modification. They provided recommendations on common factors such as smoking, alcohol, obesity, diet and nutrition and sedentary lifestyle, as well as stress and air pollution, without addressing stroke subtypes.²¹⁵

Recently, World Stroke Organization (WSO) Guideline committee reviewed the available guidelines to summarise the existing recommendations of stroke management

globally. Areas of strong agreement across guidelines were identified. For secondary prevention, lifestyle modifications were recommended (with referral to specialised services where necessary) including weight loss, regular physical exercise, smoking cessation, moderate alcohol intake, avoiding recreational drug use and reduction of salt intake.²³¹ According to WSO and the Global Burden of Disease research group, behavioural factors such as smoking, poor diet and low physical activity account for 47% of stroke burden, which highlights the importance of promoting stroke awareness and developing novel risk prevention strategies.²³²

We also reviewed the recommendations and guidelines that referred to lifestyle modifications in the prevention of post-stroke VCI.

Regarding the effect of lifestyle-based interventions (exercise, dietary change, alcohol moderation, weight loss, smoking cessation) on post-stroke cognitive impairment, ESO-EAN joint guidelines did not make recommendations due to the very low quality of evidence. The Guidelines' Expert Consensus Statement emphasised that lifestyle interventions, alone or in combination, should not be used solely for the prevention of post-stroke cognitive decline or dementia and recognised a need for further, adequately powered trials that assess the effect of monitored lifestyle interventions on cognitive decline following stroke. Stroke subtypes were not explicitly addressed.¹⁵

Recommendations of the fifth Canadian Consensus Conference on the diagnosis and treatment of dementia (CCCDTD5) from 2020 and 2022 recommended physical activity but not other lifestyle interventions to reduce the risk of dementia, including Alzheimer's and vascular dementia.²³³,²³⁴ The section of the guidelines dedicated to VCI, Canadian Consensus Conference on Diagnosis and Treatment of Dementia (CCCDTD5): Guidelines for management of vascular cognitive impairment from 2020 focused on medical management and did not address lifestyle modifications.²³⁵

Clinical practice guideline for cognitive impairment of cerebral small vessel disease by the Geriatric Neurology Group of the Chinese Society of Geriatrics in 2019 recognised the beneficial effects of physical exercise on pathological processes involved in cognitive impairment and concluded that it could reduce the risk of vascular dementia.²³⁶

The 2011 AHA/ASA Statement on Vascular Contributions to Cognitive Impairment and Dementia summarised previously published systematic literature reviews, guidelines, personal files and expert opinions and addressed in detail lifestyle modifications to prevent VCI. They recommended that in people at risk for VCI, smoking cessation is reasonable (Class IIa; Level of Evidence A), the moderation of alcohol intake, weight control and physical activity (for all: Class IIb; Level of Evidence B) may be reasonable lifestyle interventions, and that the use of antioxidants and B vitamins is not beneficial (Class III; Level of Evidence A).²³⁷ Stroke subtypes associated with cognitive impairment were not addressed specifically.
risk factor profiles differ between individuals, preventive interventions are likely enhanced by personalised multidomain approaches and could be facilitated by digital health solutions.²²⁸

In regard to secondary stroke prevention, most current guidelines and recommendations address lifestyle modifications but not in the light of specific stroke subtypes (Table 1).

The AHA/ASA 2021 Guideline for the Prevention of Stroke in Patients With Stroke and Transient Ischaemic Attack identifies medication adherence and a healthy lifestyle as key components of secondary stroke prevention, with the highest class of recommendation for smoking cessation (Class 1; Level of Evidence A, B-nonrandomised) and substance use (Class 1; Levels of Evidence B-nonrandomised, C-expert opinion), followed by physical activity (Class 1–2b; Levels of Evidence C-limited data, B-randomised, C-expert opinion, B-nonrandomised) and nutrition (Class 2a; Level of Evidence B-randomised).²¹ AHA/ASA published 2014 a scientific statement on Physical Activity and Exercise Recommendations for Stroke Survivors, recognising that physical inactivity after stroke is highly prevalent and listing evidence supporting the use of exercise training, both aerobic and strength training, for stroke survivors that need to be customised for the individual to maximise long-term adherence.²¹³

Canadian Stroke Best Practice Recommendations: Secondary Prevention of Stroke Update 2020 gives recommendations on preferable lifestyle behaviours for reducing the risk of an initial stroke and the risk of a subsequent stroke for patients with a prior history of stroke, which include a healthy balanced diet, low sodium intake, physical activity, weight management, moderate alcohol consumption, avoiding recreational drug use, smoking cessation including the use of e-cigarettes as well as controlling emerging risk factors such as air pollution.²⁴

Chinese Stroke Association guidelines for clinical management of cerebrovascular disorders from 2020 comprise a section on Cerebral small vessel disease management, which did not address lifestyle modifications.²⁸

Australian and New Zealand Clinical Guidelines for Stroke Management published in 2021 emphasised that lifestyle modifications require multimodal interventions, including education, a counselling approach and supervised/active exercise, commenced early after hospital discharge through organised processes and considering the patient's living circumstances.²⁷

Recommendations of the Spanish Society of Neurology for the prevention of stroke. Interventions on lifestyle and air pollution specifically addressed lifestyle modification. They provided recommendations on common factors such as smoking, alcohol, obesity, diet and nutrition and sedentary lifestyle, as well as stress and air pollution, without addressing stroke subtypes.²¹⁵

Recently, World Stroke Organization (WSO) Guideline committee reviewed the available guidelines to summarise the existing recommendations of stroke management

globally. Areas of strong agreement across guidelines were identified. For secondary prevention, lifestyle modifications were recommended (with referral to specialised services where necessary) including weight loss, regular physical exercise, smoking cessation, moderate alcohol intake, avoiding recreational drug use and reduction of salt intake.²³¹ According to WSO and the Global Burden of Disease research group, behavioural factors such as smoking, poor diet and low physical activity account for 47% of stroke burden, which highlights the importance of promoting stroke awareness and developing novel risk prevention strategies.²³²

We also reviewed the recommendations and guidelines that referred to lifestyle modifications in the prevention of post-stroke VCI.

Regarding the effect of lifestyle-based interventions (exercise, dietary change, alcohol moderation, weight loss, smoking cessation) on post-stroke cognitive impairment, ESO-EAN joint guidelines did not make recommendations due to the very low quality of evidence. The Guidelines' Expert Consensus Statement emphasised that lifestyle interventions, alone or in combination, should not be used solely for the prevention of post-stroke cognitive decline or dementia and recognised a need for further, adequately powered trials that assess the effect of monitored lifestyle interventions on cognitive decline following stroke. Stroke subtypes were not explicitly addressed.¹⁵

Recommendations of the fifth Canadian Consensus Conference on the diagnosis and treatment of dementia (CCCDTD5) from 2020 and 2022 recommended physical activity but not other lifestyle interventions to reduce the risk of dementia, including Alzheimer's and vascular dementia.²³³,²³⁴ The section of the guidelines dedicated to VCI, Canadian Consensus Conference on Diagnosis and Treatment of Dementia (CCCDTD5): Guidelines for management of vascular cognitive impairment from 2020 focused on medical management and did not address lifestyle modifications.²³⁵

Clinical practice guideline for cognitive impairment of cerebral small vessel disease by the Geriatric Neurology Group of the Chinese Society of Geriatrics in 2019 recognised the beneficial effects of physical exercise on pathological processes involved in cognitive impairment and concluded that it could reduce the risk of vascular dementia.²³⁶

The 2011 AHA/ASA Statement on Vascular Contributions to Cognitive Impairment and Dementia summarised previously published systematic literature reviews, guidelines, personal files and expert opinions and addressed in detail lifestyle modifications to prevent VCI. They recommended that in people at risk for VCI, smoking cessation is reasonable (Class IIa; Level of Evidence A), the moderation of alcohol intake, weight control and physical activity (for all: Class IIb; Level of Evidence B) may be reasonable lifestyle interventions, and that the use of antioxidants and B vitamins is not beneficial (Class III; Level of Evidence A).²³⁷ Stroke subtypes associated with cognitive impairment were not addressed specifically.
**Evidence-based Recommendation**

In patients with lacunar stroke, there is continued uncertainty to indicate that any specific lifestyle interventions prevent adverse clinical outcomes.

Quality of evidence: Very low ⊕

Strength of recommendation: -

**Expert Consensus Statement**

Despite lack of direct evidence, twelve of 12 MWG members suggest that it is advisable to promote healthy lifestyle modifications in patients with lacunar stroke as recommended in secondary prevention for stroke and VCI. These include regular physical exercise, maintaining healthy body weight, avoiding smoking and excess alcohol and eating a healthy balanced diet with low sodium intake.

**PICO 10:**

In patients with lacunar ischaemic stroke, do other treatments as secondary prevention, such as phosphodiesterase-3 inhibitors (e.g. cilostazol, pentoxifylline), anti-inflammatory agents (e.g. minocycline), anticoagulants, nitric oxide donors (e.g. transdermal glyceryl trinitrate), phosphodiesterase-5 inhibitors (sildenafil, tadalafil, dipyridamole), or other relevant agents not addressed in the other PICOs, compared to less intense or avoiding this intervention, reduce any recurrent stroke, recurrent ischaemic stroke, dependency, death, cognitive impairment or dementia, haemorrhagic stroke, MACE, mobility or gait disorder, and mood disorders?

**Analysis of current evidence**

The systematic literature searches for PICO 5 and 10 were performed together. The search identified 248 titles/abstracts. Of these, 46 articles were selected for full-text review, and 7 of these were selected for data extraction.46,127,130,131 Three additional articles were identified by the searches in other PICO questions,133–135 After reference screening of reviews, we added another 2 RCTs.131,136 This delivered 12 RCTs, of which 5 were assigned to PICO 10 (Supplemental Table 17, Supplement PRISMA diagrams).

For PICO 10, we found 5 studies on cilostazol and 1 study on isosorbide mononitrate.

**Cilostazol.** Cilostazol, a phosphodiesterase-3 inhibitor, not only inhibits platelet aggregation but also has vasodilating, endothelial protecting and anti-inflammatory effects, making it a promising agent in small vessel disease management. It is commonly used for peripheral vascular disease and in Asia-Pacific countries also for secondary stroke prevention.

The CSPS (2000) and CSPS-2 (2010) randomised-controlled trials both included a large proportion of lacunar stroke patients.129,130,161,162 Patients were randomised to

receive cilostazol 200 mg/daily versus placebo (CSPS) or versus aspirin (CSPS-2). Both trials are covered in PICO 6 on antiplatelet treatment.

CSPS.com (2019) studied cilostazol on top of modern recommended antiplatelet therapy, and is therefore covered in this PICO. CSPS.com was a non-blinded RCT comparing dual therapy with cilostazol plus either aspirin or clopidogrel, with monotherapy aspirin or clopidogrel in high-risk ischaemic stroke patients.162 Clopidogrel was used in 55% of patients and aspirin in 45%. The trial stopped before reaching half of the planned sample size at 1879 patients (49% lacunar stroke subtype) because of slow recruitment. Median follow-up time was 1.4 year. In lacunar stroke subtype,131 the ischaemic stroke recurrence risk was significantly lower in the dual therapy group (HR 0.41, 95% CI 0.21, 0.81), without increasing the risk of severe or life-threatening bleeding (0.36, 95% CI 0.07, 1.81). Furthermore, composite vascular events was significantly lower in the dual therapy group (HR 0.41, 95% CI 0.23, 0.75), whereas the risk of haemorrhagic stroke and death from any cause did not differ significantly between the two groups (HR 0.47, 95% CI 0.08, 2.64; and HR 3.20, 95% CI 0.33, 30.8). To be noted, discontinuation of trial medication in the cilostazol group was three times as frequently as in the control group.

These CSPS studies are from Asia-Pacific countries where epidemiology and risk factors may differ from Western/European populations, and were not primarily focused on lacunar stroke subtype. Reflecting the Asian origin of these trials, cilostazol is included in Asian stroke guidelines: the Japan Stroke Society Guideline (2021) gives a high level of evidence for the effectiveness of cilostazol for prevention in non-cardioembolic stroke, and also recommends to give dual antiplatelet therapy with cilostazol and aspirin in non-cardio-embolic stroke with multiple vascular risk factors.30 The guideline of the Chinese stroke association (2019) recommends the use of aspirin, clopidogrel, or cilostazol in ischaemic stroke caused by small vessel disease.28 According to the AHA guideline (2021), the role of cilostazol in secondary prevention after stroke related to small vessel disease is uncertain.21 The ESO guideline on secondary prevention (2022) does not give a recommendation on cilostazol.16

LACI-1 was a European phase IIa, dose-tolerability, open-label trial, randomising 57 patients with lacunar stroke to ISMN 50 mg/daily, cilostazol 200 mg/daily, both ISMN and cilostazol started immediately, or both with delayed start, all in addition to clopidogrel or aspirin prescribed as standard care.134 The trial confirmed tolerability and safety after a short-term treatment of 8 weeks. The (secondary) clinical outcomes can only be considered preliminary. The trial reported one recurrent ischaemic stroke in the ‘both drugs immediate’ group. There were no deaths or major haemorrhages. Cognition, tested with Trail making test A and B, was not different in cilostazol versus no cilostazol.
**Evidence-based Recommendation**

In patients with lacunar stroke, there is continued uncertainty to indicate that any specific lifestyle interventions prevent adverse clinical outcomes.

Quality of evidence: Very low ⊕

Strength of recommendation: -

**Expert Consensus Statement**

Despite lack of direct evidence, twelve of 12 MWG members suggest that it is advisable to promote healthy lifestyle modifications in patients with lacunar stroke as recommended in secondary prevention for stroke and VCI. These include regular physical exercise, maintaining healthy body weight, avoiding smoking and excess alcohol and eating a healthy balanced diet with low sodium intake.

**PICO 10:**

In patients with lacunar ischaemic stroke, do other treatments as secondary prevention, such as phosphodiesterase-3 inhibitors (e.g. cilostazol, pentoxifylline), anti-inflammatory agents (e.g. minocycline), anticoagulants, nitric oxide donors (e.g. transdermal glyceryl trinitrate), phosphodiesterase-5 inhibitors (sildenafil, tadalafil, dipyridamole), or other relevant agents not addressed in the other PICOs, compared to less intense or avoiding this intervention, reduce any recurrent stroke, recurrent ischaemic stroke, dependency, death, cognitive impairment or dementia, haemorrhagic stroke, MACE, mobility or gait disorder, and mood disorders?

**Analysis of current evidence**

The systematic literature searches for PICO 5 and 10 were performed together. The search identified 248 titles/abstracts. Of these, 46 articles were selected for full-text review, and 7 of these were selected for data extraction.46,127,130,131 Three additional articles were identified by the searches in other PICO questions,133–135 After reference screening of reviews, we added another 2 RCTs.131,136 This delivered 12 RCTs, of which 5 were assigned to PICO 10 (Supplemental Table 17, Supplement PRISMA diagrams).

For PICO 10, we found 5 studies on cilostazol and 1 study on isosorbide mononitrate.

**Cilostazol.** Cilostazol, a phosphodiesterase-3 inhibitor, not only inhibits platelet aggregation but also has vasodilating, endothelial protecting and anti-inflammatory effects, making it a promising agent in small vessel disease management. It is commonly used for peripheral vascular disease and in Asia-Pacific countries also for secondary stroke prevention.

The CSPS (2000) and CSPS-2 (2010) randomised-controlled trials both included a large proportion of lacunar stroke patients.129,130,161,162 Patients were randomised to

receive cilostazol 200 mg/daily versus placebo (CSPS) or versus aspirin (CSPS-2). Both trials are covered in PICO 6 on antiplatelet treatment.

CSPS.com (2019) studied cilostazol on top of modern recommended antiplatelet therapy, and is therefore covered in this PICO. CSPS.com was a non-blinded RCT comparing dual therapy with cilostazol plus either aspirin or clopidogrel, with monotherapy aspirin or clopidogrel in high-risk ischaemic stroke patients.162 Clopidogrel was used in 55% of patients and aspirin in 45%. The trial stopped before reaching half of the planned sample size at 1879 patients (49% lacunar stroke subtype) because of slow recruitment. Median follow-up time was 1.4 year. In lacunar stroke subtype,131 the ischaemic stroke recurrence risk was significantly lower in the dual therapy group (HR 0.41, 95% CI 0.21, 0.81), without increasing the risk of severe or life-threatening bleeding (0.36, 95% CI 0.07, 1.81). Furthermore, composite vascular events was significantly lower in the dual therapy group (HR 0.41, 95% CI 0.23, 0.75), whereas the risk of haemorrhagic stroke and death from any cause did not differ significantly between the two groups (HR 0.47, 95% CI 0.08, 2.64; and HR 3.20, 95% CI 0.33, 30.8). To be noted, discontinuation of trial medication in the cilostazol group was three times as frequently as in the control group.

These CSPS studies are from Asia-Pacific countries where epidemiology and risk factors may differ from Western/European populations, and were not primarily focused on lacunar stroke subtype. Reflecting the Asian origin of these trials, cilostazol is included in Asian stroke guidelines: the Japan Stroke Society Guideline (2021) gives a high level of evidence for the effectiveness of cilostazol for prevention in non-cardioembolic stroke, and also recommends to give dual antiplatelet therapy with cilostazol and aspirin in non-cardio-embolic stroke with multiple vascular risk factors.30 The guideline of the Chinese stroke association (2019) recommends the use of aspirin, clopidogrel, or cilostazol in ischaemic stroke caused by small vessel disease.28 According to the AHA guideline (2021), the role of cilostazol in secondary prevention after stroke related to small vessel disease is uncertain.21 The ESO guideline on secondary prevention (2022) does not give a recommendation on cilostazol.16

LACI-1 was a European phase IIa, dose-tolerability, open-label trial, randomising 57 patients with lacunar stroke to ISMN 50 mg/daily, cilostazol 200 mg/daily, both ISMN and cilostazol started immediately, or both with delayed start, all in addition to clopidogrel or aspirin prescribed as standard care.134 The trial confirmed tolerability and safety after a short-term treatment of 8 weeks. The (secondary) clinical outcomes can only be considered preliminary. The trial reported one recurrent ischaemic stroke in the ‘both drugs immediate’ group. There were no deaths or major haemorrhages. Cognition, tested with Trail making test A and B, was not different in cilostazol versus no cilostazol.
The subsequent LACI-2 trial was a 2 × 2 factorial design, open label, phase II trial. It included 363 patients with lacunar stroke and aimed to determine if cilostazol and ISMN are tolerated at the target dose for a year.⁴⁶ The study drugs were given on top of regular secondary prevention. Although the trial was not powered for efficacy, several clinical outcomes were reported: cilostazol did not reduce the composite outcome of recurrent stroke, TIA, myocardial infarction, dependence, any cognitive impairment, and death, nor did it reduce recurrent stroke or TIA. Cilostazol reduced dependency (mRS score of 3–6: 11.5% with cilostazol vs 17.5% without; aOR 0.46, 95% CI 0.22, 0.95). Cilostazol did not reduce cognitive impairment but tended to improve mood. The trial confirmed tolerability and safety and supports the feasibility of a large phase III trial.

For additional information on Cilostazol, please see
PICO 6 section above.

Isosorbide mononitrate (ISMN). ISMN is an NO donor. NO has multiple potential beneficial effects such as improvement of blood-brain barrier integrity, vasodilation, reduced inflammation and neuroprotection.

The previously mentioned LACI-1 trial studied the tolerability and safety of an 8-week course of ISMN 50mg/ daily (and cilostazol in a 2×2 factorial design) in 57 patients with lacunar stroke.¹²⁷ There was one recurrent ischaemic stroke in the study group that received both ISMN and cilostazol. There were no deaths or major haemorrhages. Cognition was tested with Trail making test A and B. Although time did not differ, the group on ISMN achieved more points on TMT part A (MD 2.6, 95% CI 0.1, 5.1, *p*=0.05). The subsequent similarly designed LACI-2 trial included 363 patients with lacunar stroke and aimed to determine if the trial design was feasible and if ISMN and cilostazol were safe and tolerated at the target dose for a year.⁴⁶ The trial reported clinical outcomes although it was not powered for efficacy. ISMN appeared well tolerated and safe, and in addition, ISMN reduced recurrent stroke or TIA (adjusted OR 0.23, 95% CI 0.07, 0.74). The absolute reduction in participants with any cognitive impairment was 10.4% (54.4% with ISMN and 64.8% without ISMN), and on a 7-level ordinal scale cognitive impairment was reduced aOR 0.55, 95% CI 0.36, 0.86).

The combination of ISMN and cilostazol versus none of these in LACI-2 showed reduced dependency (mRS 3–6: aOR 0.27, 95% CI 0.09, 0.82) but no effect on recurrent stroke. Combination ISMN-cilostazol reduced cognitive impairment (7-level ordinal scale aOR 0.44, 95% CI 0.23, 0.85) and reduced low mood (Zung depression scale: adjusted mean difference −5.98, 95% CI −10.77, −1.20, *p*=0.01).

Additional information

**Anticoagulation.** We did not find any studies on anticoagulation as secondary prevention specifically in patients with

lacunar stroke without atrial fibrillation (AF). However, there are some studies that can provide indirect evidence as they included a substantial proportion of lacunar stroke subtype. These trials, such as WARSS (56% lacunar stroke)²³⁸ and ESPRIT (48% small vessel stroke)²³⁹ found no evidence that warfarin is more efficacious than anti-platelet therapy in non-cardioembolic stroke patients. Moreover, in the SPIRIT trial, warfarin was associated with increased risk of intracerebral haemorrhage, particularly in patients with leukoaraiosis.²⁴⁰

We also did not find results on anticoagulation as secondary prevention in lacunar stroke subtype with AF. A lacunar stroke in a patient with AF most probably results from small vessel disease but it is challenging to rule out an embolic aetiology in clinical practice. In general, anticoagulant therapy is strongly superior to anti-platelet therapy for the prevention of recurrent stroke in ischaemic stroke patients with AF.²⁴¹,²⁴² Existing guidelines for anticoagulation in AF do not distinguish between different stroke subtypes.¹⁴ However, a 2-year observational study in 288 stroke patients (26% lacunar subtype) with AF who were receiving anticoagulation therapy showed that the stroke recurrence rate was almost twice as high in patients with lacunar stroke subtype compared to those with cardioembolic subtype despite being on anticoagulation (8.5% vs 4.6%, *p*=0.067), and the majority of recurrent events were of the lacunar subtype.²⁴³ Furthermore, anticoagulation in patients with lacunar stroke is not without risk, as most intracerebral haemorrhages in older people result from small vessel disease. A lacunar ischaemic stroke increases the risk of both future ischaemic stroke and ICH and this may change the risk-benefit ratio of anticoagulation, especially when extensive covert lesions are present, such as microbleeds and leukoaraiosis. In general, Guidelines on prevention of recurrent stroke in patients with AF recommend DOACs over vitamin K antagonists.¹⁴ However, the ESO guideline on secondary prevention in patients with AF¹⁴ did not find any data on DOAC versus vitamin K antagonists in lacunar stroke, nor in patients with any previous stroke or TIA subtype and severe SVD, and concluded that ‘theoretically, DOACs might be preferable to vitamin K antagonists in patients with severe SVD, but there are no current data to support this hypothesis’.¹⁴ Therefore the Method Working Group agreed that patients with lacunar ischaemic stroke and AF should receive anticoagulant treatment as advised in current Guidelines on anticoagulation in patients with AF.¹⁴

**Ongoing trials.** Several trials in lacunar stroke patients are ongoing but few have clinical endpoints. The use of PDE-5 inhibitors might be of interest in small vessel disease by their effect on cerebral blood flow and endothelial function. A small trial including 20 lacunar stroke cases showed that a single dose of tadalafil increased
The subsequent LACI-2 trial was a 2 × 2 factorial design, open label, phase II trial. It included 363 patients with lacunar stroke and aimed to determine if cilostazol and ISMN are tolerated at the target dose for a year.⁴⁶ The study drugs were given on top of regular secondary prevention. Although the trial was not powered for efficacy, several clinical outcomes were reported: cilostazol did not reduce the composite outcome of recurrent stroke, TIA, myocardial infarction, dependence, any cognitive impairment, and death, nor did it reduce recurrent stroke or TIA. Cilostazol reduced dependency (mRS score of 3–6: 11.5% with cilostazol vs 17.5% without; aOR 0.46, 95% CI 0.22, 0.95). Cilostazol did not reduce cognitive impairment but tended to improve mood. The trial confirmed tolerability and safety and supports the feasibility of a large phase III trial.

For additional information on Cilostazol, please see
PICO 6 section above.

*Isosorbide mononitrate (ISMN).* ISMN is an NO donor. NO has multiple potential beneficial effects such as improvement of blood-brain barrier integrity, vasodilation, reduced inflammation and neuroprotection.

The previously mentioned LACI-1 trial studied the tolerability and safety of an 8-week course of ISMN 50mg/ daily (and cilostazol in a 2×2 factorial design) in 57 patients with lacunar stroke.¹²⁷ There was one recurrent ischaemic stroke in the study group that received both ISMN and cilostazol. There were no deaths or major haemorrhages. Cognition was tested with Trail making test A and B. Although time did not differ, the group on ISMN achieved more points on TMT part A (MD 2.6, 95% CI 0.1, 5.1, *p*=0.05). The subsequent similarly designed LACI-2 trial included 363 patients with lacunar stroke and aimed to determine if the trial design was feasible and if ISMN and cilostazol were safe and tolerated at the target dose for a year.⁴⁶ The trial reported clinical outcomes although it was not powered for efficacy. ISMN appeared well tolerated and safe, and in addition, ISMN reduced recurrent stroke or TIA (adjusted OR 0.23, 95% CI 0.07, 0.74). The absolute reduction in participants with any cognitive impairment was 10.4% (54.4% with ISMN and 64.8% without ISMN), and on a 7-level ordinal scale cognitive impairment was reduced aOR 0.55, 95% CI 0.36, 0.86).

The combination of ISMN and cilostazol versus none of these in LACI-2 showed reduced dependency (mRS 3–6: aOR 0.27, 95% CI 0.09, 0.82) but no effect on recurrent stroke. Combination ISMN-cilostazol reduced cognitive impairment (7-level ordinal scale aOR 0.44, 95% CI 0.23, 0.85) and reduced low mood (Zung depression scale: adjusted mean difference −5.98, 95% CI −10.77, −1.20, *p*=0.01).

Additional information

**Anticoagulation.** We did not find any studies on anticoagulation as secondary prevention specifically in patients with

lacunar stroke without atrial fibrillation (AF). However, there are some studies that can provide indirect evidence as they included a substantial proportion of lacunar stroke subtype. These trials, such as WARSS (56% lacunar stroke)²³⁸ and ESPRIT (48% small vessel stroke)²³⁹ found no evidence that warfarin is more efficacious than anti-platelet therapy in non-cardioembolic stroke patients. Moreover, in the SPIRIT trial, warfarin was associated with increased risk of intracerebral haemorrhage, particularly in patients with leukoaraiosis.²⁴⁰

We also did not find results on anticoagulation as secondary prevention in lacunar stroke subtype with AF. A lacunar stroke in a patient with AF most probably results from small vessel disease but it is challenging to rule out an embolic aetiology in clinical practice. In general, anticoagulant therapy is strongly superior to anti-platelet therapy for the prevention of recurrent stroke in ischaemic stroke patients with AF.²⁴¹,²⁴² Existing guidelines for anticoagulation in AF do not distinguish between different stroke subtypes.¹⁴ However, a 2-year observational study in 288 stroke patients (26% lacunar subtype) with AF who were receiving anticoagulation therapy showed that the stroke recurrence rate was almost twice as high in patients with lacunar stroke subtype compared to those with cardioembolic subtype despite being on anticoagulation (8.5% vs 4.6%, *p*=0.067), and the majority of recurrent events were of the lacunar subtype.²⁴³ Furthermore, anticoagulation in patients with lacunar stroke is not without risk, as most intracerebral haemorrhages in older people result from small vessel disease. A lacunar ischaemic stroke increases the risk of both future ischaemic stroke and ICH and this may change the risk-benefit ratio of anticoagulation, especially when extensive covert lesions are present, such as microbleeds and leukoaraiosis. In general, Guidelines on prevention of recurrent stroke in patients with AF recommend DOACs over vitamin K antagonists.¹⁴ However, the ESO guideline on secondary prevention in patients with AF¹⁴ did not find any data on DOAC versus vitamin K antagonists in lacunar stroke, nor in patients with any previous stroke or TIA subtype and severe SVD, and concluded that ‘theoretically, DOACs might be preferable to vitamin K antagonists in patients with severe SVD, but there are no current data to support this hypothesis’.¹⁴ Therefore the Method Working Group agreed that patients with lacunar ischaemic stroke and AF should receive anticoagulant treatment as advised in current Guidelines on anticoagulation in patients with AF.¹⁴

**Ongoing trials.** Several trials in lacunar stroke patients are ongoing but few have clinical endpoints. The use of PDE-5 inhibitors might be of interest in small vessel disease by their effect on cerebral blood flow and endothelial function. A small trial including 20 lacunar stroke cases showed that a single dose of tadalafil increased
blood oxygen saturation in the microvasculature at 180 min post-administration, indicating improved perfusion in the cerebral microvasculature.²⁴⁴ A larger RCT (NCT05173896) is now investigating if 3 months daily intake of tadalafil is feasible in lacunar stroke patients and if it alters cerebral perfusion, neurovascular reactivity, and cognition. Sildenafil is investigated in the OxHARP study, however, the primary outcome is cerebrovascular pulsatility and reactivity and the study will not have any relevant clinical outcome measures.²⁴⁵

The effect of minocycline, an antibiotic with anti-inflammatory properties, on microglial activation and blood-brain permeability in patients with lacunar stroke is investigated in the MINERVA trial.²⁴⁶ However there will be no clinical outcomes.

**Evidence-based Recommendation**

There is continued uncertainty on the use of any other agents, such as phosphodiesterase-3 inhibitors, anti-inflammatory agents, anticoagulants, nitric oxide donors, phosphodiesterase-5 inhibitors or otherwise not mentioned in PICO 6–8, for secondary prevention in patients with lacunar ischaemic stroke, to reduce recurrent ischaemic stroke, death, cognitive impairment or dementia, haemorrhagic stroke, MACE, mobility or gait disorder, and mood disorders.

Quality of evidence: Low ⊕⊕

Strength of recommendation: -

**Expert Consensus Statement 1**

In patients with lacunar ischaemic stroke without AF, twelve of 12 MWG members recommend against the use of anticoagulation for secondary prevention, if there is no other indication.

**Expert Consensus Statement 2**

In patients with lacunar ischaemic stroke and AF, twelve of 12 MWG members recommend the use of anticoagulation for secondary prevention. The evidence for efficacy of anticoagulants over antiplatelet is strong in patients with AF, overruling stroke subtype. However, since the risk of ICH is increased in patients with lacunar stroke and severe SVD, we recommend strict risk factors control.

## Discussion

This guideline document was developed following the GRADE methodology and aims to assist physicians in decision-making regarding suspected lacunar ischaemic stroke. All recommendations and Expert Consensus Statements are summarised in Table 8.

We noted that a considerable proportion of articles were not found by the literature search and that a substantial number of additional articles were detected through other methods such as checking reference lists. This indicates that detection of relevant trials may be especially difficult for lacunar ischaemic stroke.

We considered acute treatment and secondary prevention in lacunar ischaemic stroke. We tried to reflect diagnoses, timings and practical clinical aspects of the knowledge base that will inform the management of patients with suspected lacunar ischaemic stroke. Disappointingly, there is a dearth of data on cognitive and mood outcomes despite cognitive impairment being the commonest problem after lacunar stroke and a main concern to patients. Since most data were from subgroups of trials that included all stroke or all ischaemic stroke, the most commonly available outcomes were dependency (which is less common in lacunar stroke than in other ischaemic stroke subtypes) and recurrent stroke (which in general is less common early after lacunar stroke than with large artery or cardioembolic stroke).⁴

The strengths of this work include the use of the GRADE approach as mandated by ESO. The guideline builds on the Guideline for covert SVD published in 2021.¹ We have endeavoured to amass all relevant data. While we hope we have not missed any major trials we acknowledge that it is difficult to search for trials in lacunar ischaemic stroke. We contacted authors for additional data, and wherever feasible we undertook several new meta-analyses, including a network meta-analysis on antiplatelet drugs in secondary prevention.

We also acknowledge limitations. Limitations of the data reflect the dearth of any data on many of the outcomes of interest and many interventions of interest in lacunar ischaemic stroke. There were essentially no data on cognition despite cognitive impairment being common and a main concern of patients with lacunar ischaemic stroke. Most data came from a lacunar subgroup of a larger trial, which may be limited by definition, chance, small sample and often only reporting one outcome in the subgroups. Very few trials focused on lacunar ischaemic stroke. Although many trials must have included patients with lacunar ischaemic stroke, many did not distinguish lacunar from other subtypes at all, or if they did, then often did not report any results for the lacunar subgroup, or only reported a few outcomes for the lacunar stroke patients separately. Lack of long-term follow-up in many secondary prevention trials mean that effects of interventions in lacunar stroke may not have become fully apparent, since recurrent stroke, dependency, or death typically occur late after lacunar ischaemic stroke, compared with other stroke subtypes. Finally, time constraints meant that we were not able to obtain stakeholder feedback on the guideline prior to publication, but we welcome feedback from people affected by lacunar ischaemic stroke and other forms of cSVD to help inform future guidelines, research and practice.

The Guideline is part of a series of Guidelines on the clinical management of cerebral small vessel disease: Part 1, covert cSVD, Part 2, lacunar ischaemic stroke, other Parts under consideration include 3, other stroke subtypes with a high cSVD burden, 4, cognitive, 5, mobility, and 6, mood presentations of cSVD. The Guideline Parts published so far will be updated within 5 years of publication or sooner if important new information becomes available.
blood oxygen saturation in the microvasculature at 180 min post-administration, indicating improved perfusion in the cerebral microvasculature.²⁴⁴ A larger RCT (NCT05173896) is now investigating if 3 months daily intake of tadalafil is feasible in lacunar stroke patients and if it alters cerebral perfusion, neurovascular reactivity, and cognition. Sildenafil is investigated in the OxHARP study, however, the primary outcome is cerebrovascular pulsatility and reactivity and the study will not have any relevant clinical outcome measures.²⁴⁵

The effect of minocycline, an antibiotic with anti-inflammatory properties, on microglial activation and blood-brain permeability in patients with lacunar stroke is investigated in the MINERVA trial.²⁴⁶ However there will be no clinical outcomes.

**Evidence-based Recommendation**

There is continued uncertainty on the use of any other agents, such as phosphodiesterase-3 inhibitors, anti-inflammatory agents, anticoagulants, nitric oxide donors, phosphodiesterase-5 inhibitors or otherwise not mentioned in PICO 6–8, for secondary prevention in patients with lacunar ischaemic stroke, to reduce recurrent ischaemic stroke, death, cognitive impairment or dementia, haemorrhagic stroke, MACE, mobility or gait disorder, and mood disorders.

Quality of evidence: Low ⊕⊕

Strength of recommendation: -

**Expert Consensus Statement 1**

In patients with lacunar ischaemic stroke without AF, twelve of 12 MWG members recommend against the use of anticoagulation for secondary prevention, if there is no other indication.

**Expert Consensus Statement 2**

In patients with lacunar ischaemic stroke and AF, twelve of 12 MWG members recommend the use of anticoagulation for secondary prevention. The evidence for efficacy of anticoagulants over antiplatelet is strong in patients with AF, overruling stroke subtype. However, since the risk of ICH is increased in patients with lacunar stroke and severe SVD, we recommend strict risk factors control.

Discussion

This guideline document was developed following the GRADE methodology and aims to assist physicians in decision-making regarding suspected lacunar ischaemic stroke. All recommendations and Expert Consensus Statements are summarised in Table 8.

We noted that a considerable proportion of articles were not found by the literature search and that a substantial number of additional articles were detected through other methods such as checking reference lists. This indicates that detection of relevant trials may be especially difficult for lacunar ischaemic stroke.

We considered acute treatment and secondary prevention in lacunar ischaemic stroke. We tried to reflect diagnoses, timings and practical clinical aspects of the knowledge base that will inform the management of patients with suspected lacunar ischaemic stroke. Disappointingly, there is a dearth of data on cognitive and mood outcomes despite cognitive impairment being the commonest problem after lacunar stroke and a main concern to patients. Since most data were from subgroups of trials that included all stroke or all ischaemic stroke, the most commonly available outcomes were dependency (which is less common in lacunar stroke than in other ischaemic stroke subtypes) and recurrent stroke (which in general is less common early after lacunar stroke than with large artery or cardioembolic stroke).⁴

The strengths of this work include the use of the GRADE approach as mandated by ESO. The guideline builds on the Guideline for covert SVD published in 2021.¹ We have endeavoured to amass all relevant data. While we hope we have not missed any major trials we acknowledge that it is difficult to search for trials in lacunar ischaemic stroke. We contacted authors for additional data, and wherever feasible we undertook several new meta-analyses, including a network meta-analysis on antiplatelet drugs in secondary prevention.

We also acknowledge limitations. Limitations of the data reflect the dearth of any data on many of the outcomes of interest and many interventions of interest in lacunar ischaemic stroke. There were essentially no data on cognition despite cognitive impairment being common and a main concern of patients with lacunar ischaemic stroke. Most data came from a lacunar subgroup of a larger trial, which may be limited by definition, chance, small sample and often only reporting one outcome in the subgroups. Very few trials focused on lacunar ischaemic stroke. Although many trials must have included patients with lacunar ischaemic stroke, many did not distinguish lacunar from other subtypes at all, or if they did, then often did not report any results for the lacunar subgroup, or only reported a few outcomes for the lacunar stroke patients separately. Lack of long-term follow-up in many secondary prevention trials mean that effects of interventions in lacunar stroke may not have become fully apparent, since recurrent stroke, dependency, or death typically occur late after lacunar ischaemic stroke, compared with other stroke subtypes. Finally, time constraints meant that we were not able to obtain stakeholder feedback on the guideline prior to publication, but we welcome feedback from people affected by lacunar ischaemic stroke and other forms of cSVD to help inform future guidelines, research and practice.

The Guideline is part of a series of Guidelines on the clinical management of cerebral small vessel disease: Part 1, covert cSVD, Part 2, lacunar ischaemic stroke, other Parts under consideration include 3, other stroke subtypes with a high cSVD burden, 4, cognitive, 5, mobility, and 6, mood presentations of cSVD. The Guideline Parts published so far will be updated within 5 years of publication or sooner if important new information becomes available.
<table><caption>**Table 8.** Synoptic table of all Evidence Based Recommendations and Expert Consensus Statements.</caption><thead><tr><th>Evidence Based Recommendation</th><th>Expert consensus statement</th></tr></thead><tbody><tr><td><strong>PICO 1:</strong> In patients with suspected lacunar ischaemic stroke, does thrombolytic treatment (including at extended time window and wake-up stroke, alteplase/tenecteplase/other), compared to avoiding this intervention/other thrombolytic/dose/etc, reduce recurrent ischaemic stroke, dependency, death, cognitive impairment or dementia, haemorrhagic stroke, MACE, mobility or gait disorder, and mood disorders?<br>We suggest that patients with suspected acute lacunar ischaemic stroke should be assessed for and receive treatment with 0.9 mg/kg alteplase according to current guidelines for the treatment of acute ischaemic stroke, since the limited data available suggest that the outcomes for patients with lacunar ischaemic stroke are consistent with the overall results of alteplase trials.<br>Quality of evidence: Very Low ⊕<br>Strength of recommendation: Weak for intervention ↑?</td><td><ol><li>Twelve of twelve MWG members agreed that in patients with suspected acute lacunar ischaemic stroke, with no contraindication to thrombolytic treatment according to current clinical guidelines for thrombolytic treatment (including wake up stroke), there is no evidence for withholding thrombolytic treatment. Therefore these patients should receive intravenous alteplase at standard dose (0.9 mg/kg) as quickly as possible according to current clinical guidelines.</li><li>Twelve of 12 MWG members agreed that in patients with suspected acute lacunar ischaemic stroke there are insufficient data to support use of thrombolytic drugs other than alteplase, or a lower dose of alteplase, at the present time.</li></ol><strong>PICO 2:</strong> In patients with suspected acute lacunar ischaemic stroke, does acute treatment with antiplatelets (considering single/dual, duration, and whether any particular antiplatelet or combination of antiplatelets is better), compared to avoiding/less of/alternative antiplatelet intervention, reduce recurrent ischaemic stroke, dependency, death, cognitive impairment or dementia, haemorrhagic stroke, MACE, mobility or gait disorder, and mood disorders?<br>In patients suspected acute lacunar ischaemic stroke, there is continued uncertainty about a specific combination of antiplatelet therapy over monotherapy.<br>Quality of evidence: Very low ⊕<br>Strength of recommendation: -</td></tr><tr><td><strong>PICO 3:</strong> In patients with suspected acute lacunar ischaemic stroke, does immediate antihypertensive treatment (considering agent and BP target), compared to avoiding this intervention, reduce recurrent ischaemic stroke, dependency, death, cognitive impairment or dementia, haemorrhagic stroke, MACE, mobility or gait disorder, and mood disorders?<ol><li>In hospitalised patients with suspected acute lacunar ischaemic stroke and BP &lt;220/110 mmHg, not treated with intravenous thrombolysis, we suggest against the routine use of blood pressure BP lowering agents in the hyperacute phase, unless this is necessary for a specific comorbid condition.<br>Quality of evidence: Moderate ⊕⊕⊕<br>Strength of recommendation: Weak against intervention ↓?</li><li>In patients with suspected acute lacunar ischaemic stroke undergoing intravenous thrombolysis we suggest following the same guideline as in acute ischaemic stroke at large, that is, maintaining BP below 185/110 mmHg before bolus and below 180/105 mmHg after bolus, and for 24 hours after alteplase infusion.<br>Quality of evidence: Very Low ⊕<br>Strength of recommendation: Weak for intervention ↑?</li><li>In patients with suspected acute lacunar ischaemic stroke there is continued uncertainty over the benefits and risks of temporarily stopping versus continuing previous BP lowering therapy.<br>Quality of evidence: Very Low ⊕<br>Strength of recommendation: -</li></ol></td><td><ol><li>Twelve of twelve MWG members agreed that there is insufficient evidence at present to provide a precise timeframe during which BP lowering agents should be avoided in patients with suspected acute lacunar ischaemic stroke. Based on current limited evidence, blood pressure lowering therapy should be avoided for at least 24 hours after symptom onset.</li><li>When antihypertensive drugs need to be used in patients with suspected acute lacunar ischaemic stroke undergoing intravenous thrombolysis and with BP &gt;180/105 mmHg, twelve of 12 MWG members agreed that there is no advantage/disadvantage of one antihypertensive medication over another, hence any antihypertensive drug may be used, as long as blood pressure is closely monitored.</li><li>Eleven of twelve MWG members agreed that in patients with suspected acute lacunar ischaemic stroke not treated with intravenous thrombolysis and blood pressure &gt;220/120 mmHg, careful blood pressure reduction (&lt;15% systolic blood reduction in 24 hours) is reasonable. No specific blood pressure lowering agent can be recommended.</li></ol></td></tr></tbody></table>

(Continued)
<table><caption>**Table 8.** Synoptic table of all Evidence Based Recommendations and Expert Consensus Statements.</caption><thead><tr><th>Evidence Based Recommendation</th><th>Expert consensus statement</th></tr></thead><tbody><tr><td><strong>PICO 1:</strong> In patients with suspected lacunar ischaemic stroke, does thrombolytic treatment (including at extended time window and wake-up stroke, alteplase/tenecteplase/other), compared to avoiding this intervention/other thrombolytic/dose/etc, reduce recurrent ischaemic stroke, dependency, death, cognitive impairment or dementia, haemorrhagic stroke, MACE, mobility or gait disorder, and mood disorders?<br>We suggest that patients with suspected acute lacunar ischaemic stroke should be assessed for and receive treatment with 0.9 mg/kg alteplase according to current guidelines for the treatment of acute ischaemic stroke, since the limited data available suggest that the outcomes for patients with lacunar ischaemic stroke are consistent with the overall results of alteplase trials.<br>Quality of evidence: Very Low ⊕<br>Strength of recommendation: Weak for intervention ↑?</td><td><ol><li>Twelve of twelve MWG members agreed that in patients with suspected acute lacunar ischaemic stroke, with no contraindication to thrombolytic treatment according to current clinical guidelines for thrombolytic treatment (including wake up stroke), there is no evidence for withholding thrombolytic treatment. Therefore these patients should receive intravenous alteplase at standard dose (0.9 mg/kg) as quickly as possible according to current clinical guidelines.</li><li>Twelve of 12 MWG members agreed that in patients with suspected acute lacunar ischaemic stroke there are insufficient data to support use of thrombolytic drugs other than alteplase, or a lower dose of alteplase, at the present time.</li></ol><strong>PICO 2:</strong> In patients with suspected acute lacunar ischaemic stroke, does acute treatment with antiplatelets (considering single/dual, duration, and whether any particular antiplatelet or combination of antiplatelets is better), compared to avoiding/less of/alternative antiplatelet intervention, reduce recurrent ischaemic stroke, dependency, death, cognitive impairment or dementia, haemorrhagic stroke, MACE, mobility or gait disorder, and mood disorders?<br>In patients suspected acute lacunar ischaemic stroke, there is continued uncertainty about a specific combination of antiplatelet therapy over monotherapy.<br>Quality of evidence: Very low ⊕<br>Strength of recommendation: -</td></tr><tr><td><strong>PICO 3:</strong> In patients with suspected acute lacunar ischaemic stroke, does immediate antihypertensive treatment (considering agent and BP target), compared to avoiding this intervention, reduce recurrent ischaemic stroke, dependency, death, cognitive impairment or dementia, haemorrhagic stroke, MACE, mobility or gait disorder, and mood disorders?<ol><li>In hospitalised patients with suspected acute lacunar ischaemic stroke and BP &lt;220/110 mmHg, not treated with intravenous thrombolysis, we suggest against the routine use of blood pressure BP lowering agents in the hyperacute phase, unless this is necessary for a specific comorbid condition.<br>Quality of evidence: Moderate ⊕⊕⊕<br>Strength of recommendation: Weak against intervention ↓?</li><li>In patients with suspected acute lacunar ischaemic stroke undergoing intravenous thrombolysis we suggest following the same guideline as in acute ischaemic stroke at large, that is, maintaining BP below 185/110 mmHg before bolus and below 180/105 mmHg after bolus, and for 24 hours after alteplase infusion.<br>Quality of evidence: Very Low ⊕<br>Strength of recommendation: Weak for intervention ↑?</li><li>In patients with suspected acute lacunar ischaemic stroke there is continued uncertainty over the benefits and risks of temporarily stopping versus continuing previous BP lowering therapy.<br>Quality of evidence: Very Low ⊕<br>Strength of recommendation: -</li></ol></td><td><ol><li>Twelve of twelve MWG members agreed that there is insufficient evidence at present to provide a precise timeframe during which BP lowering agents should be avoided in patients with suspected acute lacunar ischaemic stroke. Based on current limited evidence, blood pressure lowering therapy should be avoided for at least 24 hours after symptom onset.</li><li>When antihypertensive drugs need to be used in patients with suspected acute lacunar ischaemic stroke undergoing intravenous thrombolysis and with BP &gt;180/105 mmHg, twelve of 12 MWG members agreed that there is no advantage/disadvantage of one antihypertensive medication over another, hence any antihypertensive drug may be used, as long as blood pressure is closely monitored.</li><li>Eleven of twelve MWG members agreed that in patients with suspected acute lacunar ischaemic stroke not treated with intravenous thrombolysis and blood pressure &gt;220/120 mmHg, careful blood pressure reduction (&lt;15% systolic blood reduction in 24 hours) is reasonable. No specific blood pressure lowering agent can be recommended.</li></ol></td></tr></tbody></table>

(Continued)
<table><caption>**Table 8. (Continued)**</caption><thead><tr><th>Evidence Based Recommendation</th><th>Expert consensus statement</th></tr></thead><tbody><tr><td><strong>PICO 4:</strong> In patients with suspected acute lacunar ischaemic stroke and progressive symptoms, does acute treatment with antiplatelets/ anticoagulants/thrombolysis/other agent, compared to less intense or avoiding this intervention, reduce recurrent ischaemic stroke, dependency, death, cognitive impairment or dementia, haemorrhagic stroke, MACE, mobility or gait disorder, and mood disorders?<br> There is continued uncertainty regarding intervention with antiplatelets, anticoagulants, thrombolysis or other agents in patients with suspected lacunar ischaemic stroke and progressive symptoms, including early neurological deterioration, stuttering/fluctuating symptoms and capsular warning syndrome.<br> Quality of evidence: Very Low ⊕<br> Strength of recommendation: -</td><td><ol><li>Twelve of 12 MWG members agreed that in patients with suspected lacunar ischaemic stroke and progressive symptoms, there is no evidence to recommend any particular antiplatelet regimen (intensive or single), BP management regimen (raising or lowering), rt-PA, anticoagulation, statin, or other treatment.</li><li>Twelve of 12 MWG members agreed that in patients with suspected lacunar ischaemic stroke and progressive symptoms, they should be included in all trials in acute lacunar ischaemic stroke but identified as a specific subgroup with prespecified planned analysis of the treatment effect in this subgroup.</li><li>Twelve of 12 MWG members agreed that in patients with suspected lacunar ischaemic stroke and progressive symptoms, there is an urgent need to agree a consensus definition for progressive symptoms.</li></ol><strong>PICO 5:</strong> In patients with suspected acute lacunar ischaemic stroke, does acute treatment with other agents such as phosphodiesterase-3 inhibitors (e.g. cilostazol, pentoxifylline), anti-inflammatory agents (e.g. minocycline), anticoagulants, nitric oxide donors (e.g. transdermal glyceryl trinitrate), phosphodiesterase-5 inhibitors (sildenafil, tadalafil, dipyridamole), or other relevant agents not addressed in the other PICOs, compared to less intense or avoiding this intervention, reduce any recurrent stroke, recurrent ischaemic stroke, dependency, death, cognitive impairment or dementia, haemorrhagic stroke, MACE, mobility or gait disorder, and mood disorders?<br> 1. In patients with suspected acute lacunar ischaemic stroke, there is continued uncertainty over the benefits and risks of magnesium for acute treatment.<br> Quality of evidence: Low ⊕⊕<br> Strength of recommendation: -<br> 2. In patients with suspected acute lacunar ischaemic stroke, there is continued uncertainty over the benefits and risks of cilostazol for acute treatment.<br> Quality of evidence: Low ⊕⊕<br> Strength of recommendation: -<br> 3. In patients with acute lacunar ischaemic stroke, we suggest against the use of glyceryl trinitrate to reduce dependency.<br> Quality of evidence: Moderate ⊕⊕⊕<br> Strength of recommendation: Weak against intervention ↓?<br> 4. In patients with acute lacunar ischaemic stroke, we recommend against the use of therapeutic LMW heparin/heparinoid to reduce dependency.<br> Quality of evidence: Moderate ⊕⊕⊕<br> Strength of recommendation: Weak against intervention ↓?<br> 5. In patients with acute lacunar ischaemic stroke, there is continued uncertainty over the benefits and risks of Xueshuantong to reduce dependency.<br> Quality of evidence: Very low ⊕<br> Strength of recommendation: -<br> 6. In the absence of RCTs, we cannot make recommendations on the use of any other agents, such as phosphodiesterase-3 inhibitors, anti-inflammatory agents, anticoagulants, nitric oxide donors, phosphodiesterase-5 inhibitors or otherwise not mentioned in PICO 1-4, for acute treatment in patients with lacunar ischaemic stroke, to reduce any recurrent stroke, recurrent ischaemic stroke, dependency, death, cognitive impairment or dementia, haemorrhagic stroke, MACE, mobility or gait disorder, and mood disorders.<br> Quality of evidence: -<br> Strength of recommendation: -</td></tr></tbody></table>
<table><caption>**Table 8. (Continued)**</caption><thead><tr><th>Evidence Based Recommendation</th><th>Expert consensus statement</th></tr></thead><tbody><tr><td><strong>PICO 4:</strong> In patients with suspected acute lacunar ischaemic stroke and progressive symptoms, does acute treatment with antiplatelets/ anticoagulants/thrombolysis/other agent, compared to less intense or avoiding this intervention, reduce recurrent ischaemic stroke, dependency, death, cognitive impairment or dementia, haemorrhagic stroke, MACE, mobility or gait disorder, and mood disorders?<br> There is continued uncertainty regarding intervention with antiplatelets, anticoagulants, thrombolysis or other agents in patients with suspected lacunar ischaemic stroke and progressive symptoms, including early neurological deterioration, stuttering/fluctuating symptoms and capsular warning syndrome.<br> Quality of evidence: <strong>Very Low</strong> ⊕<br> Strength of recommendation: -</td><td><ol><li>Twelve of 12 MWG members agreed that in patients with suspected lacunar ischaemic stroke and progressive symptoms, there is no evidence to recommend any particular antiplatelet regimen (intensive or single), BP management regimen (raising or lowering), rt-PA, anticoagulation, statin, or other treatment.</li><li>Twelve of 12 MWG members agreed that in patients with suspected lacunar ischaemic stroke and progressive symptoms, they should be included in all trials in acute lacunar ischaemic stroke but identified as a specific subgroup with prespecified planned analysis of the treatment effect in this subgroup.</li><li>Twelve of 12 MWG members agreed that in patients with suspected lacunar ischaemic stroke and progressive symptoms, there is an urgent need to agree a consensus definition for progressive symptoms.</li></ol><strong>PICO 5:</strong> In patients with suspected acute lacunar ischaemic stroke, does acute treatment with other agents such as phosphodiesterase-3 inhibitors (e.g. cilostazol, pentoxifylline), anti-inflammatory agents (e.g. minocycline), anticoagulants, nitric oxide donors (e.g. transdermal glyceryl trinitrate), phosphodiesterase-5 inhibitors (sildenafil, tadalafil, dipyridamole), or other relevant agents not addressed in the other PICOs, compared to less intense or avoiding this intervention, reduce any recurrent stroke, recurrent ischaemic stroke, dependency, death, cognitive impairment or dementia, haemorrhagic stroke, MACE, mobility or gait disorder, and mood disorders?<br> 1. In patients with suspected acute lacunar ischaemic stroke, there is continued uncertainty over the benefits and risks of magnesium for acute treatment.<br> Quality of evidence: <strong>Low</strong> ⊕ ⊕<br> Strength of recommendation: -<br> 2. In patients with suspected acute lacunar ischaemic stroke, there is continued uncertainty over the benefits and risks of cilostazol for acute treatment.<br> Quality of evidence: <strong>Low</strong> ⊕ ⊕<br> Strength of recommendation: -<br> 3. In patients with acute lacunar ischaemic stroke, we suggest against the use of glyceryl trinitrate to reduce dependency.<br> Quality of evidence: <strong>Moderate</strong> ⊕ ⊕ ⊕<br> Strength of recommendation: <strong>Weak against intervention</strong> ↓?<br> 4. In patients with acute lacunar ischaemic stroke, we recommend against the use of therapeutic LMW heparin/heparinoid to reduce dependency.<br> Quality of evidence: <strong>Moderate</strong> ⊕ ⊕ ⊕<br> Strength of recommendation: <strong>Weak against intervention</strong> ↓?<br> 5. In patients with acute lacunar ischaemic stroke, there is continued uncertainty over the benefits and risks of Xueshuantong to reduce dependency.<br> Quality of evidence: <strong>Very low</strong> ⊕<br> Strength of recommendation: -<br> 6. In the absence of RCTs, we cannot make recommendations on the use of any other agents, such as phosphodiesterase-3 inhibitors, anti-inflammatory agents, anticoagulants, nitric oxide donors, phosphodiesterase-5 inhibitors or otherwise not mentioned in PICO 1-4, for acute treatment in patients with lacunar ischaemic stroke, to reduce any recurrent stroke, recurrent ischaemic stroke, dependency, death, cognitive impairment or dementia, haemorrhagic stroke, MACE, mobility or gait disorder, and mood disorders.<br> Quality of evidence: -<br> Strength of recommendation: -</td></tr></tbody></table>
<table><caption>**Table 8. (Continued)**</caption><thead><tr><th>Evidence Based Recommendation</th><th>Expert consensus statement</th></tr></thead><tbody><tr><td><strong>PICO 6:</strong> In patients with lacunar ischaemic stroke, does long term treatment with antiplatelets (single or dual, duration, and whether any particular antiplatelet or combination of antiplatelets is better), compared to avoiding/less of/alternative antiplatelet intervention, reduce recurrent ischaemic stroke, dependency, death, cognitive impairment or dementia, haemorrhagic stroke, MACE, mobility or gait disorder, and mood disorders?<br>In patients with suspected lacunar ischaemic stroke, for secondary prevention of long-term adverse outcomes, we recommend long term single antiplatelet therapy with aspirin or clopidogrel from 2-4 weeks after stroke onset.<br>Quality of evidence: Moderate ⊕⊕⊕<br>Strength of recommendation: Weak for intervention ↑?</td><td><ol><li>In patients with suspected lacunar ischaemic stroke twelve of 12 MWG members recommend against the use of long-term* dual or triple antiplatelet therapy. Instead, single antiplatelet therapy should be used as per the Evidence Based Recommendation, unless other conditions warrant a combination of these medications.</li><li>In patients with suspected lacunar ischaemic stroke, eleven of 12 MWG members agreed that the current evidence was inadequate to recommend routine use of cilostazol to prevent adverse long term outcomes.</li></ol><p>*Defined as more than 2-4 weeks</p></td></tr><tr><td><strong>PICO 7:</strong> In patients with lacunar ischaemic stroke, does antihypertensive treatment considering a particular agent or target, compared to less intense or avoiding this intervention given long term, reduce recurrent ischaemic stroke, dependency, death, cognitive impairment or dementia, haemorrhagic stroke, MACE, mobility or gait disorder, and mood disorders?<br>In patients with suspected lacunar ischaemic stroke we recommend the use of antihypertensive treatment to prevent recurrent stroke and MACE.<br>Quality of evidence: Low ⊕⊕<br>Strength of recommendation: Strong for intervention ↑↑</td><td><ol><li>Twelve of twelve MWG members suggest that: BP should be appropriately monitored and well controlled, when possible through use of out of office blood pressure measurements. We cannot advise any specific antihypertensive treatment.</li><li>Eleven of twelve MWG members agree that aiming for BP &lt;130/80 mmHg as generally recommended for patients with previous ischaemic stroke or TIA may be reasonable, but that drastic BP reductions and important BP variability should be avoided, probably targeting SBP between 125 and 130 mmHg and DBP between 70 and 80 mmHg.</li></ol></td></tr><tr><td><strong>PICO 8:</strong> In patients with lacunar ischaemic stroke, does treatment with lipid lowering agents (considering a particular agent, dose, target), compared to less intense or avoiding this intervention, reduce recurrent ischaemic stroke, dependency, death, cognitive impairment or dementia, haemorrhagic stroke, MACE, mobility or gait disorder, and mood disorders?<br>There is continued uncertainty regarding the effect of lipid lowering specific to lacunar stroke. However we recognise that lipid lowering is effective in reducing clinically adverse outcomes in patients with undifferentiated ischaemic stroke.<br>Quality of evidence: Low ⊕⊕<br>Strength of recommendation: -</td><td><ol><li>Twelve of 12 MWG members agreed that patients with lacunar ischaemic stroke should receive lipid lowering therapy given there is some evidence of benefit and no clear evidence of harm.</li></ol></td></tr><tr><td><strong>PICO 9:</strong> In patients with lacunar ischaemic stroke, does treatment with lifestyle interventions (e.g. smoking cessation, dietary interventions, weight reduction, physical exercise, cognitive/behavioural or social interventions, sleep/CPAP, or a mixture of these), compared to less intense or avoiding this intervention, reduce recurrent ischaemic stroke, dependency, death, cognitive impairment or dementia, haemorrhagic stroke, MACE, mobility or gait disorder, and mood disorders?<br>In patients with lacunar stroke, there is continued uncertainty to indicate that any specific lifestyle interventions prevent adverse clinical outcomes.<br>Quality of evidence: Very low ⊕<br>Strength of recommendation: -</td><td><ol><li>Despite lack of direct evidence, twelve of 12 MWG members suggest that it is advisable to promote healthy lifestyle modifications in patients with lacunar stroke as recommended in secondary prevention for stroke and VCI. These include regular physical exercise, maintaining healthy body weight, avoiding smoking and excess alcohol, and eating a healthy balanced diet with low sodium intake.</li></ol></td></tr></tbody></table>

(Continued)
<table><caption>**Table 8. (Continued)**</caption><thead><tr><th>Evidence Based Recommendation</th><th>Expert consensus statement</th></tr></thead><tbody><tr><td><strong>PICO 6:</strong> In patients with lacunar ischaemic stroke, does long term treatment with antiplatelets (single or dual, duration, and whether any particular antiplatelet or combination of antiplatelets is better), compared to avoiding/less of/alternative antiplatelet intervention, reduce recurrent ischaemic stroke, dependency, death, cognitive impairment or dementia, haemorrhagic stroke, MACE, mobility or gait disorder, and mood disorders?<br>In patients with suspected lacunar ischaemic stroke, for secondary prevention of long-term adverse outcomes, we recommend long term single antiplatelet therapy with aspirin or clopidogrel from 2-4 weeks after stroke onset.<br>Quality of evidence: Moderate ⊕⊕⊕<br>Strength of recommendation: Weak for intervention ↑?</td><td><ol><li>In patients with suspected lacunar ischaemic stroke twelve of 12 MWG members recommend against the use of long-term* dual or triple antiplatelet therapy. Instead, single antiplatelet therapy should be used as per the Evidence Based Recommendation, unless other conditions warrant a combination of these medications.</li><li>In patients with suspected lacunar ischaemic stroke, eleven of 12 MWG members agreed that the current evidence was inadequate to recommend routine use of cilostazol to prevent adverse long term outcomes.</li></ol><p>*Defined as more than 2-4 weeks</p></td></tr><tr><td><strong>PICO 7:</strong> In patients with lacunar ischaemic stroke, does antihypertensive treatment considering a particular agent or target, compared to less intense or avoiding this intervention given long term, reduce recurrent ischaemic stroke, dependency, death, cognitive impairment or dementia, haemorrhagic stroke, MACE, mobility or gait disorder, and mood disorders?<br>In patients with suspected lacunar ischaemic stroke we recommend the use of antihypertensive treatment to prevent recurrent stroke and MACE.<br>Quality of evidence: Low ⊕⊕<br>Strength of recommendation: Strong for intervention ↑↑</td><td><ol><li>Twelve of twelve MWG members suggest that: BP should be appropriately monitored and well controlled, when possible through use of out of office blood pressure measurements. We cannot advise any specific antihypertensive treatment.</li><li>Eleven of twelve MWG members agree that aiming for BP &lt;130/80 mmHg as generally recommended for patients with previous ischaemic stroke or TIA may be reasonable, but that drastic BP reductions and important BP variability should be avoided, probably targeting SBP between 125 and 130 mmHg and DBP between 70 and 80 mmHg.</li></ol></td></tr><tr><td><strong>PICO 8:</strong> In patients with lacunar ischaemic stroke, does treatment with lipid lowering agents (considering a particular agent, dose, target), compared to less intense or avoiding this intervention, reduce recurrent ischaemic stroke, dependency, death, cognitive impairment or dementia, haemorrhagic stroke, MACE, mobility or gait disorder, and mood disorders?<br>There is continued uncertainty regarding the effect of lipid lowering specific to lacunar stroke. However we recognise that lipid lowering is effective in reducing clinically adverse outcomes in patients with undifferentiated ischaemic stroke.<br>Quality of evidence: Low ⊕⊕<br>Strength of recommendation: -</td><td><ol><li>Twelve of 12 MWG members agreed that patients with lacunar ischaemic stroke should receive lipid lowering therapy given there is some evidence of benefit and no clear evidence of harm.</li></ol></td></tr><tr><td><strong>PICO 9:</strong> In patients with lacunar ischaemic stroke, does treatment with lifestyle interventions (e.g. smoking cessation, dietary interventions, weight reduction, physical exercise, cognitive/behavioural or social interventions, sleep/CPAP, or a mixture of these), compared to less intense or avoiding this intervention, reduce recurrent ischaemic stroke, dependency, death, cognitive impairment or dementia, haemorrhagic stroke, MACE, mobility or gait disorder, and mood disorders?<br>In patients with lacunar stroke, there is continued uncertainty to indicate that any specific lifestyle interventions prevent adverse clinical outcomes.<br>Quality of evidence: Very low ⊕<br>Strength of recommendation: -</td><td><ol><li>Despite lack of direct evidence, twelve of 12 MWG members suggest that it is advisable to promote healthy lifestyle modifications in patients with lacunar stroke as recommended in secondary prevention for stroke and VCI. These include regular physical exercise, maintaining healthy body weight, avoiding smoking and excess alcohol, and eating a healthy balanced diet with low sodium intake.</li></ol></td></tr></tbody></table>

(Continued)
<table><caption>**Table 8.** (Continued)</caption><thead><tr><th>Evidence Based Recommendation</th><th>Expert consensus statement</th></tr></thead><tbody><tr><td>PICO 10: In patients with lacunar ischaemic stroke, do other treatments as secondary prevention, such as phosphodiesterase-3 inhibitors (e.g. cilostazol, pentoxifylline), anti-inflammatory agents (e.g. minocycline), anticoagulants, nitric oxide donors (e.g. transdermal glyceryl trinitrate), phosphodiesterase-5 inhibitors (sildenafil, tadalafil, dipyridamole), or other relevant agents not addressed in the other PICOs, compared to less intense or avoiding this intervention, reduce any recurrent stroke, recurrent ischaemic stroke, dependency, death, cognitive impairment or dementia, haemorrhagic stroke, MACE, mobility or gait disorder, and mood disorders?</td><td></td></tr><tr><td>There is continued uncertainty on the use of any other agents, such as phosphodiesterase-3 inhibitors, anti-inflammatory agents, anticoagulants, nitric oxide donors, phosphodiesterase-5 inhibitors or otherwise not mentioned in PICO 6-8, for secondary prevention in patients with lacunar ischaemic stroke, to reduce recurrent ischaemic stroke, death, cognitive impairment or dementia, haemorrhagic stroke, MACE, mobility or gait disorder, and mood disorders.</td><td>1. In patients with lacunar ischaemic stroke without AF, twelve of 12 MWG members recommend against the use of anticoagulation for secondary prevention, if there is no other indication.</td></tr><tr><td>Quality of evidence: Low ⊕⊕<br>Strength of recommendation: -</td><td>2. In patients with lacunar ischaemic stroke and AF, twelve of 12 MWG members recommend the use of anticoagulation for secondary prevention. The evidence for efficacy of anticoagulants over antiplatelet is strong in patients with AF, overruling stroke subtype. However, since the risk of ICH is increased in patients with lacunar stroke and severe SVD, we recommend strict risk factors control.</td></tr></tbody></table>

## Implications for clinical practice

For acute interventions, specific data on lacunar ischaemic stroke were sparse for most interventions, and the quality of evidence low or very low, but in general, the findings are within the envelope of expected effects in other ischaemic stroke subtypes, are consistent with other ESO guidelines on these treatments in ischaemic stroke in general (Table 1) as follows, with caveats:

**Thrombolysis:** dependency (the main outcome measure used) is less frequent after lacunar ischaemic stroke and so is not a good measure of outcome. Thus, there is a trend in the direction of benefit with alteplase, but the available data do not show a conventionally significant effect despite our meta-analyses having nearly as much data as some individual pivotal trials such as the NINDS trial.

**Antiplatelet drugs:** No meta-analysis was possible, but considering the individual trials' data, consistent with other stroke subtypes, short-term dual (not triple) antiplatelet drugs in the acute phase may reduce recurrent stroke with little evidence of harm.

**Blood Pressure lowering:** here there were more data with consistent findings indicating that intensive BP lowering appeared harmful and should be avoided in acute lacunar ischaemic stroke unless there is another good reason to do so.

**Other agents and progressive lacunar stroke:** there were no data to suggest that any other agents were beneficial. The data for progressive stroke are very limited with very few trials, inconsistent definitions and outcomes. The current data on a range of potential agents are provided in text and supplement. Given that progressive stroke is common after lacunar stroke, this should be a major focus of future acute stroke treatment trials.

For secondary prevention, in general the data were also very limited, mostly reliant on subgroups, mostly of

moderate to very low quality, with few trials specifically in lacunar ischaemic stroke. However, for all interventions, the general findings were similar to those for ischaemic stroke in general:

**Antiplatelet drugs:** A comprehensive assessment of data on antiplatelet agents, mostly as subgroups of larger trials, identified benefit for reduction in recurrent stroke and MACE with a continuous single (not long-term dual or triple) antiplatelet drug with most evidence for aspirin or clopidogrel.

**Blood Pressure lowering:** Data on over 3000 patients in two trials specifically in lacunar ischaemic stroke which compared intensive with less intensive BP targets did not show conventional significance for preventing recurrent stroke, no effect on death, cognitive decline or dependency. Nonetheless, BP lowering is advised.

**Lipid lowering:** data were particularly sparse and limited to subgroup analyses of old trials and did not show conventional significance of benefit, but were consistent with statins' effects in any ischaemic stroke with no evidence of harm.

**Lifestyle interventions:** there was little direct evidence of any intervention in lacunar ischaemic stroke, although lifestyle interventions are common sense with little evidence of harm.

**Other interventions:** A number of mostly small trials did not identify definite benefit with any other agent, although there may be hints of benefits with some agents that may improve endothelial function, but larger trials are needed.

## Recommendations for future research

We suggest several actions that would help to improve the quantity and quality of evidence for interventions to guide
<table><caption>**Table 8.** (Continued)</caption><thead><tr><th>Evidence Based Recommendation</th><th>Expert consensus statement</th></tr></thead><tbody><tr><td>PICO 10: In patients with lacunar ischaemic stroke, do other treatments as secondary prevention, such as phosphodiesterase-3 inhibitors (e.g. cilostazol, pentoxifylline), anti-inflammatory agents (e.g. minocycline), anticoagulants, nitric oxide donors (e.g. transdermal glyceryl trinitrate), phosphodiesterase-5 inhibitors (sildenafil, tadalafil, dipyridamole), or other relevant agents not addressed in the other PICOs, compared to less intense or avoiding this intervention, reduce any recurrent stroke, recurrent ischaemic stroke, dependency, death, cognitive impairment or dementia, haemorrhagic stroke, MACE, mobility or gait disorder, and mood disorders?</td><td></td></tr><tr><td>There is continued uncertainty on the use of any other agents, such as phosphodiesterase-3 inhibitors, anti-inflammatory agents, anticoagulants, nitric oxide donors, phosphodiesterase-5 inhibitors or otherwise not mentioned in PICO 6-8, for secondary prevention in patients with lacunar ischaemic stroke, to reduce recurrent ischaemic stroke, death, cognitive impairment or dementia, haemorrhagic stroke, MACE, mobility or gait disorder, and mood disorders.</td><td>1. In patients with lacunar ischaemic stroke without AF, twelve of 12 MWG members recommend against the use of anticoagulation for secondary prevention, if there is no other indication.</td></tr><tr><td>Quality of evidence: Low ⊕⊕<br>Strength of recommendation: -</td><td>2. In patients with lacunar ischaemic stroke and AF, twelve of 12 MWG members recommend the use of anticoagulation for secondary prevention. The evidence for efficacy of anticoagulants over antiplatelet is strong in patients with AF, overruling stroke subtype. However, since the risk of ICH is increased in patients with lacunar stroke and severe SVD, we recommend strict risk factors control.</td></tr></tbody></table>

## Implications for clinical practice

For acute interventions, specific data on lacunar ischaemic stroke were sparse for most interventions, and the quality of evidence low or very low, but in general, the findings are within the envelope of expected effects in other ischaemic stroke subtypes, are consistent with other ESO guidelines on these treatments in ischaemic stroke in general (Table 1) as follows, with caveats:

**Thrombolysis:** dependency (the main outcome measure used) is less frequent after lacunar ischaemic stroke and so is not a good measure of outcome. Thus, there is a trend in the direction of benefit with alteplase, but the available data do not show a conventionally significant effect despite our meta-analyses having nearly as much data as some individual pivotal trials such as the NINDS trial.

**Antiplatelet drugs:** No meta-analysis was possible, but considering the individual trials' data, consistent with other stroke subtypes, short-term dual (not triple) antiplatelet drugs in the acute phase may reduce recurrent stroke with little evidence of harm.

**Blood Pressure lowering:** here there were more data with consistent findings indicating that intensive BP lowering appeared harmful and should be avoided in acute lacunar ischaemic stroke unless there is another good reason to do so.

**Other agents and progressive lacunar stroke:** there were no data to suggest that any other agents were beneficial. The data for progressive stroke are very limited with very few trials, inconsistent definitions and outcomes. The current data on a range of potential agents are provided in text and supplement. Given that progressive stroke is common after lacunar stroke, this should be a major focus of future acute stroke treatment trials.

For secondary prevention, in general the data were also very limited, mostly reliant on subgroups, mostly of

moderate to very low quality, with few trials specifically in lacunar ischaemic stroke. However, for all interventions, the general findings were similar to those for ischaemic stroke in general:

**Antiplatelet drugs:** A comprehensive assessment of data on antiplatelet agents, mostly as subgroups of larger trials, identified benefit for reduction in recurrent stroke and MACE with a continuous single (not long-term dual or triple) antiplatelet drug with most evidence for aspirin or clopidogrel.

**Blood Pressure lowering:** Data on over 3000 patients in two trials specifically in lacunar ischaemic stroke which compared intensive with less intensive BP targets did not show conventional significance for preventing recurrent stroke, no effect on death, cognitive decline or dependency. Nonetheless, BP lowering is advised.

**Lipid lowering:** data were particularly sparse and limited to subgroup analyses of old trials and did not show conventional significance of benefit, but were consistent with statins' effects in any ischaemic stroke with no evidence of harm.

**Lifestyle interventions:** there was little direct evidence of any intervention in lacunar ischaemic stroke, although lifestyle interventions are common sense with little evidence of harm.

**Other interventions:** A number of mostly small trials did not identify definite benefit with any other agent, although there may be hints of benefits with some agents that may improve endothelial function, but larger trials are needed.

## Recommendations for future research

We suggest several actions that would help to improve the quantity and quality of evidence for interventions to guide
management in patients with lacunar ischaemic stroke, in future.

First, trials in stroke that plan to include also patients with lacunar ischaemic stroke, should subtype lacunar and other stroke subtypes at baseline so that the lacunar strokes can be identified in future analyses. The subtyping should use currently used definitions such as the Oxfordshire Community Stroke Project (OCSP)² definition based on symptoms and signs, or the TOAST classification (although caution is required to avoid bias due to presumed causation)¹³³ and if possible, even more detailed information and nomenclature as proposed by Standards for Reporting Vascular Changes on Neuroimaging-2 (STRIVE-2) collaboration.³³ Possibly, in view of differences in outcome rates between lacunar versus non-lacunar strokes, the stroke subtype should even be included in any minimisation algorithm to ensure that treatment allocation is well balanced for baseline characteristics including stroke subtype. These trials that include patients with lacunar stroke should present as many results as possibly by stroke subtype, albeit in secondary analyses. Nonetheless, if previous trials had provided data on outcomes in lacunar stroke by treatment allocation more systematically this would, by now, have resulted in a much stronger evidence base for many basic routine stroke interventions than is currently the case.

Second, there is an urgent need for more trials dedicated to lacunar stroke, in order to improve the current clinical management. Amongst the conventional routine acute stroke treatments or secondary preventions, few showed much slight benefit (acute short term antiplatelets, long-term antiplatelets); several showed no definite benefit, with confidence intervals overlapping no effect, but ‘taken on trust’, the direction of effect is in the right direction (thrombolysis, acute phase DAPT, long-term BP lowering, long-term statins, lifestyle); and one showed harm (acute BP lowering). These findings are consistent with the data in the covert cSVD Guideline, although in the case of antiplatelet drugs in covert cSVD there was evidence of harm. Of the ‘other’ interventions and in progressive lacunar stroke, there were mostly small inconclusive trials. Furthermore, the outcomes provided in the conventional stroke interventions focused on early stroke recurrence or dependency, with little to no data on cognitive impairment, a frequent consequence and major concern to patients with lacunar stroke. Trials dedicated to lacunar stroke, which does after all account for a quarter of ischaemic strokes, could focus on recruitment practices, trial designs and outcomes (especially cognition, mood) that are more relevant to lacunar stroke, critically important to assess, and where an effective intervention is more likely to impact clinical practice.

Third, the data on aspirin and clopidogrel (conventional 'strong' antiplatelet drugs), antihypertensives and statins indicate somewhat limited effectiveness and suggest that

there is little point in attempting further trials of these agents, although the combination of aspirin and dipyridamole or aspirin and ticagrelor in acute lacunar ischaemic stroke could be of interest. This is consistent with the intrinsic nature of the underlying non-atheromatous, non-cardioembolic SVD pathology. Rather, it could be more informative to focus on emerging, newer, or novel agents with relevant modes of action to try and find more effective interventions that tackle the intrinsic pathology.

Fourth, a major issue was the difficulty in identifying the relevant literature, due to the wide range of terms used in lacunar stroke and SVD and the lack of indexing on these terms. This problem was what led to the STRIVE-1 initiative focused on SVD features on neuroimaging, which has improved the consistency of some SVD terminology already, and has now been updated with new STRIVE recommendations.³³ Other manifestations of SVD such as WMH, silent lacunar infarcts and enlarged perivascular spaces should also whenever possible be evaluated in treatment trials.

In conclusion, there is clearly a large problem for clinical aspects of lacunar stroke and SVD still to be addressed.

## Plain language summary

This guideline offers recommendations for the treatment of lacunar stroke. An ischaemic stroke happens when the blood flow to a part of the brain is interrupted causing damage to the brain. This damage causes common symptoms which can include weakness and speech. Lacunar strokes occur following damage to the small blood vessels of the brain (small vessel disease) and are common, accounting for about a quarter of all stroke cases. There is a suggestion that the treatment of patients with lacunar stroke may differ from the treatment of other types of stroke that are caused by clots going from the heart or from disease in the large blood vessels.

This guideline was written by the European Stroke Organisation who gathered an international group of experts in the area. We identified 10 key areas of uncertainty (or questions) in the treatment of lacunar stroke and then searched all of the published articles on treatment trials to try and answer these questions. For each area of uncertainty/question we assessed the quality of the research studies providing information on the topic. To make recommendations we needed to be certain that the trials were of high enough quality. If there was enough evidence to provide a recommendation we did so (all the time indicating how certain we were). If there was not enough evidence of high enough quality then we made a statement based upon our expert consensus opinion. We were keen that proposed treatments should benefit to patients and families (and not just improvement in a brain scan appearance or blood test). So for each possible treatment we looked at whether it reduced key
management in patients with lacunar ischaemic stroke, in future.

First, trials in stroke that plan to include also patients with lacunar ischaemic stroke, should subtype lacunar and other stroke subtypes at baseline so that the lacunar strokes can be identified in future analyses. The subtyping should use currently used definitions such as the Oxfordshire Community Stroke Project (OCSP)² definition based on symptoms and signs, or the TOAST classification (although caution is required to avoid bias due to presumed causation)¹³³ and if possible, even more detailed information and nomenclature as proposed by Standards for Reporting Vascular Changes on Neuroimaging-2 (STRIVE-2) collaboration.³³ Possibly, in view of differences in outcome rates between lacunar versus non-lacunar strokes, the stroke subtype should even be included in any minimisation algorithm to ensure that treatment allocation is well balanced for baseline characteristics including stroke subtype. These trials that include patients with lacunar stroke should present as many results as possibly by stroke subtype, albeit in secondary analyses. Nonetheless, if previous trials had provided data on outcomes in lacunar stroke by treatment allocation more systematically this would, by now, have resulted in a much stronger evidence base for many basic routine stroke interventions than is currently the case.

Second, there is an urgent need for more trials dedicated to lacunar stroke, in order to improve the current clinical management. Amongst the conventional routine acute stroke treatments or secondary preventions, few showed much slight benefit (acute short term antiplatelets, long-term antiplatelets); several showed no definite benefit, with confidence intervals overlapping no effect, but ‘taken on trust’, the direction of effect is in the right direction (thrombolysis, acute phase DAPT, long-term BP lowering, long-term statins, lifestyle); and one showed harm (acute BP lowering). These findings are consistent with the data in the covert cSVD Guideline, although in the case of antiplatelet drugs in covert cSVD there was evidence of harm. Of the ‘other’ interventions and in progressive lacunar stroke, there were mostly small inconclusive trials. Furthermore, the outcomes provided in the conventional stroke interventions focused on early stroke recurrence or dependency, with little to no data on cognitive impairment, a frequent consequence and major concern to patients with lacunar stroke. Trials dedicated to lacunar stroke, which does after all account for a quarter of ischaemic strokes, could focus on recruitment practices, trial designs and outcomes (especially cognition, mood) that are more relevant to lacunar stroke, critically important to assess, and where an effective intervention is more likely to impact clinical practice.

Third, the data on aspirin and clopidogrel (conventional 'strong' antiplatelet drugs), antihypertensives and statins indicate somewhat limited effectiveness and suggest that

there is little point in attempting further trials of these agents, although the combination of aspirin and dipyridamole or aspirin and ticagrelor in acute lacunar ischaemic stroke could be of interest. This is consistent with the intrinsic nature of the underlying non-atheromatous, non-cardioembolic SVD pathology. Rather, it could be more informative to focus on emerging, newer, or novel agents with relevant modes of action to try and find more effective interventions that tackle the intrinsic pathology.

Fourth, a major issue was the difficulty in identifying the relevant literature, due to the wide range of terms used in lacunar stroke and SVD and the lack of indexing on these terms. This problem was what led to the STRIVE-1 initiative focused on SVD features on neuroimaging, which has improved the consistency of some SVD terminology already, and has now been updated with new STRIVE recommendations.³³ Other manifestations of SVD such as WMH, silent lacunar infarcts and enlarged perivascular spaces should also whenever possible be evaluated in treatment trials.

In conclusion, there is clearly a large problem for clinical aspects of lacunar stroke and SVD still to be addressed.

## Plain language summary

This guideline offers recommendations for the treatment of lacunar stroke. An ischaemic stroke happens when the blood flow to a part of the brain is interrupted causing damage to the brain. This damage causes common symptoms which can include weakness and speech. Lacunar strokes occur following damage to the small blood vessels of the brain (small vessel disease) and are common, accounting for about a quarter of all stroke cases. There is a suggestion that the treatment of patients with lacunar stroke may differ from the treatment of other types of stroke that are caused by clots going from the heart or from disease in the large blood vessels.

This guideline was written by the European Stroke Organisation who gathered an international group of experts in the area. We identified 10 key areas of uncertainty (or questions) in the treatment of lacunar stroke and then searched all of the published articles on treatment trials to try and answer these questions. For each area of uncertainty/question we assessed the quality of the research studies providing information on the topic. To make recommendations we needed to be certain that the trials were of high enough quality. If there was enough evidence to provide a recommendation we did so (all the time indicating how certain we were). If there was not enough evidence of high enough quality then we made a statement based upon our expert consensus opinion. We were keen that proposed treatments should benefit to patients and families (and not just improvement in a brain scan appearance or blood test). So for each possible treatment we looked at whether it reduced key
clinical outcomes for example recurrent stroke, death, onset of memory and thinking problems or dementia, onset of reliance on others, heart attacks or other features of small vessel disease such as mobility and mood disorders.

We hope that these guidelines will help healthcare professionals and patients decide how to treat patients with lacunar stroke but also highlight where evidence is lacking and where research should focus in the future.

The questions we asked along with the answers are below:

1. Should patients with lacunar (small vessel disease) stroke receive thrombolysis (a clot busting drug in the first few hours after a stroke happens).

ANSWER: Yes – patients with lacunar stroke should receive thrombolysis if necessary (as for other types of ischaemic stroke)

2. Should patients with lacunar stroke receive anti-platelet drugs in the first few hours after the stroke happens – these act to thin the blood and are commonly used after stroke or heart attack for example, aspirin?

ANSWER: Yes - we recommend that these drugs should be started as soon as possible.

3. Should patients with lacunar stroke receive drugs to lower high blood pressure in the first 24h after a stroke happens?

ANSWER: We recommend against lowering BP drastically in the first 24h (unless this is needed for another reason).

4. Should patients who have a lacunar stroke and then experience a worsening of their symptoms be treated with specific drugs other than normal stroke treatments?

ANSWER: No –at the moment there is no research to guide recommendations here (nor is it clear exactly how to define this group).

5. Should patients with lacunar stroke receive any other drugs in the first few hours following a stroke?

ANSWER: We do not know if magnesium or cilostazol or the Chinese medicinal herb Xueshuan-tong are of benefit, we recommend against using nitrates and against using heparin in acute lacunar ischaemic stroke.

6. Should patients with lacunar stroke receive anti-platelet drugs (blood thinning drugs like aspirin) in the long term?

ANSWER: Yes - we recommend one antiplatelet drug long term (aspirin or clopidogrel) (often patients will receive both aspirin and clopidogrel for the first weeks after a stroke). There is not enough research evidence to recommend cilostazol.

7. Should patients with lacunar stroke receive drugs to lower blood pressure in the long term?

ANSWER: Yes – we recommend treating blood pressure, aiming for a level of 130/80 but avoiding drastic changes in blood pressure level.

8. Should patients with lacunar stroke receive drugs to lower cholesterol levels? ANSWER: Yes – there is general benefit for most patients following an ischaemic stroke and we recommend taking drugs to lower cholesterol.

9. Should patients with lacunar stroke adopt lifestyle measures to benefit their health?

ANSWER: Yes - Although there is a lack of direct evidence we recommend general health lifestyle modifications as recommended in stroke and dementia guidelines. These include (but are not limited to) regular physical exercise, maintaining healthy body weight, avoiding smoking and excess alcohol and eating a healthy balanced diet with low sodium (dietary salt) intake.

10. Should patients with lacunar stroke receive any other long-term treatments not mentioned above?

ANSWER- We do not know whether to use cilostazol or nitrates or not. In patients with an irregular heart beat (Atrial Fibrillation) and lacunar stroke we recommend using blood thinning drugs for example, warfarin or equivalent as for patients with other types of stroke who have atrial fibrillation, as well as treating risk factors for small vessel disease.

These recommendations will help health care professionals and patients in choosing the best treatments and also highlight where more research is needed.

## Acknowledgements

The authors would like to thank Yvonne Brüchert for assistance with meetings, referencing and organisation, and Prof Terence Quinn for methodological guidance, Dr Yajun Cheng for translating the Chinese SVD Guidelines, Prof Philip Bath and Dr Lisa Woodhouse for providing additional unpublished data from the ENOS trial, the chairs of the ESO GL Board for general guidance and the reviewers for their time and helpful insights. We thank authors of some original papers for providing additional unpublished information.

## Declaration of Conflicting Interests

The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article. For details, please see Supplemental Table 1.

## Funding

The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: Funding for the development of these guidelines was provided by
clinical outcomes for example recurrent stroke, death, onset of memory and thinking problems or dementia, onset of reliance on others, heart attacks or other features of small vessel disease such as mobility and mood disorders.

We hope that these guidelines will help healthcare professionals and patients decide how to treat patients with lacunar stroke but also highlight where evidence is lacking and where research should focus in the future.

The questions we asked along with the answers are below:

1. Should patients with lacunar (small vessel disease) stroke receive thrombolysis (a clot busting drug in the first few hours after a stroke happens).

ANSWER: Yes – patients with lacunar stroke should receive thrombolysis if necessary (as for other types of ischaemic stroke)

2. Should patients with lacunar stroke receive anti-platelet drugs in the first few hours after the stroke happens – these act to thin the blood and are commonly used after stroke or heart attack for example, aspirin?

ANSWER: Yes - we recommend that these drugs should be started as soon as possible.

3. Should patients with lacunar stroke receive drugs to lower high blood pressure in the first 24h after a stroke happens?

ANSWER: We recommend against lowering BP drastically in the first 24h (unless this is needed for another reason).

4. Should patients who have a lacunar stroke and then experience a worsening of their symptoms be treated with specific drugs other than normal stroke treatments?

ANSWER: No –at the moment there is no research to guide recommendations here (nor is it clear exactly how to define this group).

5. Should patients with lacunar stroke receive any other drugs in the first few hours following a stroke?

ANSWER: We do not know if magnesium or cilostazol or the Chinese medicinal herb Xueshuan-tong are of benefit, we recommend against using nitrates and against using heparin in acute lacunar ischaemic stroke.

6. Should patients with lacunar stroke receive anti-platelet drugs (blood thinning drugs like aspirin) in the long term?

ANSWER: Yes - we recommend one antiplatelet drug long term (aspirin or clopidogrel) (often patients will receive both aspirin and clopidogrel for the first weeks after a stroke). There is not enough research evidence to recommend cilostazol.

7. Should patients with lacunar stroke receive drugs to lower blood pressure in the long term?

ANSWER: Yes – we recommend treating blood pressure, aiming for a level of 130/80 but avoiding drastic changes in blood pressure level.

8. Should patients with lacunar stroke receive drugs to lower cholesterol levels? ANSWER: Yes – there is general benefit for most patients following an ischaemic stroke and we recommend taking drugs to lower cholesterol.

9. Should patients with lacunar stroke adopt lifestyle measures to benefit their health?

ANSWER: Yes - Although there is a lack of direct evidence we recommend general health lifestyle modifications as recommended in stroke and dementia guidelines. These include (but are not limited to) regular physical exercise, maintaining healthy body weight, avoiding smoking and excess alcohol and eating a healthy balanced diet with low sodium (dietary salt) intake.

10. Should patients with lacunar stroke receive any other long-term treatments not mentioned above?

ANSWER- We do not know whether to use cilostazol or nitrates or not. In patients with an irregular heart beat (Atrial Fibrillation) and lacunar stroke we recommend using blood thinning drugs for example, warfarin or equivalent as for patients with other types of stroke who have atrial fibrillation, as well as treating risk factors for small vessel disease.

These recommendations will help health care professionals and patients in choosing the best treatments and also highlight where more research is needed.

## Acknowledgements

The authors would like to thank Yvonne Brüchert for assistance with meetings, referencing and organisation, and Prof Terence Quinn for methodological guidance, Dr Yajun Cheng for translating the Chinese SVD Guidelines, Prof Philip Bath and Dr Lisa Woodhouse for providing additional unpublished data from the ENOS trial, the chairs of the ESO GL Board for general guidance and the reviewers for their time and helpful insights. We thank authors of some original papers for providing additional unpublished information.

## Declaration of Conflicting Interests

The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article. For details, please see Supplemental Table 1.

## Funding

The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: Funding for the development of these guidelines was provided by
the European Stroke Organisation, Basel, Switzerland. The author(s) did not receive financial support for the development, writing and/or publication of this guideline. Declarations of funding are provided in Supplemental Table 1

## Informed consent

Not applicable

## Ethical approval

Ethical approval was not necessary for the work described in this paper.

## Guarantor

Arne Lindgren, Joanna Wardlaw

## Contributorship

The PICO groups drafted the PICOs which were merged. The chairs drafted the introduction, methods and discussion based on points raised in discussion by the MWG members. Salman Hussain, Methodologist, conducted the GRADE and statistical analyses. All authors reviewed and edited the manuscript and approved the final version of the manuscript.

## ORCID iDs

Joanna M Wardlaw https://orcid.org/0000-0002-9812-6642
Hugues Chabriat https://orcid.org/0000-0001-8436-6074
Stéphanie Debette https://orcid.org/0000-0001-8675-7968
Martin Dichgans https://orcid.org/0000-0002-0654-387X
Fergus Doubal https://orcid.org/0000-0002-2769-3148
Hanna Jokinen https://orcid.org/0000-0001-7889-1120
Aristeidis H Katsanos https://orcid.org/0000-0002-6359-0023
Raffaele Ornello https://orcid.org/0000-0001-9501-4031
Leonardo Pantoni https://orcid.org/0000-0001-7357-8530
Marco Pasi https://orcid.org/0000-0001-9976-2459
Aleksandra M Pavlovic https://orcid.org/0000-0002-5987-9828
Salvatore Rudilosso https://orcid.org/0000-0002-8775-6884
Julie Staals https://orcid.org/0000-0002-9502-6937
Martin Taylor-Rowan https://orcid.org/0000-0002-3027-5369
Salman Hussain https://orcid.org/0000-0002-1691-8428
Arne G Lindgren https://orcid.org/0000-0003-1942-7330

## Supplemental material

Supplemental material for this article is available online.

## References

1. Wardlaw JM, Debette S, Jokinen H, et al. ESO guideline on covert cerebral small vessel disease. *Eur Stroke J* 2021; 6: CXI–CLXII.

2. Bamford J. Clinical examination in diagnosis and subclassification of stroke. *Lancet* 1992; 339: 400–402.

3. Jackson CA, Hutchison A, Dennis MS, et al. Differing risk factor profiles of ischemic stroke subtypes: evidence for a distinct lacunar arteriopathy? *Stroke* 2010; 41: 624–629.

4. Jackson CA, Hutchison A, Dennis MS, et al. Differences between ischemic stroke subtypes in vascular outcomes support a distinct lacunar ischemic stroke arteriopathy. A prospective, hospital-based study. *Stroke* 2009; 40: 3679–3684.

5. Makin SDJ, S Turpin, Dennis MS, et al. Cognitive impairment after lacunar stroke: systematic review and meta-analysis of incidence, prevalence and comparison with other stroke subtypes. *J Neurol Neurosurg Psychiatry* 2013; 84: 893–900.

6. Smith EE and Markus HS. New treatment approaches to modify the course of cerebral small vessel diseases. *Stroke* 2020; 51: 38–46.

7. Palacio S, Hart RG, Pearce LA, et al. Effect of addition of clopidogrel to aspirin on mortality: systematic review of randomized trials. *Stroke* 2012; 43: 2157–2162.

8. Pearce LA, McClure LA, Anderson DC, et al.; SPS3 Investigators. Effects of long-term blood pressure lowering and dual antiplatelet treatment on cognitive function in patients with recent lacunar stroke: a secondary analysis from the SPS3 randomised trial. *Lancet Neurol* 2014; 13: 1177–1185.

9. Secondary Prevention of Small Subcortical Stroke Study Group. Blood-pressure targets in patients with recent lacunar stroke: the SPS3 randomised trial. *Lancet* 2013; 382: 507–515.

10. Potter G, Doubal F, Jackson C, et al. Associations of clinical stroke misclassification ('clinical-imaging dissociation') in acute ischemic stroke. *Cerebrovasc Dis* 2010; 29: 395–402.

11. Arba F, Mair G, Phillips S, et al.; Third International Stroke Trial Collaborators. Improving clinical detection of acute lacunar stroke: analysis from the IST-3. *Stroke* 2020; 51: 1411–1418.

12. Mancuso M, Arnold M, Bersano A, et al. Monogenic cerebral small-vessel diseases: diagnosis and therapy. Consensus recommendations of the European Academy of Neurology. *Eur J Neurol* 2020; 27: 909–927.

13. Turc G, Bhogal P, Fischer U, et al. European Stroke Organisation (ESO)-European Society for minimally Invasive Neurological Therapy (ESMINT) guidelines on mechanical thrombectomy in Acute Ischaemic StrokeEndorsed by Stroke Alliance for Europe (SAFE). *Eur Stroke J* 2019; 4: 6–12.

14. Klijn CJ, Paciaroni M, Berge E, et al. Antithrombotic treatment for secondary prevention of stroke and other thromboembolic events in patients with stroke or transient ischemic attack and non-valvular atrial fibrillation: a European Stroke Organisation guideline. *Eur Stroke J* 2019; 4: 198–223.

15. Quinn TJ, Richard E, Teuschl Y, et al. European Stroke Organisation and European Academy of Neurology joint guidelines on post-stroke cognitive impairment. *Eur Stroke J* 2021; 6: I–XXXVIII.

16. Dawson J, Béjot Y, Christensen LM, et al. European Stroke Organisation (ESO) guideline on pharmacological interventions for long-term secondary prevention after ischaemic stroke or transient ischaemic attack. *Eur Stroke J* 2022; 7: I–II.

17. Ahmed N, Audebert H, Turc G, et al. Consensus statements and recommendations from the ESO-Karolinska Stroke
the European Stroke Organisation, Basel, Switzerland. The author(s) did not receive financial support for the development, writing and/or publication of this guideline. Declarations of funding are provided in Supplemental Table 1

## Informed consent

Not applicable

## Ethical approval

Ethical approval was not necessary for the work described in this paper.

## Guarantor

Arne Lindgren, Joanna Wardlaw

## Contributorship

The PICO groups drafted the PICOs which were merged. The chairs drafted the introduction, methods and discussion based on points raised in discussion by the MWG members. Salman Hussain, Methodologist, conducted the GRADE and statistical analyses. All authors reviewed and edited the manuscript and approved the final version of the manuscript.

## ORCID iDs

Joanna M Wardlaw ID https://orcid.org/0000-0002-9812-6642
Hugues Chabriat ID https://orcid.org/0000-0001-8436-6074
Stéphanie Debette ID https://orcid.org/0000-0001-8675-7968
Martin Dichgans ID https://orcid.org/0000-0002-0654-387X
Fergus Doubal ID https://orcid.org/0000-0002-2769-3148
Hanna Jokinen ID https://orcid.org/0000-0001-7889-1120
Aristeidis H Katsanos ID https://orcid.org/0000-0002-6359-0023
Raffaele Ornello ID https://orcid.org/0000-0001-9501-4031
Leonardo Pantoni ID https://orcid.org/0000-0001-7357-8530
Marco Pasi ID https://orcid.org/0000-0001-9976-2459
Aleksandra M Pavlovic ID https://orcid.org/0000-0002-5987-9828
Salvatore Rudilosso ID https://orcid.org/0000-0002-8775-6884
Julie Staals ID https://orcid.org/0000-0002-9502-6937
Martin Taylor-Rowan ID https://orcid.org/0000-0002-3027-5369
Salman Hussain ID https://orcid.org/0000-0002-1691-8428
Arne G Lindgren ID https://orcid.org/0000-0003-1942-7330

## Supplemental material

Supplemental material for this article is available online.

## References

1. Wardlaw JM, Debette S, Jokinen H, et al. ESO guideline on covert cerebral small vessel disease. *Eur Stroke J* 2021; 6: CXI–CLXII.

2. Bamford J. Clinical examination in diagnosis and subclassification of stroke. *Lancet* 1992; 339: 400–402.

3. Jackson CA, Hutchison A, Dennis MS, et al. Differing risk factor profiles of ischemic stroke subtypes: evidence for a distinct lacunar arteriopathy? *Stroke* 2010; 41: 624–629.

4. Jackson CA, Hutchison A, Dennis MS, et al. Differences between ischemic stroke subtypes in vascular outcomes support a distinct lacunar ischemic stroke arteriopathy. A prospective, hospital-based study. *Stroke* 2009; 40: 3679–3684.

5. Makin SDJ, S Turpin, Dennis MS, et al. Cognitive impairment after lacunar stroke: systematic review and meta-analysis of incidence, prevalence and comparison with other stroke subtypes. *J Neurol Neurosurg Psychiatry* 2013; 84: 893–900.

6. Smith EE and Markus HS. New treatment approaches to modify the course of cerebral small vessel diseases. *Stroke* 2020; 51: 38–46.

7. Palacio S, Hart RG, Pearce LA, et al. Effect of addition of clopidogrel to aspirin on mortality: systematic review of randomized trials. *Stroke* 2012; 43: 2157–2162.

8. Pearce LA, McClure LA, Anderson DC, et al.; SPS3 Investigators. Effects of long-term blood pressure lowering and dual antiplatelet treatment on cognitive function in patients with recent lacunar stroke: a secondary analysis from the SPS3 randomised trial. *Lancet Neurol* 2014; 13: 1177–1185.

9. Secondary Prevention of Small Subcortical Stroke Study Group. Blood-pressure targets in patients with recent lacunar stroke: the SPS3 randomised trial. *Lancet* 2013; 382: 507–515.

10. Potter G, Doubal F, Jackson C, et al. Associations of clinical stroke misclassification ('clinical-imaging dissociation') in acute ischemic stroke. *Cerebrovasc Dis* 2010; 29: 395–402.

11. Arba F, Mair G, Phillips S, et al.; Third International Stroke Trial Collaborators. Improving clinical detection of acute lacunar stroke: analysis from the IST-3. *Stroke* 2020; 51: 1411–1418.

12. Mancuso M, Arnold M, Bersano A, et al. Monogenic cerebral small-vessel diseases: diagnosis and therapy. Consensus recommendations of the European Academy of Neurology. *Eur J Neurol* 2020; 27: 909–927.

13. Turc G, Bhogal P, Fischer U, et al. European Stroke Organisation (ESO)-European Society for minimally Invasive Neurological Therapy (ESMINT) guidelines on mechanical thrombectomy in Acute Ischaemic Stroke Endorsed by Stroke Alliance for Europe (SAFE). *Eur Stroke J* 2019; 4: 6–12.

14. Klijn CJ, Paciaroni M, Berge E, et al. Antithrombotic treatment for secondary prevention of stroke and other thromboembolic events in patients with stroke or transient ischemic attack and non-valvular atrial fibrillation: a European Stroke Organisation guideline. *Eur Stroke J* 2019; 4: 198–223.

15. Quinn TJ, Richard E, Teuschl Y, et al. European Stroke Organisation and European Academy of Neurology joint guidelines on post-stroke cognitive impairment. *Eur Stroke J* 2021; 6: I–XXXVIII.

16. Dawson J, Béjot Y, Christensen LM, et al. European Stroke Organisation (ESO) guideline on pharmacological interventions for long-term secondary prevention after ischaemic stroke or transient ischaemic attack. *Eur Stroke J* 2022; 7: I–II.

17. Ahmed N, Audebert H, Turc G, et al. Consensus statements and recommendations from the ESO-Karolinska Stroke
Update Conference, Stockholm 11–13 November 2018. *Eur Stroke J* 2019; 4: 307–317.

18. Bassetti CLA, Randerath W, Vignatelli L, et al. EAN/ERS/ESO/ESRS statement on the impact of sleep disorders on risk and outcome of stroke. *Eur J Neurol* 2020; 27: 1117–1136.

19. Berge E, Whiteley W, Audebert H, et al. European Stroke Organisation (ESO) guidelines on intravenous thrombolysis for acute ischaemic stroke. *Eur Stroke J* 2021; 6: I–LXII.

20. Fonseca AC, Merwick Dennis M, et al. European Stroke Organisation (ESO) guidelines on management of transient ischaemic attack. *Eur Stroke J* 2021; 6: Clxiii–clxxxvi.

21. Kleindorfer DO, Towfighi A, Chaturvedi S, et al. 2021 Guideline for the Prevention of stroke in patients with stroke and transient ischemic attack: a guideline from the American Heart Association/American Stroke Association. *Stroke* 2021; 52: e364–e467.

22. Powers WJ, Rabinstein AA and Ackerson T. Correction to: guidelines for the early management of patients with acute ischemic stroke: 2019 update to the 2018 Guidelines for the early management of acute ischemic stroke: a guideline for healthcare professionals from the American Heart Association/American Stroke Association. *Stroke* 2019; 50: e344–e418.

23. Smith EE, Saposnik G, Biessels GJ, et al.; American Heart Association Stroke Council; Council on Cardiovascular Radiology and Intervention; Council on Functional Genomics and Translational Biology; and Council on Hypertension. Prevention of stroke in patients with silent cerebrovascular disease: a scientific statement for healthcare professionals from the American Heart Association/American Stroke Association. *Stroke* 2017; 48: e44–e71.

24. Gladstone DJ, Lindsay MP, Douketis J, et al.; Canadian Stroke Consortium. Canadian stroke best practice recommendations: secondary prevention of stroke update 2020. *Can J Neurol Sci* 2022; 49: 315–337.

25. Heran M, Lindsay P, Gubitz G, et al. Canadian stroke best practice recommendations: acute Stroke Management, 7sEdition Practice Guidelines Update, 2022. *Can J Neurol Sci* 2022; 1–31.

26. Royal College of Physicians of London Intercollegiate Stroke Working Party. *National clinical guidelines for stroke*. Report no. 5th, London, 2016.

27. Stroke Foundation. Australian and New Zealand Clinical Guidelines for Stroke Management. https://informme.org.au/guidelines/living-clinical-guidelines-for-stroke-management (2021, accessed 30 March 2023).

28. Liu L, Chen W, Zhou H, et al.; Chinese Stroke Association Stroke Council Guideline Writing Committee. Chinese Stroke Association guidelines for clinical management of cerebrovascular disorders: executive summary and 2019 update of clinical management of ischaemic cerebrovascular diseases. *Stroke Vasc Neurol* 2020; 5: 159–176.

29. Chinese Society of Neurology; Chinese Stroke Society. Chinese guideline for diagnosis and treatment of cerebral small vessel disease 2020. *Chin J Neurol* 2022; 55: 807–818.

30. Miyamoto S, Ogasawara K, Kuroda S, et al.; Committee for Stroke Guideline 2021, the Japan Stroke Society. Japan Stroke Society guideline 2021 for the treatment of stroke. *Int J Stroke* 2022; 17: 1039–1049.

31. IST-3 collaborative group. Association between brain imaging signs, early and late outcomes, and response to intravenous alteplase after acute ischaemic stroke in the third International Stroke Trial (IST-3): secondary analysis of a randomised controlled trial. *Lancet Neurol* 2015; 14: 485–496.

32. Rudilosso S, Urra X, San Román L, et al. Perfusion deficits and mismatch in patients with acute lacunar infarcts studied with whole-brain CT perfusion. *Am J Neuroradiol* 2015; 36: 1407–1412.

33. Duering M, Biessels GJ, Brodtmann A, et al. Neuroimaging standards for research into small vessel disease—advances since 2013. *Lancet Neurol* 2023; 22: 602–618.

34. Clancy U, Gilmartin D, Jochems ACC, et al. Neuropsychiatric symptoms associated with cerebral small vessel disease: a systematic review and meta-analysis. *Lancet Psychiatry* 2021; 8: 225–236.

35. Steiner T, Dichgans M, Norrving B, et al. European Stroke Organisation (ESO) standard operating procedure for the preparation and publishing of guidelines. *Eur Stroke J* 2021; 6: CXXII–CXXXIV.

36. Guyatt GH, Oxman AD, Schünemann HJ, et al. GRADE guidelines: a new series of articles in the Journal of Clinical Epidemiology. *J Clin Epidemiol* 2011; 64: 380–382.

37. Higgins, JPT, Thomas, J, Chandler, J, et al. (eds.). *Cochrane handbook for systematic reviews of interventions*. 64th ed. Chichester, UK: John Wiley & Sons, 2023. Available from www.training.cochrane.org/handbook

38. Chaimani A, Caldwell DM, Li T, et al. Undertaking network meta-analyses. In: *Cochrane handbook for systematic reviews of interventions*. John Wiley & Sons, Inc., 2019, 285–320.

39. Donegan S, Williamson P, D'Alessandro U, et al. Assessing key assumptions of network meta-analysis: a review of methods. *Res Synth Methods* 2013; 4: 291–323.

40. Lu G and Ades AE. Assessing evidence inconsistency in mixed treatment comparisons. *J Am Stat Assoc* 2006; 101: 447–459.

41. White IR. Network meta-analysis. *Stata J* 2015; 15: 951–985.

42. White IR, Barrett JK, Jackson D, et al. Consistency and inconsistency in network meta-analysis: model estimation using multivariate meta-regression. *Res Synth Methods* 2012; 3: 111–125.

43. Sterne JAC, Savović J, Page MJ, et al. RoB 2: a revised tool for assessing risk of bias in randomised trials. *BMJ* 2019; 366: 14898.

44. Harrison JK, Reid J, Quinn TJ, et al. Using quality assessment tools to critically appraise ageing research: a guide for clinicians. *Age Ageing* 2017; 46: 359–365.

45. Pantoni L, Fierini F and Poggesi A. Thrombolysis in acute stroke patients with cerebral small vessel disease. *Cerebrovasc Dis* 2014; 37: 5–13.

46. Wardlaw JM, Woodhouse LJ, Mhlanga II, et al.; Lacunar Intervention Trial-2 (LACI-2) Investigator Group. Isosorbide mononitrate and cilostazol treatment in patients with symptomatic cerebral small vessel disease: the lacunar intervention trial-2 (LACI-2) randomized clinical trial. *JAMA Neurol* 2023; 80: 682–692.

47. The National Institute of Neurological Disorders and Stroke (NINDS) rt-PA Stroke Study Group, Caplan LR. Tissue plas-
Update Conference, Stockholm 11–13 November 2018. *Eur Stroke J* 2019; 4: 307–317.

18. Bassetti CLA, Randerath W, Vignatelli L, et al. EAN/ERS/ESO/ESRS statement on the impact of sleep disorders on risk and outcome of stroke. *Eur J Neurol* 2020; 27: 1117–1136.

19. Berge E, Whiteley W, Audebert H, et al. European Stroke Organisation (ESO) guidelines on intravenous thrombolysis for acute ischaemic stroke. *Eur Stroke J* 2021; 6: I–LXII.

20. Fonseca AC, Merwick Dennis M, et al. European Stroke Organisation (ESO) guidelines on management of transient ischaemic attack. *Eur Stroke J* 2021; 6: Clxiii–clxxxvi.

21. Kleindorfer DO, Towfighi A, Chaturvedi S, et al. 2021 Guideline for the Prevention of stroke in patients with stroke and transient ischemic attack: a guideline from the American Heart Association/American Stroke Association. *Stroke* 2021; 52: e364–e467.

22. Powers WJ, Rabinstein AA and Ackerson T. Correction to: guidelines for the early management of patients with acute ischemic stroke: 2019 update to the 2018 Guidelines for the early management of acute ischemic stroke: a guideline for healthcare professionals from the American Heart Association/American Stroke Association. *Stroke* 2019; 50: e344–e418.

23. Smith EE, Saposnik G, Biessels GJ, et al.; American Heart Association Stroke Council; Council on Cardiovascular Radiology and Intervention; Council on Functional Genomics and Translational Biology; and Council on Hypertension. Prevention of stroke in patients with silent cerebrovascular disease: a scientific statement for healthcare professionals from the American Heart Association/American Stroke Association. *Stroke* 2017; 48: e44–e71.

24. Gladstone DJ, Lindsay MP, Douketis J, et al.; Canadian Stroke Consortium. Canadian stroke best practice recommendations: secondary prevention of stroke update 2020. *Can J Neurol Sci* 2022; 49: 315–337.

25. Heran M, Lindsay P, Gubitz G, et al. Canadian stroke best practice recommendations: acute Stroke Management, 7sEdition Practice Guidelines Update, 2022. *Can J Neurol Sci* 2022; 1–31.

26. Royal College of Physicians of London Intercollegiate Stroke Working Party. *National clinical guidelines for stroke*. Report no. 5th, London, 2016.

27. Stroke Foundation. Australian and New Zealand Clinical Guidelines for Stroke Management. https://informme.org.au/guidelines/living-clinical-guidelines-for-stroke-management (2021, accessed 30 March 2023).

28. Liu L, Chen W, Zhou H, et al.; Chinese Stroke Association Stroke Council Guideline Writing Committee. Chinese Stroke Association guidelines for clinical management of cerebrovascular disorders: executive summary and 2019 update of clinical management of ischaemic cerebrovascular diseases. *Stroke Vasc Neurol* 2020; 5: 159–176.

29. Chinese Society of Neurology; Chinese Stroke Society. Chinese guideline for diagnosis and treatment of cerebral small vessel disease 2020. *Chin J Neurol* 2022; 55: 807–818.

30. Miyamoto S, Ogasawara K, Kuroda S, et al.; Committee for Stroke Guideline 2021, the Japan Stroke Society. Japan Stroke Society guideline 2021 for the treatment of stroke. *Int J Stroke* 2022; 17: 1039–1049.

31. IST-3 collaborative group. Association between brain imaging signs, early and late outcomes, and response to intravenous alteplase after acute ischaemic stroke in the third International Stroke Trial (IST-3): secondary analysis of a randomised controlled trial. *Lancet Neurol* 2015; 14: 485–496.

32. Rudilosso S, Urra X, San Román L, et al. Perfusion deficits and mismatch in patients with acute lacunar infarcts studied with whole-brain CT perfusion. *Am J Neuroradiol* 2015; 36: 1407–1412.

33. Duering M, Biessels GJ, Brodtmann A, et al. Neuroimaging standards for research into small vessel disease—advances since 2013. *Lancet Neurol* 2023; 22: 602–618.

34. Clancy U, Gilmartin D, Jochems ACC, et al. Neuropsychiatric symptoms associated with cerebral small vessel disease: a systematic review and meta-analysis. *Lancet Psychiatry* 2021; 8: 225–236.

35. Steiner T, Dichgans M, Norrving B, et al. European Stroke Organisation (ESO) standard operating procedure for the preparation and publishing of guidelines. *Eur Stroke J* 2021; 6: CXXII–CXXXIV.

36. Guyatt GH, Oxman AD, Schünemann HJ, et al. GRADE guidelines: a new series of articles in the Journal of Clinical Epidemiology. *J Clin Epidemiol* 2011; 64: 380–382.

37. Higgins, JPT, Thomas, J, Chandler, J, et al. (eds.). *Cochrane handbook for systematic reviews of interventions*. 64th ed. Chichester, UK: John Wiley & Sons, 2023. Available from www.training.cochrane.org/handbook

38. Chaimani A, Caldwell DM, Li T, et al. Undertaking network meta-analyses. In: *Cochrane handbook for systematic reviews of interventions*. John Wiley & Sons, Inc., 2019, 285–320.

39. Donegan S, Williamson P, D'Alessandro U, et al. Assessing key assumptions of network meta-analysis: a review of methods. *Res Synth Methods* 2013; 4: 291–323.

40. Lu G and Ades AE. Assessing evidence inconsistency in mixed treatment comparisons. *J Am Stat Assoc* 2006; 101: 447–459.

41. White IR. Network meta-analysis. *Stata J* 2015; 15: 951–985.

42. White IR, Barrett JK, Jackson D, et al. Consistency and inconsistency in network meta-analysis: model estimation using multivariate meta-regression. *Res Synth Methods* 2012; 3: 111–125.

43. Sterne JAC, Savović J, Page MJ, et al. RoB 2: a revised tool for assessing risk of bias in randomised trials. *BMJ* 2019; 366: 14898.

44. Harrison JK, Reid J, Quinn TJ, et al. Using quality assessment tools to critically appraise ageing research: a guide for clinicians. *Age Ageing* 2017; 46: 359–365.

45. Pantoni L, Fierini F and Poggesi A. Thrombolysis in acute stroke patients with cerebral small vessel disease. *Cerebrovasc Dis* 2014; 37: 5–13.

46. Wardlaw JM, Woodhouse LJ, Mhlanga II, et al.; Lacunar Intervention Trial-2 (LACI-2) Investigator Group. Isosorbide mononitrate and cilostazol treatment in patients with symptomatic cerebral small vessel disease: the lacunar intervention trial-2 (LACI-2) randomized clinical trial. *JAMA Neurol* 2023; 80: 682–692.

47. The National Institute of Neurological Disorders and Stroke (NINDS) rt-PA Stroke Study Group, Caplan LR. Tissue plas-
minogen activator for acute ischemic stroke. *New Engl J Med* 1999; 341: 1240-1241.

48. The IST-3 Collaborative Group. The benefits and harms of intravenous thrombolysis with recombinant tissue plasminogen activator within 6 h of acute ischaemic stroke (the third international stroke trial [IST-3]): a randomised controlled trial. *Lancet* 2012; 379: 2352-2363.

49. Khatri P, Tayama D, Cohen G, et al.; PRISMS and IST-3 Collaborative Groups. Effect of intravenous recombinant tissue-type plasminogen activator in patients with mild stroke in the Third International Stroke Trial-3: post hoc analysis. *Stroke* 2015; 46: 2325-2327.

50. Barow E, Boutitie F, Cheng B, et al.; WAKE-UP Investigators. Functional outcome of intravenous thrombolysis in patients with lacunar infarcts in the WAKE-UP trial. *JAMA Neurol* 2019; 76: 641-649.

51. Zhou Z, Delcourt C, Xia C, et al. Low-Dose vs standard-dose alteplase in acute lacunar ischemic stroke: the ENCHANTED trial. *Neurology* 2021; 96: e1512-e1526.

52. Khatri P, Kleindorfer DO, Devlin T, et al.; PRISMS Investigators. Effect of alteplase vs aspirin on functional outcome for patients with acute ischemic stroke and minor nondisabling neurologic deficits: the PRISMS randomized clinical trial. *JAMA* 2018; 320: 156-166.

53. Chen H-S, Cui Y, Zhou Z-H, et al.; ARAMIS Investigators. Dual antiplatelet therapy vs alteplase for patients with minor nondisabling acute ischemic stroke: the ARAMIS Randomized Clinical Trial. *JAMA* 2023; 329: 2135-2144.

54. Eggers CCJ, Bocksrucker C and Seyfang L; Austrian Stroke Unit Registry Collaborators. The efficacy of thrombolysis in lacunar stroke - evidence from the Austrian stroke unit registry. *Eur J Neurol* 2017; 24: 780-787.

55. Marcelinus K, Liu H, Zhang K, et al. Efficacy and safety of alteplase on treatment of acute single small subcortical infarction. *Curr Neurovasc Res* 2022; 19: 255-266.

56. Whiteley WN, Slot KB, Fernandes P, et al. Risk factors for intracranial hemorrhage in acute ischemic stroke patients treated with recombinant tissue plasminogen activator: a systematic review and meta-analysis of 55 studies. *Stroke* 2012; 43: 2904-2909.

57. CAST (Chinese Acute Stroke Trial) Collaborative Group, Chen ZM. CAST: randomised placebo-controlled trial of early aspirin use in 20 000 patients with acute ischaemic stroke. *Lancet* 1997; 349: 1641-1649.

58. Kwok CS, Shoamanesh A, Copley HC, et al. Efficacy of antiplatelet therapy in secondary prevention following lacunar stroke: pooled analysis of randomized trials. *Stroke* 2015; 46: 1014-1023.

59. The International Stroke Trial (IST): a randomised trial of aspirin, subcutaneous heparin, both, or neither among 19435 patients with acute ischaemic stroke. International Stroke Trial Collaborative Group. *Lancet* 1997; 349: 1569-1581.

60. Bath PM, Woodhouse LJ, Appleton JP, et al.; TARDIS Investigators. Antiplatelet therapy with aspirin, clopidogrel, and dipyridamole versus clopidogrel alone or aspirin and dipyridamole in patients with acute cerebral ischaemia (TARDIS): a randomised, open-label, phase 3 superiority trial. *Lancet* 2018; 391: 850-859.

61. Wang Y, Wang Y, Zhao X, et al.; CHANCE Investigators. Clopidogrel with aspirin in acute minor stroke or transient ischemic attack. *New Engl J Med* 2013; 369: 11-19.

62. Johnston SC, Easton JD, Farrant M, et al. Clopidogrel and aspirin in acute ischemic stroke and high-risk TIA. *New Engl J Med* 2018; 379: 215-225.

63. Shoamanesh A, Mundl H, Smith EE, et al. Factor XIa inhibition with asundexian after acute non-cardioembolic ischaemic stroke (PACIFIC-Stroke): an international, randomised, double-blind, placebo-controlled, phase 2b trial. *Lancet* 2022; 400: 997-1007.

64. Wang G, Yang X, Jing J, et al. Clopidogrel plus aspirin in patients with different types of single small subcortical infarction. *Front Neurol* 2021; 12.

65. Wang Y, Meng X, Wang A, et al.; CHANCE-2 Investigators. Ticagrelor versus clopidogrel in CYP2C19 loss-of-function carriers with stroke or TIA. *New Engl J Med* 2021; 385: 2520-2530.

66. Xie X, Jing J, Meng X, et al.; CHANCE-2 Investigators. Dual antiplatelet therapies and causes in minor stroke or transient ischemic attack: a prespecified analysis in the CHANCE-2 Trial. *Stroke* 2023; 54: 2241-2250.

67. Shoamanesh A. Is there still a role for dual antiplatelet therapy in the secondary prevention of lacunar stroke? *Stroke* 2023; 54: 2251-2253.

68. Kennedy J, Hill MD, Ryckborst KJ, et al.; FASTER Investigators. Fast assessment of stroke and transient ischaemic attack to prevent early recurrence (FASTER): a randomised controlled pilot trial. *Lancet Neurol* 2007; 6: 961-969.

69. Johnston SC, Amarenco P, Denison H, et al. Ticagrelor and aspirin or aspirin alone in acute ischemic stroke or TIA. *New Engl J Med* 2020; 383: 207-217.

70. Liu L, Wong KS, Leng X, et al.; CHANCE Investigators. Dual antiplatelet therapy in stroke and ICAS: subgroup analysis of CHANCE. *Neurology* 2015; 85: 1154-1162.

71. Dawson J, Merwick Webb A, et al.; European Stroke Organisation. European stroke organisation expedited recommendation for the use of short-term dual antiplatelet therapy early after minor stroke and high-risk TIA. *Eur Stroke J* 2021; 6: CLXXXVII-CXCI.

72. He J, Zhang Y, Xu T, et al.; CATIS Investigators. Effects of immediate blood pressure reduction on death and major disability in patients with acute ischemic stroke: the Catis randomized clinical trial. *JAMA* 2014; 311: 479-489.

73. Sandset EC, Bath PM, Boysen G, et al.; SCAST Study Group. The angiotensin-receptor blocker candesartan for treatment of acute stroke (SCAST): a randomised, placebo-controlled, double-blind trial. *Lancet* 2011; 377: 741-750.

74. ENOS Trial Investigators. Efficacy of nitric oxide, with or without continuing antihypertensive treatment, for management of high blood pressure in acute stroke (ENOS): a partial-factorial randomised controlled trial. *Lancet* 2015; 385: 617-628.

75. Oh MS, Yu KH, Hong KS, et al.; Valsartan Efficacy oN modesT blood pressUre REduction in acute ischemic stroke (VENTURE) study group. Modest blood pressure reduction with valsartan in acute ischemic stroke: a prospective, randomized, open-label, blinded-end-point trial. *Int J Stroke* 2015; 10: 745-751.
minogen activator for acute ischemic stroke. *New Engl J Med* 1999; 341: 1240-1241.

48. The IST-3 Collaborative Group. The benefits and harms of intravenous thrombolysis with recombinant tissue plasminogen activator within 6 h of acute ischaemic stroke (the third international stroke trial [IST-3]): a randomised controlled trial. *Lancet* 2012; 379: 2352-2363.

49. Khatri P, Tayama D, Cohen G, et al.; PRISMS and IST-3 Collaborative Groups. Effect of intravenous recombinant tissue-type plasminogen activator in patients with mild stroke in the Third International Stroke Trial-3: post hoc analysis. *Stroke* 2015; 46: 2325-2327.

50. Barow E, Boutitie F, Cheng B, et al.; WAKE-UP Investigators. Functional outcome of intravenous thrombolysis in patients with lacunar infarcts in the WAKE-UP trial. *JAMA Neurol* 2019; 76: 641-649.

51. Zhou Z, Delcourt C, Xia C, et al. Low-Dose vs standard-dose alteplase in acute lacunar ischemic stroke: the ENCHANTED trial. *Neurology* 2021; 96: e1512-e1526.

52. Khatri P, Kleindorfer DO, Devlin T, et al.; PRISMS Investigators. Effect of alteplase vs aspirin on functional outcome for patients with acute ischemic stroke and minor nondisabling neurologic deficits: the PRISMS randomized clinical trial. *JAMA* 2018; 320: 156-166.

53. Chen H-S, Cui Y, Zhou Z-H, et al.; ARAMIS Investigators. Dual antiplatelet therapy vs alteplase for patients with minor nondisabling acute ischemic stroke: the ARAMIS Randomized Clinical Trial. *JAMA* 2023; 329: 2135-2144.

54. Eggers CCJ, Bocksrucker C and Seyfang L; Austrian Stroke Unit Registry Collaborators. The efficacy of thrombolysis in lacunar stroke - evidence from the Austrian stroke unit registry. *Eur J Neurol* 2017; 24: 780-787.

55. Marcelinus K, Liu H, Zhang K, et al. Efficacy and safety of alteplase on treatment of acute single small subcortical infarction. *Curr Neurovasc Res* 2022; 19: 255-266.

56. Whiteley WN, Slot KB, Fernandes P, et al. Risk factors for intracranial hemorrhage in acute ischemic stroke patients treated with recombinant tissue plasminogen activator: a systematic review and meta-analysis of 55 studies. *Stroke* 2012; 43: 2904-2909.

57. CAST (Chinese Acute Stroke Trial) Collaborative Group, Chen ZM. CAST: randomised placebo-controlled trial of early aspirin use in 20 000 patients with acute ischaemic stroke. *Lancet* 1997; 349: 1641-1649.

58. Kwok CS, Shoamanesh A, Copley HC, et al. Efficacy of antiplatelet therapy in secondary prevention following lacunar stroke: pooled analysis of randomized trials. *Stroke* 2015; 46: 1014-1023.

59. The International Stroke Trial (IST): a randomised trial of aspirin, subcutaneous heparin, both, or neither among 19435 patients with acute ischaemic stroke. International Stroke Trial Collaborative Group. *Lancet* 1997; 349: 1569-1581.

60. Bath PM, Woodhouse LJ, Appleton JP, et al.; TARDIS Investigators. Antiplatelet therapy with aspirin, clopidogrel, and dipyridamole versus clopidogrel alone or aspirin and dipyridamole in patients with acute cerebral ischaemia (TARDIS): a randomised, open-label, phase 3 superiority trial. *Lancet* 2018; 391: 850-859.

61. Wang Y, Wang Y, Zhao X, et al.; CHANCE Investigators. Clopidogrel with aspirin in acute minor stroke or transient ischemic attack. *New Engl J Med* 2013; 369: 11-19.

62. Johnston SC, Easton JD, Farrant M, et al. Clopidogrel and aspirin in acute ischemic stroke and high-risk TIA. *New Engl J Med* 2018; 379: 215-225.

63. Shoamanesh A, Mundl H, Smith EE, et al. Factor XIa inhibition with asundexian after acute non-cardioembolic ischaemic stroke (PACIFIC-Stroke): an international, randomised, double-blind, placebo-controlled, phase 2b trial. *Lancet* 2022; 400: 997-1007.

64. Wang G, Yang X, Jing J, et al. Clopidogrel plus aspirin in patients with different types of single small subcortical infarction. *Front Neurol* 2021; 12.

65. Wang Y, Meng X, Wang A, et al.; CHANCE-2 Investigators. Ticagrelor versus clopidogrel in CYP2C19 loss-of-function carriers with stroke or TIA. *New Engl J Med* 2021; 385: 2520-2530.

66. Xie X, Jing J, Meng X, et al.; CHANCE-2 Investigators. Dual antiplatelet therapies and causes in minor stroke or transient ischemic attack: a prespecified analysis in the CHANCE-2 Trial. *Stroke* 2023; 54: 2241-2250.

67. Shoamanesh A. Is there still a role for dual antiplatelet therapy in the secondary prevention of lacunar stroke? *Stroke* 2023; 54: 2251-2253.

68. Kennedy J, Hill MD, Ryckborst KJ, et al.; FASTER Investigators. Fast assessment of stroke and transient ischaemic attack to prevent early recurrence (FASTER): a randomised controlled pilot trial. *Lancet Neurol* 2007; 6: 961-969.

69. Johnston SC, Amarenco P, Denison H, et al. Ticagrelor and aspirin or aspirin alone in acute ischemic stroke or TIA. *New Engl J Med* 2020; 383: 207-217.

70. Liu L, Wong KS, Leng X, et al.; CHANCE Investigators. Dual antiplatelet therapy in stroke and ICAS: subgroup analysis of CHANCE. *Neurology* 2015; 85: 1154-1162.

71. Dawson J, Merwick Webb A, et al.; European Stroke Organisation. European stroke organisation expedited recommendation for the use of short-term dual antiplatelet therapy early after minor stroke and high-risk TIA. *Eur Stroke J* 2021; 6: CLXXXVII-CXCI.

72. He J, Zhang Y, Xu T, et al.; CATIS Investigators. Effects of immediate blood pressure reduction on death and major disability in patients with acute ischemic stroke: the Catis randomized clinical trial. *JAMA* 2014; 311: 479-489.

73. Sandset EC, Bath PM, Boysen G, et al.; SCAST Study Group. The angiotensin-receptor blocker candesartan for treatment of acute stroke (SCAST): a randomised, placebo-controlled, double-blind trial. *Lancet* 2011; 377: 741-750.

74. ENOS Trial Investigators. Efficacy of nitric oxide, with or without continuing antihypertensive treatment, for management of high blood pressure in acute stroke (ENOS): a partial-factorial randomised controlled trial. *Lancet* 2015; 385: 617-628.

75. Oh MS, Yu KH, Hong KS, et al.; Valsartan Efficacy oN modesT blood pressUre REduction in acute ischemic stroke (VENTURE) study group. Modest blood pressure reduction with valsartan in acute ischemic stroke: a prospective, randomized, open-label, blinded-end-point trial. *Int J Stroke* 2015; 10: 745-751.
76. Anderson C, Huang Y, Lindley R, et al. Intensive blood pressure reduction with intravenous thrombolysis therapy for acute ischaemic stroke (ENCHANTED): an international, randomised, open-label, blinded-endpoint, phase 3 trial. *Lancet* 2019; 393: 877–888.

77. Geeganage CM and Bath PM. Relationship between therapeutic changes in blood pressure and outcomes in acute stroke: a metaregression. *Hypertension* 2009; 54: 775–781.

78. Tikhonoff V, Zhang H, Richart T, et al. Blood pressure as a prognostic factor after acute stroke. *Lancet Neurol* 2009; 8: 938–948.

79. Berge E, Cohen G, Lindley RI, et al. Effects of blood pressure and blood pressure-lowering treatment during the first 24 hours among patients in the Third International Stroke Trial of thrombolytic treatment for acute ischemic stroke. *Stroke* 2015; 46: 3362–3369.

80. Ahmed N, Wahlgren N, Brainin M, et al.; SITS Investigators. Relationship of blood pressure, antihypertensive therapy, and outcome in ischemic stroke treated with intravenous thrombolysis: retrospective analysis from safe implementation of thrombolysis in stroke-international stroke thrombolysis register (SITS-ISTR). *Stroke* 2009; 40: 2442–2449.

81. Aries MJ, Elting JW, De Keyser J, et al. Cerebral autoregulation in stroke: a review of transcranial Doppler studies. *Stroke* 2010; 41: 2697–2704.

82. Sandset EC, Jusufovic M, Sandset PM, et al.; SCAST Study Group. Effects of blood pressure-lowering treatment in different subtypes of acute ischemic stroke. *Stroke* 2015; 46: 877–879.

83. Zhou Z, Xia C, Carcel C, et al. Intensive versus guideline-recommended blood pressure reduction in acute lacunar stroke with intravenous thrombolysis therapy: the ENCHANTED trial. *Eur J Neurol* 2021; 28: 783–793.

84. Zhu Z, Guo D, Shi M, et al. Effect of immediate blood pressure reduction on post-stroke depression in ischemic stroke patients: a substudy of Catis trial. *J Affect Disord* 2022; 300: 195–202.

85. Sandset EC, Anderson CS, Bath PM, et al. European Stroke Organisation (ESO) guidelines on blood pressure management in acute ischaemic stroke and intracerebral haemorrhage. *Eur Stroke J* 2021; 6: Xlviii–lxxxix.

86. Potter JF, Robinson TG, Ford GA, et al. Controlling hypertension and hypotension immediately post-stroke (CHHIPS): a randomised, placebo-controlled, double-blind pilot trial. *Lancet Neurol* 2009; 8: 48–56.

87. Yuan F, Yang F, Zhao J, et al. Controlling hypertension after severe cerebrovascular event (CHASE): a randomised, multicenter, controlled study. *Int J Stroke* 2021; 16: 456–465.

88. Muir KW, Lees KR, Ford I, et al.; Intravenous Magnesium Efficacy in Stroke (IMAGES) Study Investigators. Magnesium for acute stroke (Intravenous Magnesium efficacy in stroke trial): randomised controlled trial. *Lancet* 2004; 363: 439–445.

89. Schrader J, Lüders S, Kulschewski A, et al.; Acute Candesartan Cilexetil Therapy in Stroke Survivors Study Group. The ACCESS Study: evaluation of Acute candesartan Cilexetil Therapy in stroke survivors. *Stroke* 2003; 34: 1699–1703.

90. Squire IB, Lees KR, Pryse-Phillips W, et al. The effects of lifarizine in acute cerebral infarction: a pilot safety study. *Cerebrovasc Dis* 1996; 6: 156–160.

91. Horn J, de Haan RJ, Vermeulen M, et al. Very early nimodipine use in stroke (VENUS): a randomized, double-blind, placebo-controlled trial. *Stroke* 2001; 32: 461–465.

92. Kaste M, Fogelholm R, Erilä T, et al. A randomized, double-blind, placebo-controlled trial of nimodipine in acute ischemic hemispheric stroke. *Stroke* 1994; 25: 1348–1353.

93. Norris JW, Le Brun LH and Anderson BA. Intravenous nimodipine in acute ischaemic stroke. *Cerebrovasc Dis* 1994; 4: 194–196.

94. Azcona A and Lataste X. Isradipine in patients with acute ischaemic cerebral infarction. An overview of the Asclepios Programme. *Drugs* 1990; 40 Suppl 2: 52–57.

95. Barer DH, Cruickshank JM, Ebrahim SB, et al. Low dose beta blockade in acute stroke ("BEST" trial): an evaluation. *Br Med J* 1988; 296: 737–741.

96. Ahmed N and Wahlgren NG. Effects of blood pressure lowering in the acute phase of total anterior circulation infarcts and other stroke subtypes. *Cerebrovasc Dis* 2003; 15: 235–243.

97. Ahmed N, Näsman P and Wahlgren NG. Effect of intravenous nimodipine on blood pressure and outcome after acute stroke. *Stroke* 2000; 31: 1250–1255.

98. Ankolekar S, Fuller M, Cross I, et al. Feasibility of an ambulance-based stroke trial, and safety of glyceryl trinitrate in ultra-acute stroke: the rapid intervention with glyceryl trinitrate in hypertensive stroke trial (RIGHT, ISRCTN66434824). *Stroke* 2013; 44: 3120–3128.

99. Bath PM, Scutt P and Anderson CS.; RIGHT-2 Investigators Prehospital transdermal glyceryl trinitrate in patients with ultra-acute presumed stroke (RIGHT-2): an ambulance-based, randomised, sham-controlled, blinded, phase 3 trial. *Lancet* 2019; 393: 1009–1020.

100. Powers WJ, Rabinstein AA, Ackerson T, et al.; American Heart Association Stroke Council. 2018 guidelines for the early management of patients with acute ischemic stroke: a guideline for healthcare professionals from the American Heart Association/American Stroke Association. *Stroke* 2018; 49: e46–e110.

101. Shin DW, Gorelick PB and Bae HJ ; Clinical Research Collaboration for Stroke in Korea (CRCS-K) Investigators. Time-dependent shift of the relationship between systolic blood pressure and clinical outcome in acute lacunar stroke. *Int J Stroke* 2022; 17: 400–406.

102. Shin JA, Lee KJ, Lee JS, et al. Relationship between blood pressure and outcome changes over time in acute ischemic stroke. *Neurology* 2020; 95: e1362–e1371.

103. Sare GM, Ali M, Shuaib A, et al.; VISTA Collaboration. Relationship between hyperacute blood pressure and outcome after ischemic stroke: data from the VISTA collaboration. *Stroke* 2009; 40: 2098–2103.

104. Libman RB, Sacco RL, Shi T, et al. Neurologic improvement in pure motor hemiparesis. Implications for clinical trials. *Neurology* 1992; 42: 1713–1716.

105. Del Bene A, Palumbo V, Lamassa M, et al. Progressive lacunar stroke: review of mechanisms, prognostic features, and putative treatments. *Int J Stroke* 2012; 7: 321–329.
76. Anderson C, Huang Y, Lindley R, et al. Intensive blood pressure reduction with intravenous thrombolysis therapy for acute ischaemic stroke (ENCHANTED): an international, randomised, open-label, blinded-endpoint, phase 3 trial. *Lancet* 2019; 393: 877–888.

77. Geeganage CM and Bath PM. Relationship between therapeutic changes in blood pressure and outcomes in acute stroke: a metaregression. *Hypertension* 2009; 54: 775–781.

78. Tikhonoff V, Zhang H, Richart T, et al. Blood pressure as a prognostic factor after acute stroke. *Lancet Neurol* 2009; 8: 938–948.

79. Berge E, Cohen G, Lindley RI, et al. Effects of blood pressure and blood pressure-lowering treatment during the first 24 hours among patients in the Third International Stroke Trial of thrombolytic treatment for acute ischemic stroke. *Stroke* 2015; 46: 3362–3369.

80. Ahmed N, Wahlgren N, Brainin M, et al.; SITS Investigators. Relationship of blood pressure, antihypertensive therapy, and outcome in ischemic stroke treated with intravenous thrombolysis: retrospective analysis from safe implementation of thrombolysis in stroke-international stroke thrombolysis register (SITS-ISTR). *Stroke* 2009; 40: 2442–2449.

81. Aries MJ, Elting JW, De Keyser J, et al. Cerebral autoregulation in stroke: a review of transcranial Doppler studies. *Stroke* 2010; 41: 2697–2704.

82. Sandset EC, Jusufovic M, Sandset PM, et al.; SCAST Study Group. Effects of blood pressure-lowering treatment in different subtypes of acute ischemic stroke. *Stroke* 2015; 46: 877–879.

83. Zhou Z, Xia C, Carcel C, et al. Intensive versus guideline-recommended blood pressure reduction in acute lacunar stroke with intravenous thrombolysis therapy: the ENCHANTED trial. *Eur J Neurol* 2021; 28: 783–793.

84. Zhu Z, Guo D, Shi M, et al. Effect of immediate blood pressure reduction on post-stroke depression in ischemic stroke patients: a substudy of Catis trial. *J Affect Disord* 2022; 300: 195–202.

85. Sandset EC, Anderson CS, Bath PM, et al. European Stroke Organisation (ESO) guidelines on blood pressure management in acute ischaemic stroke and intracerebral haemorrhage. *Eur Stroke J* 2021; 6: Xlviii–lxxxix.

86. Potter JF, Robinson TG, Ford GA, et al. Controlling hypertension and hypotension immediately post-stroke (CHHIPS): a randomised, placebo-controlled, double-blind pilot trial. *Lancet Neurol* 2009; 8: 48–56.

87. Yuan F, Yang F, Zhao J, et al. Controlling hypertension after severe cerebrovascular event (CHASE): a randomised, multicenter, controlled study. *Int J Stroke* 2021; 16: 456–465.

88. Muir KW, Lees KR, Ford I, et al.; Intravenous Magnesium Efficacy in Stroke (IMAGES) Study Investigators. Magnesium for acute stroke (Intravenous Magnesium efficacy in stroke trial): randomised controlled trial. *Lancet* 2004; 363: 439–445.

89. Schrader J, Lüders S, Kulschewski A, et al.; Acute Candesartan Cilexetil Therapy in Stroke Survivors Study Group. The ACCESS Study: evaluation of Acute candesartan Cilexetil Therapy in stroke survivors. *Stroke* 2003; 34: 1699–1703.

90. Squire IB, Lees KR, Pryse-Phillips W, et al. The effects of lifarizine in acute cerebral infarction: a pilot safety study. *Cerebrovasc Dis* 1996; 6: 156–160.

91. Horn J, de Haan RJ, Vermeulen M, et al. Very early nimodipine use in stroke (VENUS): a randomized, double-blind, placebo-controlled trial. *Stroke* 2001; 32: 461–465.

92. Kaste M, Fogelholm R, Erilä T, et al. A randomized, double-blind, placebo-controlled trial of nimodipine in acute ischemic hemispheric stroke. *Stroke* 1994; 25: 1348–1353.

93. Norris JW, Le Brun LH and Anderson BA. Intravenous nimodipine in acute ischaemic stroke. *Cerebrovasc Dis* 1994; 4: 194–196.

94. Azcona A and Lataste X. Isradipine in patients with acute ischaemic cerebral infarction. An overview of the Asclepios Programme. *Drugs* 1990; 40 Suppl 2: 52–57.

95. Barer DH, Cruickshank JM, Ebrahim SB, et al. Low dose beta blockade in acute stroke ("BEST" trial): an evaluation. *Br Med J* 1988; 296: 737–741.

96. Ahmed N and Wahlgren NG. Effects of blood pressure lowering in the acute phase of total anterior circulation infarcts and other stroke subtypes. *Cerebrovasc Dis* 2003; 15: 235–243.

97. Ahmed N, Näsman P and Wahlgren NG. Effect of intravenous nimodipine on blood pressure and outcome after acute stroke. *Stroke* 2000; 31: 1250–1255.

98. Ankolekar S, Fuller M, Cross I, et al. Feasibility of an ambulance-based stroke trial, and safety of glyceryl trinitrate in ultra-acute stroke: the rapid intervention with glyceryl trinitrate in hypertensive stroke trial (RIGHT, ISRCTN66434824). *Stroke* 2013; 44: 3120–3128.

99. Bath PM, Scutt P and Anderson CS.; RIGHT-2 Investigators Prehospital transdermal glyceryl trinitrate in patients with ultra-acute presumed stroke (RIGHT-2): an ambulance-based, randomised, sham-controlled, blinded, phase 3 trial. *Lancet* 2019; 393: 1009–1020.

100. Powers WJ, Rabinstein AA, Ackerson T, et al.; American Heart Association Stroke Council. 2018 guidelines for the early management of patients with acute ischemic stroke: a guideline for healthcare professionals from the American Heart Association/American Stroke Association. *Stroke* 2018; 49: e46–e110.

101. Shin DW, Gorelick PB and Bae HJ; Clinical Research Collaboration for Stroke in Korea (CRCS-K) Investigators. Time-dependent shift of the relationship between systolic blood pressure and clinical outcome in acute lacunar stroke. *Int J Stroke* 2022; 17: 400–406.

102. Shin JA, Lee KJ, Lee JS, et al. Relationship between blood pressure and outcome changes over time in acute ischemic stroke. *Neurology* 2020; 95: e1362–e1371.

103. Sare GM, Ali M, Shuaib A, et al.; VISTA Collaboration. Relationship between hyperacute blood pressure and outcome after ischemic stroke: data from the VISTA collaboration. *Stroke* 2009; 40: 2098–2103.

104. Libman RB, Sacco RL, Shi T, et al. Neurologic improvement in pure motor hemiparesis. Implications for clinical trials. *Neurology* 1992; 42: 1713–1716.

105. Del Bene A, Palumbo V, Lamassa M, et al. Progressive lacunar stroke: review of mechanisms, prognostic features, and putative treatments. *Int J Stroke* 2012; 7: 321–329.
106. Huang YC, Tsai YH, Lee JD, et al. Hemodynamic factors may play a critical role in neurological deterioration occurring within 72 hrs after lacunar stroke. *PLOS ONE* 9(10): e108395.

107. Duan Z, Sun W, Liu W, et al. Acute diffusion-weighted imaging lesion patterns predict progressive small subcortical infarct in the perforator territory of the middle cerebral artery. *Int J Stroke* 2015; 10: 207–212.

108. Berberich A, Schneider C, Herweh C, et al. Risk factors associated with progressive lacunar strokes and benefit from dual antiplatelet therapy. *Eur J Neurol* 2020; 27: 817–824.

109. Shimizu H, Tominaga T, Ogawa A, et al.; Tohoku Acute Stroke Progressing Stroke Study Group. Cilostazol for the prevention of acute progressing stroke: a multicenter, randomized controlled trial. *J Stroke Cerebrovasc Dis* 2013; 22: 449–456.

110. Fukuma K. Abstract T P65: early statin intervention can reduce the early neurological deterioration and recurrence in acute lacunar stroke. Abstract. *Stroke* 2015; 46.

111. Nakase T, Sasaki M and Suzuki A. The effect of acute medication with cilostazol, an anti-platelet drug, on the outcome of small vessel brain infarction. *J Stroke Cerebrovasc Dis* 2014; 23: 1409–1415.

112. Nishi R, Mano T, Kobayashi Y, et al. Argatroban, aspirin, and clopidogrel combination therapy for acute penetrating artery infarction: a pilot study]. *Brain Nerve* 2016; 68: 181–189.

113. Yamamoto Y, Ohara T, Ishii R, et al. A combined treatment for acute larger lacunar-type infarction. *J Stroke Cerebrovasc Dis* 2011; 20: 387–394.

114. Yamamoto Y, Nagakane Y, Ohara T, et al. Intensive blood pressure-lowering treatment in patients with acute lacunar infarction. *J Stroke Cerebrovasc Dis* 2013; 22: 1273–1278.

115. Lim TS, Hong JM, Lee JS, et al. Induced-hypertension in progressing lacunar infarction. *J Neurol Sci* 2011; 308: 72–76.

116. Kang MJ, Yang JW, Lee YB, et al. The role of phenylephrine in patients with small deep subcortical infarct and progressive weakness. *J Neurol Sci* 2017; 377: 107–111.

117. Chausson N, Joux J, Saint-Vil M, et al. Infarction in the anterior choroidal artery territory: clinical progression and prognosis factors. *J Stroke Cerebrovasc Dis* 2014; 23: 2012–2017.

118. Foschi M, Pavolucci L, Rondelli F, et al.; On behalf of the Bologna TIA Study Group. Capsular warning syndrome: features, risk profile, and prognosis in a large prospective TIA cohort. *Cerebrovasc Dis* 2023; 52: 218–225.

119. Camps-Renom P, Delgado-Mederos R, Martínez-Domeño A, et al. Clinical characteristics and outcome of the capsular warning syndrome: a multicenter study. *Int J Stroke* 2015; 10: 571–575.

120. Li W, Wu Y and Li XS. Correction: intravenous tirofiban therapy for patients with capsular warning syndrome. *Stroke Vasc Neurol* 2019; 4: 108–127.

121. He L, Xu R, Wang J, et al. Capsular warning syndrome: clinical analysis and treatment. *BMC Neurol* 2019; 19: 285.

122. Tassi R, Cerase A, Acampa M, et al. Stroke warning syndrome: 18 new cases. *J Neurol Sci* 2013; 331: 168–171.

123. Hawkes MA, Braksick SA, Zhang W, et al. Can we stop the stuttering in stroke? Interventions in 40 patients with acute lacunes. *J Neurol Sci* 2019; 401: 1–4.

124. Lodder J and Gorsselink EL. Progressive stroke caused by CT-verified small deep infarcts; relation with the size of the infarct and clinical outcome. *Acta Neurol Scand* 1985; 71: 328–330.

125. Yamamoto Y, Oiwa K, Hayashi M, et al. [Coagulation and fibrinolytic activation in lacunar infarct patients]. *Rinsho Shinkeigaku* 1999; 39: 1104–1108.

126. Berberich A, Schneider C, Reiff T, et al. Dual antiplatelet therapy improves functional outcome in patients with progressive lacunar strokes. *Stroke* 2019; 50: 1007–1009.

127. Blair GW, Appleton JP, Flaherty K, et al. Tolerability, safety and intermediary pharmacological effects of cilostazol and isosorbide mononitrate, alone and combined, in patients with lacunar ischaemic stroke: the LA Cunar Intervention-1 (LACI-1) trial, a randomised clinical trial. *-med* 2019; 11: 34–43.

128. Bath PM, Mhlanga I, Woodhouse LJ, et al. Cilostazol and isosorbide mononitrate for the prevention of progression of cerebral small vessel disease: baseline data and statistical analysis plan for the Lacunar Intervention Trial-2 (LACI-2) (ISRCTN14911850). *Stroke Vasc Neurol* 2022; 8: 134–143.

129. Uchiyama S, Shinohara Y, Katayama Y, et al. Benefit of cilostazol in patients with high risk of bleeding: subanalysis of cilostazol stroke prevention study 2. *Cerebrovasc Dis* 2014; 37: 296–303.

130. Shinohara Y, Katayama Y, Uchiyama S, et al.; CSPS 2 group. Cilostazol for prevention of secondary stroke (CSPS 2): an aspirin-controlled, double-blind, randomised non-inferiority trial. *Lancet Neurol* 2010; 9: 959–968.

131. Nishiyama Y, Kimura K, Otsuka T, et al.; CSPS.com Trial Investigators. Dual antiplatelet therapy with cilostazol for secondary prevention in lacunar stroke: subanalysis of the CSPS.com Trial. *Stroke* 2023; 54: 697–705.

132. Uchiyama S; for the CSPS 2 Group. Abstract 2559: subgroup analysis of the cilostazol stroke prevention study 2 (CSPS 2). Abstract. *Stroke* 2012; 43.

133. The Publications Committee for the Trial of ORG 10172 in Acute Stroke Treatment (TOAST) Investigators. Low molecular weight heparinoid, ORG 10172 (danaparoid), and outcome after acute ischemic stroke: a randomized controlled trial. The Publications Committee for the trial of ORG 10172 in acute stroke treatment (TOAST) investigators. *JAMA* 1998; 279: 1265–1272.

134. Bath PM, Lindenstrom E, Boysen G, et al. Tinzaparin in acute ischaemic stroke (TAIST): a randomised aspirin-controlled trial. *Lancet* 2001; 358: 702–710.

135. Gui Q, Yang Y, Ying S, et al. Xueshuantong improves cerebral blood perfusion in elderly patients with lacunar infarction. *Neural Regen Res* 2013; 8: 792–801.

136. Han SW, Lee SS, Kim SH, et al. Effect of cilostazol in acute lacunar infarction based on pulsatility index of transcranial Doppler (ECLIPse): a multicenter, randomized, double-blind, placebo-controlled trial. *Eur Neurol* 2013; 69: 33–40.

137. Bradford A and Lees K. Design of the intravenous magnesium efficacy in acute stroke (IMAGES) trial. *Curr Control Trials Cardiovasc Med* 2000; 1: 184–190.

138. Muir KW, Lees KR, Ford I, et al.; Intravenous Magnesium Efficacy in Stroke (IMAGES) Study Investigators. Magnesium for acute stroke (Intravenous Magnesium efficacy in stroke trial): randomised controlled trial. *Lancet* 2004; 363: 439–445.
106. Huang YC, Tsai YH, Lee JD, et al. Hemodynamic factors may play a critical role in neurological deterioration occurring within 72 hrs after lacunar stroke. *PLOS ONE* 9(10): e108395.

107. Duan Z, Sun W, Liu W, et al. Acute diffusion-weighted imaging lesion patterns predict progressive small subcortical infarct in the perforator territory of the middle cerebral artery. *Int J Stroke* 2015; 10: 207–212.

108. Berberich A, Schneider C, Herweh C, et al. Risk factors associated with progressive lacunar strokes and benefit from dual antiplatelet therapy. *Eur J Neurol* 2020; 27: 817–824.

109. Shimizu H, Tominaga T, Ogawa A, et al.; Tohoku Acute Stroke Progressing Stroke Study Group. Cilostazol for the prevention of acute progressing stroke: a multicenter, randomized controlled trial. *J Stroke Cerebrovasc Dis* 2013; 22: 449–456.

110. Fukuma K. Abstract T P65: early statin intervention can reduce the early neurological deterioration and recurrence in acute lacunar stroke. Abstract. *Stroke* 2015; 46.

111. Nakase T, Sasaki M and Suzuki A. The effect of acute medication with cilostazol, an anti-platelet drug, on the outcome of small vessel brain infarction. *J Stroke Cerebrovasc Dis* 2014; 23: 1409–1415.

112. Nishi R, Mano T, Kobayashi Y, et al. Argatroban, aspirin, and clopidogrel combination therapy for acute penetrating artery infarction: a pilot study]. *Brain Nerve* 2016; 68: 181–189.

113. Yamamoto Y, Ohara T, Ishii R, et al. A combined treatment for acute larger lacunar-type infarction. *J Stroke Cerebrovasc Dis* 2011; 20: 387–394.

114. Yamamoto Y, Nagakane Y, Ohara T, et al. Intensive blood pressure-lowering treatment in patients with acute lacunar infarction. *J Stroke Cerebrovasc Dis* 2013; 22: 1273–1278.

115. Lim TS, Hong JM, Lee JS, et al. Induced-hypertension in progressing lacunar infarction. *J Neurol Sci* 2011; 308: 72–76.

116. Kang MJ, Yang JW, Lee YB, et al. The role of phenylephrine in patients with small deep subcortical infarct and progressive weakness. *J Neurol Sci* 2017; 377: 107–111.

117. Chausson N, Joux J, Saint-Vil M, et al. Infarction in the anterior choroidal artery territory: clinical progression and prognosis factors. *J Stroke Cerebrovasc Dis* 2014; 23: 2012–2017.

118. Foschi M, Pavolucci L, Rondelli F, et al.; On behalf of the Bologna TIA Study Group. Capsular warning syndrome: features, risk profile, and prognosis in a large prospective TIA cohort. *Cerebrovasc Dis* 2023; 52: 218–225.

119. Camps-Renom P, Delgado-Mederos R, Martínez-Domeño A, et al. Clinical characteristics and outcome of the capsular warning syndrome: a multicenter study. *Int J Stroke* 2015; 10: 571–575.

120. Li W, Wu Y and Li XS. Correction: intravenous tirofiban therapy for patients with capsular warning syndrome. *Stroke Vasc Neurol* 2019; 4: 108–127.

121. He L, Xu R, Wang J, et al. Capsular warning syndrome: clinical analysis and treatment. *BMC Neurol* 2019; 19: 285.

122. Tassi R, Cerase A, Acampa M, et al. Stroke warning syndrome: 18 new cases. *J Neurol Sci* 2013; 331: 168–171.

123. Hawkes MA, Braksick SA, Zhang W, et al. Can we stop the stuttering in stroke? Interventions in 40 patients with acute lacunes. *J Neurol Sci* 2019; 401: 1–4.

124. Lodder J and Gorsselink EL. Progressive stroke caused by CT-verified small deep infarcts; relation with the size of the infarct and clinical outcome. *Acta Neurol Scand* 1985; 71: 328–330.

125. Yamamoto Y, Oiwa K, Hayashi M, et al. [Coagulation and fibrinolytic activation in lacunar infarct patients]. *Rinsho Shinkeigaku* 1999; 39: 1104–1108.

126. Berberich A, Schneider C, Reiff T, et al. Dual antiplatelet therapy improves functional outcome in patients with progressive lacunar strokes. *Stroke* 2019; 50: 1007–1009.

127. Blair GW, Appleton JP, Flaherty K, et al. Tolerability, safety and intermediary pharmacological effects of cilostazol and isosorbide mononitrate, alone and combined, in patients with lacunar ischaemic stroke: the LA Cunar Intervention-1 (LACI-1) trial, a randomised clinical trial. *-med* 2019; 11: 34–43.

128. Bath PM, Mhlanga I, Woodhouse LJ, et al. Cilostazol and isosorbide mononitrate for the prevention of progression of cerebral small vessel disease: baseline data and statistical analysis plan for the Lacunar Intervention Trial-2 (LACI-2) (ISRCTN14911850). *Stroke Vasc Neurol* 2022; 8: 134–143.

129. Uchiyama S, Shinohara Y, Katayama Y, et al. Benefit of cilostazol in patients with high risk of bleeding: subanalysis of cilostazol stroke prevention study 2. *Cerebrovasc Dis* 2014; 37: 296–303.

130. Shinohara Y, Katayama Y, Uchiyama S, et al.; CSPS 2 group. Cilostazol for prevention of secondary stroke (CSPS 2): an aspirin-controlled, double-blind, randomised non-inferiority trial. *Lancet Neurol* 2010; 9: 959–968.

131. Nishiyama Y, Kimura K, Otsuka T, et al.; CSPS.com Trial Investigators. Dual antiplatelet therapy with cilostazol for secondary prevention in lacunar stroke: subanalysis of the CSPS.com Trial. *Stroke* 2023; 54: 697–705.

132. Uchiyama S; for the CSPS 2 Group. Abstract 2559: subgroup analysis of the cilostazol stroke prevention study 2 (CSPS 2). Abstract. *Stroke* 2012; 43.

133. The Publications Committee for the Trial of ORG 10172 in Acute Stroke Treatment (TOAST) Investigators. Low molecular weight heparinoid, ORG 10172 (danaparoid), and outcome after acute ischemic stroke: a randomized controlled trial. The Publications Committee for the trial of ORG 10172 in acute stroke treatment (TOAST) investigators. *JAMA* 1998; 279: 1265–1272.

134. Bath PM, Lindenstrom E, Boysen G, et al. Tinzaparin in acute ischaemic stroke (TAIST): a randomised aspirin-controlled trial. *Lancet* 2001; 358: 702–710.

135. Gui Q, Yang Y, Ying S, et al. Xueshuantong improves cerebral blood perfusion in elderly patients with lacunar infarction. *Neural Regen Res* 2013; 8: 792–801.

136. Han SW, Lee SS, Kim SH, et al. Effect of cilostazol in acute lacunar infarction based on pulsatility index of transcranial Doppler (ECLIPse): a multicenter, randomized, double-blind, placebo-controlled trial. *Eur Neurol* 2013; 69: 33–40.

137. Bradford A and Lees K. Design of the intravenous magnesium efficacy in acute stroke (IMAGES) trial. *Curr Control Trials Cardiovasc Med* 2000; 1: 184–190.

138. Muir KW, Lees KR, Ford I, et al.; Intravenous Magnesium Efficacy in Stroke (IMAGES) Study Investigators. Magnesium for acute stroke (Intravenous Magnesium efficacy in stroke trial): randomised controlled trial. *Lancet* 2004; 363: 439–445.
139. Aslanyan S, Weir CJ, Muir KW, et al.; IMAGES Study Investigators. Magnesium for treatment of acute lacunar stroke syndromes: further analysis of the IMAGES trial. *Stroke* 2007; 38: 1269–1273.

140. Afshari D, Moradian N and Rezaei M. Evaluation of the intravenous magnesium sulfate effect in clinical improvement of patients with acute ischemic stroke. *Clin Neurol Neurosurg* 2013; 115: 400–404.

141. Willmot MR and Bath PM. The potential of nitric oxide therapeutics in stroke. *Expert Opin Investig Drugs* 2003; 12: 455–470.

142. Appleton JP, Woodhouse LJ, Adami A, et al.; ENOS Investigators. Imaging markers of small vessel disease and brain frailty, and outcomes in acute stroke. *Neurology* 2020; 94: e439–e452.

143. Nakamura T, Tsuruta S and Uchiyama S. Cilostazol combined with aspirin prevents early neurological deterioration in patients with acute ischemic stroke: a pilot study. *J Neurol Sci* 2012; 313: 22–26.

144. Lee YS, Bae HJ, Kang DW, et al. Cilostazol in acute ischemic stroke treatment (CAIST trial): a randomized double-blind non-inferiority trial. *Cerebrovasc Dis* 2011; 32: 65–71.

145. Aoki J, Iguchi Y, Urabe T, et al.; ADS Investigators. Acute aspirin plus cilostazol dual therapy for noncardioembolic stroke patients within 48 hours of symptom onset. *J Am Heart Assoc* 2019; 8: e012652.

146. Bousser MG, Eschwege E, Haguenau M, et al. “Aicla” controlled trial of aspirin and dipyridamole in the secondary prevention of athero-thrombotic cerebral ischemia. *Stroke* 1983; 14: 5–14.

147. Ariesen MJ, Algra A and Kappelle LJ. Antiplatelet drugs in the secondary prevention after stroke: differential efficacy in large versus small vessel disease? A subgroup analysis from ESPS-2. *Stroke* 2006; 37: 134–138.

148. Shinohara Y, Nishimaru K, Sawada T, et al.; S-ACCESS Study Group. Sarpogrelate-aspirin comparative clinical study for efficacy and safety in secondary prevention of cerebral infarction (S-ACCESS): a randomized, double-blind, aspirin-controlled trial. *Stroke* 2008; 39: 1827–1833.

149. Kitazono T, Toyoda K, Kitagawa K, et al. Efficacy and safety of prasugrel by stroke subtype: a sub-analysis of the prastro-i randomized controlled trial. *J Atheroscler Thromb* 2021; 28: 169–180.

150. Gent M, Blakely JA, Easton JD, et al. The Canadian American ticlopidine Study (CATS) in thromboembolic stroke. *Lancet* 1989; 1: 1215–1220.

151. Gorelick PB, Leurgans S, Richardson D, et al. African American antiplatelet stroke prevention study: clinical trial design. *J Stroke Cerebrovasc Dis* 1998; 7: 426–434.

152. Han SW, Kim Y-J, Ahn SH, et al.; MAESTRO Study Investigators. Protocol for the comparison of triflusal and clopidogrel in secondary prevention of stroke based on cytochrome P450 2C19 genotyping (MASETRO study): a multicenter, randomized, open-label, parallel-group trial. *Int J Stroke* 2016; 11: 485–491.

153. Diener HC, Bogousslavsky J, Brass LM, et al.; MATCH investigators. Aspirin and clopidogrel compared with clopidogrel alone after recent ischaemic stroke or transient ischaemic attack in high-risk patients (MATCH): randomised, double-blind, placebo-controlled trial. *Lancet* 2004; 364: 331–337.

154. ESPRIT Study Group, et al. Halkes PH, van Gijn J and Kappelle LJ. Aspirin plus dipyridamole versus aspirin alone after cerebral ischaemia of arterial origin (ESPRIT): randomised controlled trial. *Lancet* 2006; 367: 1665–1673.

155. Sacco RL, Diener HC, Yusuf S, et al. Aspirin and extended-release dipyridamole versus clopidogrel for recurrent stroke. *New Engl J Med* 2008; 359: 1238–1251.

156. Bousser MG, Amarenco P, Chamorro A, et al.; PERFORM Study Investigators. Terutroban versus aspirin in patients with cerebral ischaemic events (PERFORM): a randomised, double-blind, parallel-group trial. *Lancet* 2011; 377: 2013–2022.

157. Uchiyama S, Fukuuchi Y and Yamaguchi T. The safety and efficacy of clopidogrel versus ticlopidine in Japanese stroke patients: combined results of two Phase III, multicenter, randomized clinical trials. *J Neurol* 2009; 256: 888–897.

158. Fukuuchi Y, Tohgi H, Okudera T, et al. A randomized, double-blind study comparing the safety and efficacy of clopidogrel versus ticlopidine in Japanese patients with non-cardioembolic cerebral infarction. *Cerebrovasc Dis* 2008; 25: 40–49.

159. Morrow DA, Alberts MJ, Mohr JP, et al.; Thrombin Receptor Antagonist in Secondary Prevention of Atherothrombotic Ischemic Events–TIMI 50 Steering Committee and Investigators. Efficacy and safety of vorapaxar in patients with prior ischemic stroke. *Stroke* 2013; 44: 691–698.

160. Amarenco P, Albers GW, Denison H, et al.; SOCRATES Steering Committee and Investigators. Efficacy and safety of ticagrelor versus aspirin in acute stroke or transient ischaemic attack of atherosclerotic origin: a subgroup analysis of SOCRATES, a randomised, double-blind, controlled trial. *Lancet Neurol* 2017; 16: 301–310.

161. Gotoh F, Tohgi H, Hirai S, et al. Cilostazol stroke prevention study: a placebo-controlled double-blind trial for secondary prevention of cerebral infarction. *J Stroke Cerebrovasc Dis* 2000; 9: 147–157.

162. Matsumoto M. Cilostazol in secondary prevention of stroke: impact of the Cilostazol Stroke Prevention Study. *Atheroscler Suppl* 2005; 6: 33–40.

163. Han SW, Kim YJ, Ahn SH, et al. Effects of triflusal and clopidogrel on the secondary prevention of stroke based on cytochrome p450 2C19 genotyping. *Stroke* 2017; 19: 356–364.

164. Gorelick PB, Richardson D, Kelly M, et al.; African American Antiplatelet Stroke Prevention Study Investigators. Aspirin and ticlopidine for prevention of recurrent stroke in black patients: a randomized trial. *JAMA* 2003; 289: 2947–2957.

165. Benavente OR, Hart RG, McClure LA, et al.; SPS3 Investigators. Effects of clopidogrel added to aspirin in patients with recent lacunar stroke: the Secondary Prevention of Small Subcortical Stroke (SPS3) Trial. *New Engl J Med* 2012; 367: 817–825.

166. Rogers KC, Oliphant CS and Finks SW. Clinical efficacy and safety of cilostazol: a critical review of the literature. *Drugs* 2015; 75: 377–395.

167. Shinohara Y, Gotoh F, Tohgi H, et al. Antiplatelet cilostazol is beneficial in diabetic and/or hypertensive ischemic stroke patients. Subgroup analysis of the cilostazol stroke prevention study. *Cerebrovasc Dis* 2008; 26: 63–70.

168. Hou X, Cen K, Cui Y, et al. Antiplatelet therapy for secondary prevention of lacunar stroke: a systematic review and
139. Aslanyan S, Weir CJ, Muir KW, et al.; IMAGES Study Investigators. Magnesium for treatment of acute lacunar stroke syndromes: further analysis of the IMAGES trial. *Stroke* 2007; 38: 1269–1273.

140. Afshari D, Moradian N and Rezaei M. Evaluation of the intravenous magnesium sulfate effect in clinical improvement of patients with acute ischemic stroke. *Clin Neurol Neurosurg* 2013; 115: 400–404.

141. Willmot MR and Bath PM. The potential of nitric oxide therapeutics in stroke. *Expert Opin Investig Drugs* 2003; 12: 455–470.

142. Appleton JP, Woodhouse LJ, Adami A, et al.; ENOS Investigators. Imaging markers of small vessel disease and brain frailty, and outcomes in acute stroke. *Neurology* 2020; 94: e439–e452.

143. Nakamura T, Tsuruta S and Uchiyama S. Cilostazol combined with aspirin prevents early neurological deterioration in patients with acute ischemic stroke: a pilot study. *J Neurol Sci* 2012; 313: 22–26.

144. Lee YS, Bae HJ, Kang DW, et al. Cilostazol in acute ischemic stroke treatment (CAIST trial): a randomized double-blind non-inferiority trial. *Cerebrovasc Dis* 2011; 32: 65–71.

145. Aoki J, Iguchi Y, Urabe T, et al.; ADS Investigators. Acute aspirin plus cilostazol dual therapy for noncardioembolic stroke patients within 48 hours of symptom onset. *J Am Heart Assoc* 2019; 8: e012652.

146. Bousser MG, Eschwege E, Haguenau M, et al. “Aicla” controlled trial of aspirin and dipyridamole in the secondary prevention of athero-thrombotic cerebral ischemia. *Stroke* 1983; 14: 5–14.

147. Ariesen MJ, Algra A and Kappelle LJ. Antiplatelet drugs in the secondary prevention after stroke: differential efficacy in large versus small vessel disease? A subgroup analysis from ESPS-2. *Stroke* 2006; 37: 134–138.

148. Shinohara Y, Nishimaru K, Sawada T, et al.; S-ACCESS Study Group. Sarpogrelate-aspirin comparative clinical study for efficacy and safety in secondary prevention of cerebral infarction (S-ACCESS): a randomized, double-blind, aspirin-controlled trial. *Stroke* 2008; 39: 1827–1833.

149. Kitazono T, Toyoda K, Kitagawa K, et al. Efficacy and safety of prasugrel by stroke subtype: a sub-analysis of the prastro-i randomized controlled trial. *J Atheroscler Thromb* 2021; 28: 169–180.

150. Gent M, Blakely JA, Easton JD, et al. The Canadian American ticlopidine Study (CATS) in thromboembolic stroke. *Lancet* 1989; 1: 1215–1220.

151. Gorelick PB, Leurgans S, Richardson D, et al. African American antiplatelet stroke prevention study: clinical trial design. *J Stroke Cerebrovasc Dis* 1998; 7: 426–434.

152. Han SW, Kim Y-J, Ahn SH, et al.; MAESTRO Study Investigators. Protocol for the comparison of triflusal and clopidogrel in secondary prevention of stroke based on cytochrome P450 2C19 genotyping (MASETRO study): a multicenter, randomized, open-label, parallel-group trial. *Int J Stroke* 2016; 11: 485–491.

153. Diener HC, Bogousslavsky J, Brass LM, et al.; MATCH investigators. Aspirin and clopidogrel compared with clopidogrel alone after recent ischaemic stroke or transient ischaemic attack in high-risk patients (MATCH): randomised, double-blind, placebo-controlled trial. *Lancet* 2004; 364: 331–337.

154. ESPRIT Study Group, et al. Halkes PH, van Gijn J and Kappelle LJ. Aspirin plus dipyridamole versus aspirin alone after cerebral ischaemia of arterial origin (ESPRIT): randomised controlled trial. *Lancet* 2006; 367: 1665–1673.

155. Sacco RL, Diener HC, Yusuf S, et al. Aspirin and extended-release dipyridamole versus clopidogrel for recurrent stroke. *New Engl J Med* 2008; 359: 1238–1251.

156. Bousser MG, Amarenco P, Chamorro A, et al.; PERFORM Study Investigators. Terutroban versus aspirin in patients with cerebral ischaemic events (PERFORM): a randomised, double-blind, parallel-group trial. *Lancet* 2011; 377: 2013–2022.

157. Uchiyama S, Fukuuchi Y and Yamaguchi T. The safety and efficacy of clopidogrel versus ticlopidine in Japanese stroke patients: combined results of two Phase III, multicenter, randomized clinical trials. *J Neurol* 2009; 256: 888–897.

158. Fukuuchi Y, Tohgi H, Okudera T, et al. A randomized, double-blind study comparing the safety and efficacy of clopidogrel versus ticlopidine in Japanese patients with non-cardioembolic cerebral infarction. *Cerebrovasc Dis* 2008; 25: 40–49.

159. Morrow DA, Alberts MJ, Mohr JP, et al.; Thrombin Receptor Antagonist in Secondary Prevention of Atherothrombotic Ischemic Events–TIMI 50 Steering Committee and Investigators. Efficacy and safety of vorapaxar in patients with prior ischemic stroke. *Stroke* 2013; 44: 691–698.

160. Amarenco P, Albers GW, Denison H, et al.; SOCRATES Steering Committee and Investigators. Efficacy and safety of ticagrelor versus aspirin in acute stroke or transient ischaemic attack of atherosclerotic origin: a subgroup analysis of SOCRATES, a randomised, double-blind, controlled trial. *Lancet Neurol* 2017; 16: 301–310.

161. Gotoh F, Tohgi H, Hirai S, et al. Cilostazol stroke prevention study: a placebo-controlled double-blind trial for secondary prevention of cerebral infarction. *J Stroke Cerebrovasc Dis* 2000; 9: 147–157.

162. Matsumoto M. Cilostazol in secondary prevention of stroke: impact of the Cilostazol Stroke Prevention Study. *Atheroscler Suppl* 2005; 6: 33–40.

163. Han SW, Kim YJ, Ahn SH, et al. Effects of triflusal and clopidogrel on the secondary prevention of stroke based on cytochrome p450 2C19 genotyping. *Stroke* 2017; 19: 356–364.

164. Gorelick PB, Richardson D, Kelly M, et al.; African American Antiplatelet Stroke Prevention Study Investigators. Aspirin and ticlopidine for prevention of recurrent stroke in black patients: a randomized trial. *JAMA* 2003; 289: 2947–2957.

165. Benavente OR, Hart RG, McClure LA, et al.; SPS3 Investigators. Effects of clopidogrel added to aspirin in patients with recent lacunar stroke: the Secondary Prevention of Small Subcortical Stroke (SPS3) Trial. *New Engl J Med* 2012; 367: 817–825.

166. Rogers KC, Oliphant CS and Finks SW. Clinical efficacy and safety of cilostazol: a critical review of the literature. *Drugs* 2015; 75: 377–395.

167. Shinohara Y, Gotoh F, Tohgi H, et al. Antiplatelet cilostazol is beneficial in diabetic and/or hypertensive ischemic stroke patients. Subgroup analysis of the cilostazol stroke prevention study. *Cerebrovasc Dis* 2008; 26: 63–70.

168. Hou X, Cen K, Cui Y, et al. Antiplatelet therapy for secondary prevention of lacunar stroke: a systematic review and
network meta-analysis. *Eur J Clin Pharmacol* 2023; 79: 63-70.

169. CAPRIE Steering Committee. A randomised, blinded, trial of clopidogrel versus aspirin in patients at risk of ischaemic events (CAPRIE). *Lancet* 1996; 348: 1329-1339.

170. McDonough CW, McClure LA, Mitchell BD, et al. CYP2C19 metabolizer status and clopidogrel efficacy in the secondary prevention of small subcortical strokes (SPS3) study. *J Am Heart Assoc* 2015; 4: e001652

171. McHutchison C, Blair GW, Appleton JP, et al. Cilostazol for secondary prevention of stroke and cognitive decline: systematic review and meta-analysis. *Stroke* 2020; 51: 2374-2385.

172. Markus HS, Egle M, Croall ID, et al.; PRESERVE Study Team. PRESERVE: randomized trial of intensive versus standard blood pressure control in small vessel disease. *Stroke* 2021; 52: 2484-2493.

173. Ikeme JC, Pergola PE, Scherzer R, et al. Cerebral white matter hyperintensities, kidney function decline, and recurrent stroke after intensive blood pressure lowering: results from the secondary prevention of small subcortical strokes (SPS3) trial. *J Am Heart Assoc* 2019; 8: e010091

174. Blum MR, Scherzer R, Ikeme JC, et al. Functional health and white matter hyperintensities as effect modifiers of blood pressure-lowering on cognitive function and vascular events in older secondary prevention of small subcortical strokes trial participants. *J Hypertens* 2020; 38: 1578-1585.

175. Shoamanesh A, Pearce LA, Bazan C, et al.; SPS3 Trial Investigators. Microbleeds in the secondary prevention of small subcortical strokes trial: stroke, mortality, and treatment interactions. *Ann Neurol* 2017; 82: 196-207.

176. Odden MC, McClure LA, Sawaya BP, et al. Achieved blood pressure and outcomes in the secondary prevention of small subcortical strokes trial. *Hypertension* 2016; 67: 63-69.

177. Ku E, Scherzer R, Odden MC, et al. Patterns of blood pressure response during intensive BP lowering and clinical events: results from the secondary prevention of small subcortical strokes trial. *Blood Press* 2018; 27: 73-81.

178. Whelton P, Carey R, Aronow W, et al. ACC/AHA/AAPA/ABC/ACPM/AGS/APhA/ASH/ASPC/NMA/PCNA Guideline for the Prevention, Detection, Evaluation, and Management of high blood pressure in adults: executive summary: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. *Circulation* 2017; 138: e426-e483.

179. Kernan WN, Ovbiagele B, Black HR, et al.; American Heart Association Stroke Council, Council on Cardiovascular and Stroke Nursing, Council on Clinical Cardiology, and Council on Peripheral Vascular Disease. Guidelines for the prevention of stroke in patients with stroke and transient ischemic attack: a guideline for healthcare professionals from the American Heart Association/American Stroke Association. *Stroke* 2014; 45: 2160-2236.

180. PROGRESS Collaborative Group. Randomised trial of a perindopril-based blood-pressure-lowering regimen among 6,105 individuals with previous stroke or transient ischaemic attack. *Lancet* 2001; 358: 1033-1041.

181. Yusuf S, Sleight P, Pogue J, et al.; Heart Outcomes Prevention Evaluation Study Investigators. Effects of an

angiotensin-converting-enzyme inhibitor, ramipril, on cardiovascular events in high-risk patients. *New Engl J Med* 2000; 342: 145-153.

182. Yusuf S, Diener HC, Sacco RL, et al. Telmisartan to prevent recurrent stroke and cardiovascular events. *New Engl J Med* 2008; 359: 1225-1237.

183. Hypertension-Stroke Cooperative Study Group. Effect of antihypertensive treatment on stroke recurrence. Hypertension-Stroke Cooperative Study Group. *JAMA* 1974; 229: 409-418.

184. PATS Collaborating Group. Post-stroke antihypertensive treatment study. A preliminary result. *Chin Med J* 1995; 108: 710-717.

185. Gayet JL. The study on cognition and prognosis in the elderly (SCOPE): principal results of a randomized double-blind intervention trial. *J Hypertens* 2003; 21: 1771.

186. The Dutch TIA Trial Study Group. Trial of secondary prevention with atenolol after transient ischemic attack or non-disabling ischemic stroke. The Dutch TIA Trial Study Group. *Stroke* 1993; 24: 543-548.

187. Eriksson S, Olofsson BO and Wester PO. Atenolol in secondary prevention after stroke. *Cerebrovasc Dis* 1995; 5: 21-25.

188. Liu L, Zhang Y, Liu G, et al.; FEVER Study Group. The felodipine event reduction (FEVER) study: a randomized long-term placebo-controlled trial in Chinese hypertensive patients. *J Hypertens* 2005; 23: 2157-2172.

189. MacDonald TM, Williams B, Webb DJ, et al.; British Hypertension Society Programme of Prevention And Treatment of Hypertension With Algorithm-based Therapy (PATHWAY). Combination therapy is superior to sequential monotherapy for the initial treatment of hypertension: a double-blind randomized controlled trial. *J Am Heart Assoc* 2017; 6: e006986.

190. Brown MJ, McInnes GT, Papst CC, et al. Aliskiren and the calcium channel blocker amlodipine combination as an initial treatment strategy for hypertension control (ACCELERATE): a randomised, parallel-group trial. *Lancet* 2011; 377: 312-320.

191. Wald DS, Law M, Morris JK, et al. Combination therapy versus monotherapy in reducing blood pressure: meta-analysis on 11,000 participants from 42 trials. *Am J Med* 2009; 122: 290-300.

192. Williams B, Mancia G, Spiering W, et al.; ESC Scientific Document Group. 2018 ESC/ESH Guidelines for the management of arterial hypertension. *Eur Heart J* 2018; 39: 3021-3104.

193. Webb AJ, Fischer U, Mehta Z, et al. Effects of antihypertensive-drug class on interindividual variation in blood pressure and risk of stroke: a systematic review and meta-analysis. *Lancet* 2010; 375: 906-915.

194. Law MR, Morris JK and Wald NJ. Use of blood pressure lowering drugs in the prevention of cardiovascular disease: meta-analysis of 147 randomised trials in the context of expectations from prospective epidemiological studies. *BMJ* 2009; 338: b1665.

195. Arima H, Chalmers J, Woodward M, et al. Lower target blood pressures are safe and effective for the prevention of recurrent stroke: the PROGRESS trial. *J Hypertens* 2006; 24: 1201-1208.