# European stroke organisation (ESO) guideline on cerebral small vessel disease, part 2, lacunar ischaemic stroke

Joanna M Wardlaw, Hugues Chabriat, Frank-Erik de Leeuw, Stephanie Debette, Martin Dichgans, Fergus Doubal, Hanna Jokinen, Aristeidis H Katsanos, Raffaele Ornello, Leonardo Pantoni, et al.

<figure><img src="image_1.png" /></figure>

## To cite this version:

Joanna M Wardlaw, Hugues Chabriat, Frank-Erik de Leeuw, Stephanie Debette, Martin Dichgans, et al.. European stroke organisation (ESO) guideline on cerebral small vessel disease, part 2, lacunar ischaemic stroke. European Stroke Journal, 2024, 9 (1), pp.5-68. 10.1177/23969873231219416. hal-04570520

HAL Id: hal-04570520

https://hal.science/hal-04570520

Submitted on 7 May 2024

HAL is a multi-disciplinary open access archive for the deposit and dissemination of scientific research documents, whether they are published or not. The documents may come from teaching and research institutions in France or abroad, or from public or private research centers.

L'archive ouverte pluridisciplinaire HAL, est destinée au dépôt et à la diffusion de documents scientifiques de niveau recherche, publiés ou non, émanant des établissements d'enseignement et de recherche français ou étrangers, des laboratoires publics ou privés.

<figure><img src="image_2.png" /></figure>
# European stroke organisation (ESO) guideline on cerebral small vessel disease, part 2, lacunar ischaemic stroke

Joanna M Wardlaw, Hugues Chabriat, Frank-Erik de Leeuw, Stephanie Debette, Martin Dichgans, Fergus Doubal, Hanna Jokinen, Aristeidis H Katsanos, Raffaele Ornello, Leonardo Pantoni, et al.

<figure><img src="image_1.png" /></figure>

## To cite this version:

Joanna M Wardlaw, Hugues Chabriat, Frank-Erik de Leeuw, Stephanie Debette, Martin Dichgans, et al.. European stroke organisation (ESO) guideline on cerebral small vessel disease, part 2, lacunar ischaemic stroke. European Stroke Journal, 2024, 9 (1), pp.5-68. 10.1177/23969873231219416. hal-04570520

HAL Id: hal-04570520

https://hal.science/hal-04570520v1

Submitted on 7 May 2024

HAL is a multi-disciplinary open access
archive for the deposit and dissemination of sci-
entific research documents, whether they are pub-
lished or not. The documents may come from
teaching and research institutions in France or
abroad, or from public or private research centers.

L'archive ouverte pluridisciplinaire HAL, est
destinée au dépôt et à la diffusion de documents
scientifiques de niveau recherche, publiés ou non,
émanant des établissements d'enseignement et de
recherche français ou étrangers, des laboratoires
publics ou privés.

<figure><img src="image_2.png" /></figure>
# European stroke organisation (ESO) guideline on cerebral small vessel disease, part 2, lacunar ischaemic stroke

European Stroke Journal
2024, Vol. 9(1) 5–68
© European Stroke Organisation 2023

<figure><img src="image_3.png" /></figure>

Article reuse guidelines:
sagepub.com/journals-permissions
DOI: 10.1177/23969873231219416
journals.sagepub.com/home/eso

<figure><img src="image_4.png" /></figure>

Sage

Joanna M Wardlaw<fnref n="1" />,*, ID, Hugues Chabriat<fnref n="2" /> ID,
Frank-Erik de Leeuw<fnref n="3" />, Stéphanie Debette<fnref n="4" /> ID, Martin Dichgans<fnref n="5" /> ID,
Fergus Doubal<fnref n="6" /> ID, Hanna Jokinen<fnref n="7" /> ID, Aristeidis H Katsanos<fnref n="8" /> ID,
Raffaele Ornello<fnref n="9" /> ID, Leonardo Pantoni<fnref n="10" /> ID, Marco Pasi<fnref n="11" /> ID,
Aleksandra M Pavlovic<fnref n="12" /> ID, Salvatore Rudilosso<fnref n="13" /> ID,
Reinhold Schmidt<fnref n="14" />, Julie Staals<fnref n="15" /> ID, Martin Taylor-Rowan<fnref n="16" /> ID,
Salman Hussain<fnref n="17" /> ID and Arne G Lindgren<fnref n="18" />* ID

## Abstract

A quarter of ischaemic strokes are lacunar subtype, typically neurologically mild, usually resulting from intrinsic cerebral small vessel pathology, with risk factor profiles and outcome rates differing from other stroke subtypes. This European Stroke Organisation (ESO) guideline provides evidence-based recommendations to assist with clinical decisions about management of lacunar ischaemic stroke to prevent adverse clinical outcomes. The guideline was developed according to ESO standard operating procedures and Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) methodology. We addressed acute treatment (including progressive lacunar stroke) and secondary prevention in lacunar ischaemic stroke, and prioritised the interventions of thrombolysis, antiplatelet drugs, blood pressure lowering, lipid lowering, lifestyle, and other interventions and their potential effects on the clinical outcomes recurrent stroke, dependency, major adverse cardiovascular events, death, cognitive decline, mobility, gait, or mood

## Corresponding authors:

Joanna M Wardlaw, University of Edinburgh, Chancellor's Building, 49 Little France Crescent, Edinburgh EH16 4SB, UK.

Email: joanna.wardlaw@ed.ac.uk

Arne G Lindgren, Department of Neurology, Skåne University Hospital, Lund, Neurologimottagningen, Skånes Universitetssjukhus, 22185 Lund, Sweden.

Email: arne.lindgren@med.lu.se

<footnote n="1">¹Centre for Clinical Brain Sciences, UK Dementia Research Institute, University of Edinburgh, Edinburgh, UK</footnote>

<footnote n="2">²CNVT and Department of Neurology, Hopital Lariboisière, Paris, France</footnote>

<footnote n="3">³Department of Neurology, Radboud University Nijmegen Medical Center, Nijmegen, The Netherlands</footnote>

<footnote n="4">⁴Bordeaux Population Health Research Center; University of Bordeaux - Inserm U1219; Bordeaux; Department of Neurology, Institute for Neurodegenerative Diseases, Bordeaux University Hospital, Bordeaux, France</footnote>

<footnote n="5">⁵Institute for Stroke and Dementia Research (ISD), LMU University Hospital, LMU Munich, Medical Center, Munich; Munich Cluster for Systems Neurology (SyNergy), Munich; German Center for Neurodegenerative Diseases (DZNE, Munich), Munich; German Centre for Cardiovascular Research (DZHK, Munich), Munich, Germany</footnote>

<footnote n="6">⁶Centre for Clinical Brain Sciences, University of Edinburgh, Chancellor's Building, Edinburgh, UK</footnote>

<footnote n="7">⁷Neurocenter, Helsinki University Hospital and University of Helsinki, HUS, Helsinki, Finland</footnote>

<footnote n="8">⁸Neurology, McMaster University & Population Health Research Institute, Hamilton, ON, Canada</footnote>

<footnote n="9">⁹Neurology/Department of Biotechnological and Applied Clinical Sciences, University of L'Aquila, L'Aquila, Italy</footnote>

<footnote n="10">¹⁰Neurology and Stroke Unit, Luigi Sacco Hospital, Milan, Italy</footnote>

<footnote n="11">¹¹Department of Neurology, University of Tours, Tours, France</footnote>

<footnote n="12">¹²University of Belgrade, Faculty of Special Education and Rehabilitation, Belgrade, Serbia</footnote>

<footnote n="13">¹³Comprehensive Stroke Center, Department of Neurology, Hospital Clínic of Barcelona, Barcelona, Spain</footnote>

<footnote n="14">¹⁴Department of Neurology, Medical University Graz, Graz, Austria</footnote>

<footnote n="15">¹⁵Department of Neurology and CARIM School for cardiovascular diseases, MUMC+, Maastricht, The Netherlands</footnote>

<footnote n="16">¹⁶School of Health and Wellbeing; General Practice and Primary Care, Clarice Pears Building, University of Glasgow, Glasgow, UK</footnote>

<footnote n="17">¹⁷European Stroke Organisation, Basel, Switzerland</footnote>

<footnote n="18">¹⁸Department of Clinical Sciences Lund, Neurology, Lund University; Department of Neurology, Skåne University Hospital, Lund, Skånes Universitetssjukhus, Lund, Sweden</footnote>

<footnote>*Equal contribution.</footnote>
# European stroke organisation (ESO) guideline on cerebral small vessel disease, part 2, lacunar ischaemic stroke

European Stroke Journal
2024, Vol. 9(1) 5–68
© European Stroke Organisation 2023

<figure><img src="image_3.png" /></figure>

Article reuse guidelines:
sagepub.com/journals-permissions
DOI: 10.1177/23969873231219416
journals.sagepub.com/home/eso

<figure><img src="image_4.png" /></figure>

Sage

Joanna M Wardlaw<fnref n="1" />,*, ID, Hugues Chabriat<fnref n="2" /> ID,
Frank-Erik de Leeuw<fnref n="3" />, Stéphanie Debette<fnref n="4" /> ID, Martin Dichgans<fnref n="5" /> ID,
Fergus Doubal<fnref n="6" /> ID, Hanna Jokinen<fnref n="7" /> ID, Aristeidis H Katsanos<fnref n="8" /> ID,
Raffaele Ornello<fnref n="9" /> ID, Leonardo Pantoni<fnref n="10" /> ID, Marco Pasi<fnref n="11" /> ID,
Aleksandra M Pavlovic<fnref n="12" /> ID, Salvatore Rudilosso<fnref n="13" /> ID,
Reinhold Schmidt<fnref n="14" />, Julie Staals<fnref n="15" /> ID, Martin Taylor-Rowan<fnref n="16" /> ID,
Salman Hussain<fnref n="17" /> ID and Arne G Lindgren<fnref n="18" />* ID

## Abstract

A quarter of ischaemic strokes are lacunar subtype, typically neurologically mild, usually resulting from intrinsic cerebral small vessel pathology, with risk factor profiles and outcome rates differing from other stroke subtypes. This European Stroke Organisation (ESO) guideline provides evidence-based recommendations to assist with clinical decisions about management of lacunar ischaemic stroke to prevent adverse clinical outcomes. The guideline was developed according to ESO standard operating procedures and Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) methodology. We addressed acute treatment (including progressive lacunar stroke) and secondary prevention in lacunar ischaemic stroke, and prioritised the interventions of thrombolysis, antiplatelet drugs, blood pressure lowering, lipid lowering, lifestyle, and other interventions and their potential effects on the clinical outcomes recurrent stroke, dependency, major adverse cardiovascular events, death, cognitive decline, mobility, gait, or mood

## Corresponding authors:

Joanna M Wardlaw, University of Edinburgh, Chancellor's Building, 49 Little France Crescent, Edinburgh EH16 4SB, UK.

Email: joanna.wardlaw@ed.ac.uk

Arne G Lindgren, Department of Neurology, Skåne University Hospital, Lund, Neurologimottagningen, Skånes Universitetssjukhus, 22185 Lund, Sweden.

Email: arne.lindgren@med.lu.se

<footnote n="1">¹Centre for Clinical Brain Sciences, UK Dementia Research Institute, University of Edinburgh, Edinburgh, UK</footnote>

<footnote n="2">²CNVT and Department of Neurology, Hopital Lariboisière, Paris, France</footnote>

<footnote n="3">³Department of Neurology, Radboud University Nijmegen Medical Center, Nijmegen, The Netherlands</footnote>

<footnote n="4">⁴Bordeaux Population Health Research Center; University of Bordeaux - Inserm U1219; Bordeaux; Department of Neurology, Institute for Neurodegenerative Diseases, Bordeaux University Hospital, Bordeaux, France</footnote>

<footnote n="5">⁵Institute for Stroke and Dementia Research (ISD), LMU University Hospital, LMU Munich, Medical Center, Munich; Munich Cluster for Systems Neurology (SyNergy), Munich; German Center for Neurodegenerative Diseases (DZNE, Munich), Munich; German Centre for Cardiovascular Research (DZHK, Munich), Munich, Germany</footnote>

<footnote n="6">⁶Centre for Clinical Brain Sciences, University of Edinburgh, Chancellor's Building, Edinburgh, UK</footnote>

<footnote n="7">⁷Neurocenter, Helsinki University Hospital and University of Helsinki, HUS, Helsinki, Finland</footnote>

<footnote n="8">⁸Neurology, McMaster University & Population Health Research Institute, Hamilton, ON, Canada</footnote>

<footnote n="9">⁹Neurology/Department of Biotechnological and Applied Clinical Sciences, University of L'Aquila, L'Aquila, Italy</footnote>

<footnote n="10">¹⁰Neurology and Stroke Unit, Luigi Sacco Hospital, Milan, Italy</footnote>

<footnote n="11">¹¹Department of Neurology, University of Tours, Tours, France</footnote>

<footnote n="12">¹²University of Belgrade, Faculty of Special Education and Rehabilitation, Belgrade, Serbia</footnote>

<footnote n="13">¹³Comprehensive Stroke Center, Department of Neurology, Hospital Clínic of Barcelona, Barcelona, Spain</footnote>

<footnote n="14">¹⁴Department of Neurology, Medical University Graz, Graz, Austria</footnote>

<footnote n="15">¹⁵Department of Neurology and CARIM School for cardiovascular diseases, MUMC+, Maastricht, The Netherlands</footnote>

<footnote n="16">¹⁶School of Health and Wellbeing; General Practice and Primary Care, Clarice Pears Building, University of Glasgow, Glasgow, UK</footnote>

<footnote n="17">¹⁷European Stroke Organisation, Basel, Switzerland</footnote>

<footnote n="18">¹⁸Department of Clinical Sciences Lund, Neurology, Lund University; Department of Neurology, Skåne University Hospital, Lund, Skånes Universitetssjukhus, Lund, Sweden</footnote>

<footnote>*Equal contribution.</footnote>
disorders. We systematically reviewed the literature, assessed the evidence and where feasible formulated evidence-based recommendations, and expert consensus statements. We found little direct evidence, mostly of low quality. We recommend that patients with suspected acute lacunar ischaemic stroke receive intravenous alteplase, antiplatelet drugs and avoid blood pressure lowering according to current acute ischaemic stroke guidelines. For secondary prevention, we recommend single antiplatelet treatment long-term, blood pressure control, and lipid lowering according to current guidelines. We recommend smoking cessation, regular exercise, other healthy lifestyle modifications, and avoid obesity for general health benefits. We cannot make any recommendation concerning progressive stroke or other drugs. Large randomised controlled trials with clinically important endpoints, including cognitive endpoints, are a priority for lacunar ischaemic stroke.

## Keywords

Guideline, systematic review, stroke, small vessel disease, lacunar stroke, alteplase, thrombolysis, antiplatelet, antihypertensive, lipid lowering

Date received: 4 October 2023; accepted: 22 November 2023

## Introduction

Cerebral small vessel disease (cSVD) is a common cause of stroke, lacunar stroke about 25% of all ischaemic strokes and the major cause of intracerebral haemorrhage.¹ It also causes cognitive impairment, mobility and mood disorders, or it can be covert and detected on a brain scan performed for other purposes. cSVD is due to intrinsic disease in the perforating cerebral arterioles, thought to be at least partly due to endothelial or other vascular wall dysfunction.

This guideline is the second in a series of ESO Guidelines addressing management of patients with cSVD and focuses on ischaemic stroke resulting from cSVD, that is, management of patients with clinically suspected or presumed lacunar ischaemic stroke. The first of the series addressed covert cSVD.¹

We define ‘lacunar ischaemic stroke’ as ‘a combination of clinical findings suggestive of acute stroke due to a small subcortical ischaemic lesion (which may or may not be visible on brain imaging) thought to be due to cerebral small arterial vessel disease (i.e. no obvious large artery/cardioembolic cause)’, (Panel 1).² All mentions of ‘lacunar ischaemic stroke’ in this guideline refer to patients presenting with a stroke where symptoms and signs are consistent in time and location with a recent small subcortical infarct. It does not refer to lacunes seen on brain imaging without clearly related acute symptoms. Lacunar ischaemic stroke has a somewhat different risk factor and outcome profile compared to other stroke subtypes. Carotid or vertebrobasilar stenosis and cardioembolic sources are unusual.³ Lacunar stroke is associated with increased risk of recurrent stroke, death or dependency⁴ and cognitive impairment,⁵ in the long term.

Currently, patients with lacunar ischaemic stroke receive acute treatment (e.g. thrombolysis) and secondary prevention (i.e. antiplatelet drug(s), antihypertensive treatment, lipid lowering, and lifestyle advice) as for other types of ischaemic stroke. However, although many patients with

## Panel I – Common Lacunar Syndromes

**Yes:** Pure motor stroke involving more than one body location, e.g. face, upper extremity, lower extremity

Pure sensory stroke involving more than one body location, e.g. face, upper extremity, lower extremity

Sensory-motor stroke, involving more than one body location, e.g. face, upper extremity, lower extremity

Ataxic hemiparesis

Dysarthria clumsy hand syndrome

**No:** Monoparesis

Hemispatial neglect

Dysphasia

Visual loss

Any other higher cerebral dysfunction

Isolated dysarthria

Isolated ataxia

Isolated vertigo

Worst NIHSS >8

Headache

Alteration of consciousness

These suggest:
**a cortical infarct,**
**a large subcortical infarct, or infarct in cerebellum or brainstem.**
**May also be seen in people without stroke.**

lacunar ischaemic stroke were included in acute stroke treatment and secondary prevention trials, the results were rarely analysed separately for lacunar stroke.⁶ Additionally, the only large trial to test dual versus single antiplatelet drugs long term stopped prematurely due to hazard,⁷ and found that intensive versus guideline blood pressure lowering did not reduce recurrent stroke or prevent cognitive decline.⁸,⁹ Hence it is uncertain whether current treatment or prevention approaches are best suited for treatment in lacunar ischaemic stroke.

The aim of this guideline is to provide recommendations to guide cerebrovascular disease care providers to reach clinical decisions when assessing patients with suspected or presumed lacunar ischaemic stroke, along with investigation and management strategies to reduce the risk of recurrent stroke, long-term disability, cognitive, mobility, and mood disorders.
disorders. We systematically reviewed the literature, assessed the evidence and where feasible formulated evidence-based recommendations, and expert consensus statements. We found little direct evidence, mostly of low quality. We recommend that patients with suspected acute lacunar ischaemic stroke receive intravenous alteplase, antiplatelet drugs and avoid blood pressure lowering according to current acute ischaemic stroke guidelines. For secondary prevention, we recommend single antiplatelet treatment long-term, blood pressure control, and lipid lowering according to current guidelines. We recommend smoking cessation, regular exercise, other healthy lifestyle modifications, and avoid obesity for general health benefits. We cannot make any recommendation concerning progressive stroke or other drugs. Large randomised controlled trials with clinically important endpoints, including cognitive endpoints, are a priority for lacunar ischaemic stroke.

## Keywords

Guideline, systematic review, stroke, small vessel disease, lacunar stroke, alteplase, thrombolysis, antiplatelet, antihypertensive, lipid lowering

Date received: 4 October 2023; accepted: 22 November 2023

## Introduction

Cerebral small vessel disease (cSVD) is a common cause of stroke, lacunar stroke about 25% of all ischaemic strokes and the major cause of intracerebral haemorrhage.¹ It also causes cognitive impairment, mobility and mood disorders, or it can be covert and detected on a brain scan performed for other purposes. cSVD is due to intrinsic disease in the perforating cerebral arterioles, thought to be at least partly due to endothelial or other vascular wall dysfunction.

This guideline is the second in a series of ESO Guidelines addressing management of patients with cSVD and focuses on ischaemic stroke resulting from cSVD, that is, management of patients with clinically suspected or presumed lacunar ischaemic stroke. The first of the series addressed covert cSVD.¹

We define ‘lacunar ischaemic stroke’ as ‘a combination of clinical findings suggestive of acute stroke due to a small subcortical ischaemic lesion (which may or may not be visible on brain imaging) thought to be due to cerebral small arterial vessel disease (i.e. no obvious large artery/ cardioembolic cause)’, (Panel 1).² All mentions of ‘lacunar ischaemic stroke’ in this guideline refer to patients presenting with a stroke where symptoms and signs are consistent in time and location with a recent small subcortical infarct. It does not refer to lacunes seen on brain imaging without clearly related acute symptoms. Lacunar ischaemic stroke has a somewhat different risk factor and outcome profile compared to other stroke subtypes. Carotid or vertebrobasilar stenosis and cardioembolic sources are unusual.³ Lacunar stroke is associated with increased risk of recurrent stroke, death or dependency⁴ and cognitive impairment,⁵ in the long term.

Currently, patients with lacunar ischaemic stroke receive acute treatment (e.g. thrombolysis) and secondary prevention (i.e. antiplatelet drug(s), antihypertensive treatment, lipid lowering, and lifestyle advice) as for other types of ischaemic stroke. However, although many patients with

## Panel I – Common Lacunar Syndromes

**Yes:** Pure motor stroke involving more than one body location, e.g. face, upper extremity, lower extremity

Pure sensory stroke involving more than one body location, e.g. face, upper extremity, lower extremity

Sensory-motor stroke, involving more than one body location, e.g. face, upper extremity, lower extremity

Ataxic hemiparesis

Dysarthria clumsy hand syndrome

**No:** Monoparesis

Hemispatial neglect

Dysphasia

Visual loss

Any other higher cerebral dysfunction

Isolated dysarthria

Isolated ataxia

Isolated vertigo

Worst NIHSS >8

Headache

Alteration of consciousness

These suggest:
**a cortical infarct,**
**a large subcortical infarct, or infarct in cerebellum or brainstem.**
**May also be seen in people without stroke.**

lacunar ischaemic stroke were included in acute stroke treatment and secondary prevention trials, the results were rarely analysed separately for lacunar stroke.⁶ Additionally, the only large trial to test dual versus single antiplatelet drugs long term stopped prematurely due to hazard,⁷ and found that intensive versus guideline blood pressure lowering did not reduce recurrent stroke or prevent cognitive decline.⁸,⁹ Hence it is uncertain whether current treatment or prevention approaches are best suited for treatment in lacunar ischaemic stroke.

The aim of this guideline is to provide recommendations to guide cerebrovascular disease care providers to reach clinical decisions when assessing patients with suspected or presumed lacunar ischaemic stroke, along with investigation and management strategies to reduce the risk of recurrent stroke, long-term disability, cognitive, mobility, and mood disorders.
We first describe the selection of topics and some general advice on clinical assessment and diagnosis in lacunar stroke, prior to presenting the findings of each Population, Intervention, Comparator and Outcome (PICO) question.

## Advice on clinical assessment and diagnostics in lacunar ischaemic stroke

The Guideline Module Working Group (MWG) was conscious that lacunar ischaemic stroke is a somewhat neglected subtype of stroke and felt that it would be useful to provide some key background in order to use this guideline effectively.

**Clinical assessment:** Lacunar syndromes are described in Panel 1.² However, these symptoms and signs may overlap with cortical stroke syndromes in 15%-20% of cases ('clinical-imaging mismatch')¹⁰ and may be difficult to recognise in the acute stages. Some clinical findings increase the likelihood that an ischaemic stroke is due to lacunar infarction in the acute phase. For example, within 6h of symptom onset, neither lacunar clinical syndromes or NIHSS alone have good sensitivity or specificity for small subcortical infarcts, but the combination of a lacunar syndrome (the five commonest being: pure motor stroke, pure sensory stroke, sensory-motor stroke, ataxic hemiparesis and dysarthria clumsy hand) and stroke severity of NIHSS <7, gives a high specificity, positive and negative predictive values to detect acute small subcortical infarction.¹¹ Conversely, the presence of higher cortical dysfunction

such as neglect, dysphasia, visual loss, suggests a cortical or larger subcortical infarct. Pre-existing lacunes, leukoaraiosis/other neuroimaging markers of SVD, elevated BP and history of diabetes may also increase the likelihood of a new stroke being due to a small subcortical infarct (summarised in Ref.¹¹).

**Underlying causes/differential diagnoses not to be missed (Panel 2):** Small subcortical infarcts are not always due to sporadic intrinsic small vessel disease. It is important to avoid missing situations where an alternative guideline-based treatment should be considered. Clinical and/or imaging features that point to higher likelihood of cardio- or atherothromboembolic sources in a patient presenting with a lacunar clinical syndrome and/or a small subcortical infarct include: isolated subcortical infarct without any other signs of SVD on neuroimaging, cortical combined with subcortical infarcts; multiple contemporaneous infarcts involving more than one main arterial territory; large subcortical infarcts (as a guide>2 cm max diameter in the acute stage, but perceived size may depend on imaging modality); arterial dissection; and rare differential diagnoses of monogenic SVD (e.g. with unusually high burden of white matter hyperintensities (WMH), lacunes, microbleeds, and vascular risk factors in relation to age; lesion distribution; and family history¹²) especially in younger people. Cardioembolic and large artery disease (i.e. atherothromboembolic sources, dissection, embolic stroke of unknown source) should be managed according to the relevant guidelines (Table 1).

<table><caption>**Panel 2.** Alternative ischaemic cerebrovascular causes with specific treatments that are not to be missed in patients with suspected lacunar stroke, and standard investigations; note that practice varies between countries and hospitals and this is general guidance.</caption><thead><tr><th>Alternative cause</th><th>Clues that the cause is NOT intrinsic small vessel disease</th><th>Investigations</th></tr></thead><tbody><tr><td>Cardioembolic:</td><td><ul><li>Clinical history, symptoms, and findings suggesting cardiac disease</li><li>Contemporaneous cortical and small subcortical infarcts</li><li>Multiple contemporaneous infarcts in different arterial territories which may include a small subcortical infarct</li><li>Large subcortical infarct on imaging (as a guide, >2 cm axial diameter in the acute stage, although cardioembolic infarcts can be smaller and perceived size may depend on the type of imaging)</li></ul></td><td><p><strong>*Brain imaging, neck artery imaging, BP, routine haematology, blood glucose, lipids, coagulation, liver, kidney function tests, proteinuria</strong></p><p><strong>*ECG</strong><br><em>Cardiac echocardiography including PFO detection**</em><br>Prolonged ECG monitoring</em></p></td></tr><tr><td>Large artery atherothromboembolism</td><td><ul><li>Contemporaneous cortical and small subcortical infarcts</li><li>Large subcortical infarct on imaging (>2 cm axial diameter in the acute stage)</li><li>Manifestations of atherosclerosis in other organs e.g. coronary arteries, aorta, extremities</li></ul></td><td><p><strong>*Carotid/vertebral artery imaging, using ultrasound, CTA, or MRA</strong></p></td></tr><tr><td>Arterial dissection</td><td><ul><li>Clinical symptoms and findings suggesting dissection</li><li>Odd-shaped subcortical infarct</li><li>Presence of cortical infarct</li></ul></td><td><p><strong>*Carotid/vertebral artery imaging, using ultrasound, CTA, or MRA</strong></p></td></tr><tr><td>Intracranial atheromatous stenosis</td><td><ul><li>Large subcortical infarct (>2 cm axial diameter)</li><li>Long tubular infarct (>2 cm long) extending from the inferior perforating substance superiorly into the basal ganglia</li></ul></td><td><p>Intracranial CT or MR angiography. Vessel wall MRI</p></td></tr><tr><td>Rare monogenic causes</td><td><ul><li>Worse WMH, more lacunes, perivascular spaces, and microbleeds than usual for age, and vascular risk factors</li><li>Concomitant other manifestations from other organs, for example, eye, skin, heart, ear, kidney</li><li>Cerebral lesion distribution</li><li>Young onset</li><li>Family history</li></ul></td><td><p>Genetic testing</p></td></tr></tbody></table>

<footnote>*Should be routine in all ischaemic strokes including lacunar.</footnote>

<footnote>**PFO detection usually clinically relevant only for patients under 60-65 years of age.</footnote>
We first describe the selection of topics and some general advice on clinical assessment and diagnosis in lacunar stroke, prior to presenting the findings of each Population, Intervention, Comparator and Outcome (PICO) question.

## Advice on clinical assessment and diagnostics in lacunar ischaemic stroke

The Guideline Module Working Group (MWG) was conscious that lacunar ischaemic stroke is a somewhat neglected subtype of stroke and felt that it would be useful to provide some key background in order to use this guideline effectively.

**Clinical assessment:** Lacunar syndromes are described in Panel 1.² However, these symptoms and signs may overlap with cortical stroke syndromes in 15%-20% of cases ('clinical-imaging mismatch')¹⁰ and may be difficult to recognise in the acute stages. Some clinical findings increase the likelihood that an ischaemic stroke is due to lacunar infarction in the acute phase. For example, within 6h of symptom onset, neither lacunar clinical syndromes or NIHSS alone have good sensitivity or specificity for small subcortical infarcts, but the combination of a lacunar syndrome (the five commonest being: pure motor stroke, pure sensory stroke, sensory-motor stroke, ataxic hemiparesis and dysarthria clumsy hand) and stroke severity of NIHSS <7, gives a high specificity, positive and negative predictive values to detect acute small subcortical infarction.¹¹ Conversely, the presence of higher cortical dysfunction

such as neglect, dysphasia, visual loss, suggests a cortical or larger subcortical infarct. Pre-existing lacunes, leukoaraiosis/other neuroimaging markers of SVD, elevated BP and history of diabetes may also increase the likelihood of a new stroke being due to a small subcortical infarct (summarised in Ref.¹¹).

**Underlying causes/differential diagnoses not to be missed (Panel 2):** Small subcortical infarcts are not always due to sporadic intrinsic small vessel disease. It is important to avoid missing situations where an alternative guideline-based treatment should be considered. Clinical and/or imaging features that point to higher likelihood of cardio- or atherothromboembolic sources in a patient presenting with a lacunar clinical syndrome and/or a small subcortical infarct include: isolated subcortical infarct without any other signs of SVD on neuroimaging, cortical combined with subcortical infarcts; multiple contemporaneous infarcts involving more than one main arterial territory; large subcortical infarcts (as a guide>2 cm max diameter in the acute stage, but perceived size may depend on imaging modality); arterial dissection; and rare differential diagnoses of monogenic SVD (e.g. with unusually high burden of white matter hyperintensities (WMH), lacunes, microbleeds, and vascular risk factors in relation to age; lesion distribution; and family history¹²) especially in younger people. Cardioembolic and large artery disease (i.e. atherothromboembolic sources, dissection, embolic stroke of unknown source) should be managed according to the relevant guidelines (Table 1).

<table><caption>**Panel 2.** Alternative ischaemic cerebrovascular causes with specific treatments that are not to be missed in patients with suspected lacunar stroke, and standard investigations; note that practice varies between countries and hospitals and this is general guidance.</caption><thead><tr><th>Alternative cause</th><th>Clues that the cause is NOT intrinsic small vessel disease</th><th>Investigations</th></tr></thead><tbody><tr><td>Cardioembolic:</td><td><ul><li>Clinical history, symptoms, and findings suggesting cardiac disease</li><li>Contemporaneous cortical and small subcortical infarcts</li><li>Multiple contemporaneous infarcts in different arterial territories which may include a small subcortical infarct</li><li>Large subcortical infarct on imaging (as a guide, >2 cm axial diameter in the acute stage, although cardioembolic infarcts can be smaller and perceived size may depend on the type of imaging)</li></ul></td><td><p><strong>*Brain imaging, neck artery imaging, BP, routine haematology, blood glucose, lipids, coagulation, liver, kidney function tests, proteinuria</strong></p><p><strong>*ECG</strong></p><p>*Cardiac echocardiography including PFO detection**</p><p>Prolonged ECG monitoring</p></td></tr><tr><td>Large artery atherothromboembolism</td><td><ul><li>Contemporaneous cortical and small subcortical infarcts</li><li>Large subcortical infarct on imaging (>2 cm axial diameter in the acute stage)</li><li>Manifestations of atherosclerosis in other organs e.g. coronary arteries, aorta, extremities</li></ul></td><td><p><strong>*Carotid/vertebral artery imaging, using ultrasound, CTA, or MRA</strong></p></td></tr><tr><td>Arterial dissection</td><td><ul><li>Clinical symptoms and findings suggesting dissection</li><li>Odd-shaped subcortical infarct</li><li>Presence of cortical infarct</li></ul></td><td><p><strong>*Carotid/vertebral artery imaging, using ultrasound, CTA, or MRA</strong></p></td></tr><tr><td>Intracranial atheromatous stenosis</td><td><ul><li>Large subcortical infarct (>2 cm axial diameter)</li><li>Long tubular infarct (>2 cm long) extending from the inferior perforating substance superiorly into the basal ganglia</li></ul></td><td><p>Intracranial CT or MR angiography. Vessel wall MRI</p></td></tr><tr><td>Rare monogenic causes</td><td><ul><li>Worse WMH, more lacunes, perivascular spaces, and microbleeds than usual for age, and vascular risk factors</li><li>Concomitant other manifestations from other organs, for example, eye, skin, heart, ear, kidney</li><li>Cerebral lesion distribution</li><li>Young onset</li><li>Family history</li></ul></td><td><p>Genetic testing</p></td></tr></tbody></table>

<footnote>*Should be routine in all ischaemic strokes including lacunar.</footnote>

<footnote>**PFO detection usually clinically relevant only for patients under 60-65 years of age.</footnote>
<table><caption>**Table I.** Current guidelines on acute treatment or prevention of stroke relevant to presumed lacunar ischaemic stroke.</caption><thead><tr><th>Name of guideline</th><th>Date pub</th><th>Key findings related to acute phase treatment of SVD related stroke</th><th>Key findings related to secondary prevention of SVD related stroke</th><th>Key findings when presence SVD influences other treatments</th></tr></thead><tbody><tr><td>ESO Guidelines</td><td></td><td></td><td></td><td></td></tr><tr><td>ESO Guideline on covert cerebral small vessel disease</td><td>2021</td><td>Nil specific – focussed on patients with SVD and no diagnosis stroke/TIA/Cognitive impairment</td><td>Nil</td><td>Nil</td></tr><tr><td>European Stroke Organisation (ESO) – European Society for Minimally Invasive Neurological Therapy (ESMINT) Guidelines on Mechanical Thrombectomy in Acute Ischaemic Stroke<sup>13</sup></td><td>2019</td><td>Nil</td><td>Nil</td><td>Nil</td></tr><tr><td>A European Stroke Organisation (ESO) guideline on antithrombotic treatment for secondary prevention of stroke and other thromboembolic events in patients with stroke or transient ischaemic attack and non-valvular atrial fibrillation.<sup>14</sup></td><td>2019</td><td>Nil</td><td>Recommendations are weak regarding treatment with oral anticoagulants in . . . specific patient subgroups including those with small vessel disease, because of a lack of strong evidence; Recommendations. In patients with non-valvular AF, previous ischemic stroke or TIA and SVD, we cannot make recommendations about whether non-vitamin K antagonist oral anticoagulants should be preferred over vitamin K antagonists for reducing recurrent stroke or thromboembolism; Quality of evidence – Low; Strength of recommendation: Weak</td><td>No randomised controlled trials investigating the efficacy and safety of: antiplatelet therapy compared to no antithrombotic treatment; vitamin K antagonists versus antiplatelet therapy, or direct oral anticoagulants versus vitamin K antagonists, for prevention of recurrent stroke or other adverse outcomes in patients with non-valvular AF and SVD (WMH and CMBs).</td></tr><tr><td>European Stroke Organisation and European Academy of Neurology joint guidelines on post-stroke cognitive impairment<sup>15</sup></td><td>2021</td><td>Nil on treatment, focussed on post stroke cognitive impairment</td><td>Nil</td><td>Nil</td></tr><tr><td>European Stroke Organisation (ESO) guideline on pharmacological interventions for long-term secondary prevention after ischaemic stroke or transient ischaemic attack<sup>16</sup></td><td>2022</td><td>Nil</td><td>Nil</td><td>Nil</td></tr><tr><td>Consensus statements and recommendations from the ESO-Karolinska Stroke Update Conference, Stockholm 11–13 November 2018<sup>17</sup></td><td>11–13 November 2018</td><td>Nil</td><td>Nil</td><td>Individual decision making on OAC after ICH should consider (Grade C): quality of BP control, age, ICH location, burden of small vessel disease (cerebral microbleeds (CMBs), leukoaraiosis, cortical superficial siderosis, CAA), additional antiplatelet therapy. OAC in patients with evidence of CMBs should not be withheld (Grade C).</td></tr><tr><td>EAN/ERS/ESO/ESRS statement on the impact of sleep disorders on risk and outcome of stroke<sup>18</sup></td><td>2020</td><td>Nil</td><td>Nil</td><td>Nil</td></tr><tr><td>European Stroke Organisation (ESO) guidelines on intravenous thrombolysis for acute ischaemic stroke<sup>19</sup></td><td>2021</td><td>Although there are ongoing discussions about the use of IVT in patients with lacunar stroke, there is currently no strong evidence that it should be avoided</td><td>Nil</td><td>IVT is recommended in the presence of a small-to-moderate burden of white matter lesions and suggested in the presence of a high burden of lesions When CMB burden is unknown or known to be low (e.g. &lt;10), we suggest intravenous thrombolysis with alteplase. When CMB burden has been previously reported to be high (e.g. &gt;10), we suggest no intravenous thrombolysis. All members suggest against screening with MRI to assess CMB burden before making a treatment decision regarding IVT</td></tr></tbody></table>

(Continued)
<table><caption>**Table I.** Current guidelines on acute treatment or prevention of stroke relevant to presumed lacunar ischaemic stroke.</caption><thead><tr><th>Name of guideline</th><th>Date pub</th><th>Key findings related to acute phase treatment of SVD related stroke</th><th>Key findings related to secondary prevention of SVD related stroke</th><th>Key findings when presence SVD influences other treatments</th></tr></thead><tbody><tr><td>ESO Guidelines</td><td></td><td></td><td></td><td></td></tr><tr><td>ESO Guideline on covert cerebral small vessel disease</td><td>2021</td><td>Nil specific – focussed on patients with SVD and no diagnosis stroke/TIA/Cognitive impairment</td><td>Nil</td><td>Nil</td></tr><tr><td>European Stroke Organisation (ESO) – European Society for Minimally Invasive Neurological Therapy (ESMINT) Guidelines on Mechanical Thrombectomy in Acute Ischaemic Stroke<sup>13</sup></td><td>2019</td><td>Nil</td><td>Nil</td><td>Nil</td></tr><tr><td>A European Stroke Organisation (ESO) guideline on antithrombotic treatment for secondary prevention of stroke and other thromboembolic events in patients with stroke or transient ischaemic attack and non-valvular atrial fibrillation.<sup>14</sup></td><td>2019</td><td>Nil</td><td>Recommendations are weak regarding treatment with oral anticoagulants in . . . specific patient subgroups including those with small vessel disease, because of a lack of strong evidence; Recommendations. In patients with non-valvular AF, previous ischemic stroke or TIA and SVD, we cannot make recommendations about whether non-vitamin K antagonist oral anticoagulants should be preferred over vitamin K antagonists for reducing recurrent stroke or thromboembolism; Quality of evidence – Low; Strength of recommendation: Weak</td><td>No randomised controlled trials investigating the efficacy and safety of: antiplatelet therapy compared to no antithrombotic treatment; vitamin K antagonists versus antiplatelet therapy, or direct oral anticoagulants versus vitamin K antagonists, for prevention of recurrent stroke or other adverse outcomes in patients with non-valvular AF and SVD (WMH and CMBs).</td></tr><tr><td>European Stroke Organisation and European Academy of Neurology joint guidelines on post-stroke cognitive impairment<sup>15</sup></td><td>2021</td><td>Nil on treatment, focussed on post stroke cognitive impairment</td><td>Nil</td><td>Nil</td></tr><tr><td>European Stroke Organisation (ESO) guideline on pharmacological interventions for long-term secondary prevention after ischaemic stroke or transient ischaemic attack<sup>16</sup></td><td>2022</td><td>Nil</td><td>Nil</td><td>Nil</td></tr><tr><td>Consensus statements and recommendations from the ESO-Karolinska Stroke Update Conference, Stockholm 11–13 November 2018<sup>17</sup></td><td>11–13 November 2018</td><td>Nil</td><td>Nil</td><td>Individual decision making on OAC after ICH should consider (Grade C): quality of BP control, age, ICH location, burden of small vessel disease (cerebral microbleeds (CMBs), leukoaraiosis, cortical superficial siderosis, CAA), additional antiplatelet therapy. OAC in patients with evidence of CMBs should not be withheld (Grade C).</td></tr><tr><td>EAN/ERS/ESO/ESRS statement on the impact of sleep disorders on risk and outcome of stroke<sup>18</sup></td><td>2020</td><td>Nil</td><td>Nil</td><td>Nil</td></tr><tr><td>European Stroke Organisation (ESO) guidelines on intravenous thrombolysis for acute ischaemic stroke<sup>19</sup></td><td>2021</td><td>Although there are ongoing discussions about the use of IVT in patients with lacunar stroke, there is currently no strong evidence that it should be avoided</td><td>Nil</td><td>IVT is recommended in the presence of a small-to-moderate burden of white matter lesions and suggested in the presence of a high burden of lesions When CMB burden is unknown or known to be low (e.g. &lt;10), we suggest intravenous thrombolysis with alteplase. When CMB burden has been previously reported to be high (e.g. &gt;10), we suggest no intravenous thrombolysis. All members suggest against screening with MRI to assess CMB burden before making a treatment decision regarding IVT</td></tr></tbody></table>

(Continued)
<table><caption>**Table I. (Continued)**</caption><thead><tr><th>Name of guideline</th><th>Date pub</th><th>Key findings related to acute phase treatment of SVD related stroke</th><th>Key findings related to secondary prevention of SVD related stroke</th><th>Key findings when presence SVD influences other treatments</th></tr></thead><tbody><tr><td>European Stroke Organisation (ESO) guidelines on management of transient ischaemic attack<sup>20</sup></td><td>2021</td><td>Nil</td><td>Low risk TIA was defined by absence of high risk features (i.e. those in whom brain-tissue damage has not been detected on diffusion-weighted imaging, with no documented stenosis in the ipsilateral cerebral artery, no major cardiac source of embolism, no small vessel disease, and an ABCD2 score of less than 4)</td><td>Nil</td></tr><tr><td>Other European Guidelines Monogenic cerebral small-vessel diseases: diagnosis and therapy. Consensus recommendations of the European Academy of Neurology<sup>12</sup></td><td>2020</td><td>Patients with CADASIL should not receive thrombolysis for acute small-vessel ischaemic stroke (which is almost always the case)</td><td>Anticoagulants are not recommended for stroke prophylaxis in CADASIL due to the risk of intracerebral haemorrhage, but they are not contraindicated if there is another strong indication (e.g. atrial fibrillation, pulmonary embolus)</td><td>Nil</td></tr><tr><td>AHA/ASA 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<sup>21</sup></td><td>2021</td><td>Nil</td><td>In patients with ischemic stroke related to small vessel disease, the usefulness of cilostazol for secondary stroke prevention is uncertain. Targeted strategies for secondary prevention after small vessel stroke that also reduce the risk of vascular dementia are lacking. Studies that showed benefit from PFO closure excluded lacunar strokes</td><td>Nil</td></tr><tr><td>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<sup>22</sup></td><td>2019</td><td>Nil</td><td>For prevention of recurrent stroke, the use of MRI is reasonable in some patients with AIS to provide additional information to guide selection of appropriate secondary stroke prevention treatments. [Two studies from the 1990s evaluating repeat neuroimaging recommended repeat CT over additional MRI for most clinical situations in AIS with the exceptions of documenting lacunar and infratentorial infarcts, but they did not present evidence of a benefit on outcome for these situations]</td><td>Administration of IV alteplase in eligible patients without first obtaining MRI to exclude cerebral microbleeds (CMBs) is recommended<br>In otherwise eligible patients who have previously had a small number (1–10) of CMBs demonstrated on MRI, administration of IV alteplase is reasonable.<br>In otherwise eligible patients who have previously had a high burden of CMBs (>10) demonstrated on MRI, treatment with IV alteplase may be associated with an increased risk of sICH, and the benefits of treatment are uncertain.<br>Treatment may be reasonable if there is the potential for substantial benefit.<br>It is reasonable to provide anticoagulation therapy to patients with microbleeds when there is an indication (e.g. AF).<br>It is reasonable to provide antiplatelet therapy to patients with microbleeds when there is an indication.<br>It is reasonable to administer intravenous alteplase to patients with acute ischemic stroke and evidence of microbleeds if it is otherwise indicated.<br>It is reasonable to perform endovascular thrombectomy in patients with acute ischemic stroke and evidence of microbleeds.</td></tr><tr><td>AHA/ASA Scientific Statement – Prevention of Stroke in Patients With Silent Cerebrovascular Disease<sup>23</sup></td><td>2017</td><td>Nil</td><td>Nil</td><td>Nil</td></tr><tr><td>Canadian Stroke Best Practice Recommendations Canadian Stroke Best Practice Recommendations – secondary prevention<sup>24</sup></td><td>2020</td><td>Nil</td><td>Recommends aggressive blood pressure in patients with lacunar stroke (systolic target of consistently lower than 130mmHg)</td><td>Lacunar stroke contraindicates PFO closure</td></tr></tbody></table>

(Continued)
<table><caption>**Table I. (Continued)**</caption><thead><tr><th>Name of guideline</th><th>Date pub</th><th>Key findings related to acute phase treatment of SVD related stroke</th><th>Key findings related to secondary prevention of SVD related stroke</th><th>Key findings when presence SVD influences other treatments</th></tr></thead><tbody><tr><td>European Stroke Organisation (ESO) guidelines on management of transient ischaemic attack<sup>20</sup></td><td>2021</td><td>Nil</td><td>Low risk TIA was defined by absence of high risk features (i.e. those in whom brain-tissue damage has not been detected on diffusion-weighted imaging, with no documented stenosis in the ipsilateral cerebral artery, no major cardiac source of embolism, no small vessel disease, and an ABCD2 score of less than 4)</td><td>Nil</td></tr><tr><td>Other European Guidelines Monogenic cerebral small-vessel diseases: diagnosis and therapy. Consensus recommendations of the European Academy of Neurology<sup>12</sup></td><td>2020</td><td>Patients with CADASIL should not receive thrombolysis for acute small-vessel ischaemic stroke (which is almost always the case)</td><td>Anticoagulants are not recommended for stroke prophylaxis in CADASIL due to the risk of intracerebral haemorrhage, but they are not contraindicated if there is another strong indication (e.g. atrial fibrillation, pulmonary embolus)</td><td>Nil</td></tr><tr><td>AHA/ASA 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<sup>21</sup></td><td>2021</td><td>Nil</td><td>In patients with ischemic stroke related to small vessel disease, the usefulness of cilostazol for secondary stroke prevention is uncertain. Targeted strategies for secondary prevention after small vessel stroke that also reduce the risk of vascular dementia are lacking. Studies that showed benefit from PFO closure excluded lacunar strokes</td><td>Nil</td></tr><tr><td>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<sup>22</sup></td><td>2019</td><td>Nil</td><td>For prevention of recurrent stroke, the use of MRI is reasonable in some patients with AIS to provide additional information to guide selection of appropriate secondary stroke prevention treatments. [Two studies from the 1990s evaluating repeat neuroimaging recommended repeat CT over additional MRI for most clinical situations in AIS with the exceptions of documenting lacunar and infratentorial infarcts, but they did not present evidence of a benefit on outcome for these situations]</td><td>Administration of IV alteplase in eligible patients without first obtaining MRI to exclude cerebral microbleeds (CMBs) is recommended<br>In otherwise eligible patients who have previously had a small number (1–10) of CMBs demonstrated on MRI, administration of IV alteplase is reasonable.<br>In otherwise eligible patients who have previously had a high burden of CMBs (>10) demonstrated on MRI, treatment with IV alteplase may be associated with an increased risk of sICH, and the benefits of treatment are uncertain.<br>Treatment may be reasonable if there is the potential for substantial benefit.<br>It is reasonable to provide anticoagulation therapy to patients with microbleeds when there is an indication (e.g. AF).<br>It is reasonable to provide antiplatelet therapy to patients with microbleeds when there is an indication.<br>It is reasonable to administer intravenous alteplase to patients with acute ischemic stroke and evidence of microbleeds if it is otherwise indicated.<br>It is reasonable to perform endovascular thrombectomy in patients with acute ischemic stroke and evidence of microbleeds.</td></tr><tr><td>AHA/ASA Scientific Statement – Prevention of Stroke in Patients With Silent Cerebrovascular Disease<sup>23</sup></td><td>2017</td><td>Nil</td><td>Nil</td><td>Nil</td></tr><tr><td>Canadian Stroke Best Practice Recommendations Canadian Stroke Best Practice Recommendations – secondary prevention<sup>24</sup></td><td>2020</td><td>Nil</td><td>Recommends aggressive blood pressure in patients with lacunar stroke (systolic target of consistently lower than 130mmHg)</td><td>Lacunar stroke contraindicates PFO closure</td></tr></tbody></table>

(Continued)
<table><caption>**Table I. (Continued)**</caption><thead><tr><th>Name of guideline</th><th>Date pub</th><th>Key findings related to acute phase treatment of SVD related stroke</th><th>Key findings related to secondary prevention of SVD related stroke</th><th>Key findings when presence SVD influences other treatments</th></tr></thead><tbody><tr><td>Canadian Stroke Best Practice Recommendations – acute management<sup>25</sup><br/>UK-based guidelines</td><td>2022</td><td>Nil</td><td>Nil</td><td>Nil</td></tr><tr><td>Royal College of Physicians – National clinical guideline for stroke<sup>26</sup></td><td>2016</td><td>Nil</td><td>Mentioning the SPSS3 trial that suggests targeting a systolic BP of below 130 mmHg in patients with recent lacunar stroke</td><td>Reminding that pre-existing SVD should be assessed when evaluating the association between statin use and cerebral haemorrhage</td></tr><tr><td>NICE guideline – Stroke and transient ischaemic attack in over 16s: diagnosis and initial management: https://www.nice.org.uk/guidance/NG128</td><td>2019</td><td>Nil</td><td>Nil</td><td>Nil</td></tr><tr><td>Australia/New Zealand Australian and New Zealand Clinical Guidelines for Stroke Management – Acute stroke management<sup>27</sup></td><td>2021</td><td>Mentions a substudy of WAKE-UP which was able to show a very similar benefit of alteplase in the lacunar subgroup compared to non-lacunar patients, providing reassurance that lacunar stroke patients do indeed benefit from thrombolysis.</td><td>Secondary prevention with antihypertensives in patients with recent lacunar stroke is safe and effective.</td><td>CMBs at brain MRI do not contraindicate i.v. thrombolysis</td></tr><tr><td>Australian and New Zealand Clinical Guidelines for Stroke Management – Secondary prevention<sup>27</sup></td><td>2021</td><td>Nil</td><td>Antiplatelet treatment (without specific drug preference) is effective for secondary lacunar stroke prevention</td><td>Patients with lacunar stroke should not undergo PFO closure</td></tr><tr><td>Asian countries Chinese Stroke Association guidelines for clinical management of cerebrovascular disorders: executive summary and 2019 update of clinical management of ischaemic cerebrovascular diseases<sup>28</sup><br/>Also see Chinese guideline for diagnosis and treatment of cerebral small vessel disease 2020.<sup>29</sup></td><td>2020</td><td>At present, it is recommended to manage blood pressure, and use of aspirin, clopidogrel or cilostazol (class I, level of evidence B). The blood pressure of patients should be closely monitored (class IIa, level of evidence B). Control of systolic and diastolic pressure is the key factor to control the incidence and progression of cerebral small vessel disease (class IIa, level of evidence B). It is necessary to monitor the 24 hours ambulatory blood pressure in patients with cerebral small vessel disease. When conditions permit, it is best to detect changes in blood pressure during head upright tilt test (class I, level of evidence B).</td><td>Nil</td><td>Routine use of MRI to identify intracranial microhaemorrhage, which can affect decisions to IV thrombolysis, is not recommended (class III, level of evidence B). Prethrombolytic MRI examination showed that IV thrombolysis was reasonable in patients with a number of (I–10) cerebral microbleeds (class IIa, level of evidence B). Prethrombolytic MRI examination showed that IV thrombolysis was associated with an increased risk of symptomatic intracerebral haemorrhage in patients with a number of (> 10) cerebral microbleeds, and the clinical benefit is not clear. If there may be significant potential benefits, IV thrombolysis may be reasonable (class IIa, level of evidence B).</td></tr><tr><td>Japanese Stroke Guidelines<sup>30</sup></td><td>2021</td><td>Nil</td><td>In patients who experience ischemic stroke or TIA, without bilateral severe carotid artery stenosis and occlusion of major intracranial artery, who present with lacunar infarction, or undergoing antithrombotic therapy, as lower target value of blood pressure is favourable if possible, a target value of &lt;130/80 mmHg for antihypertensive therapy is reasonable (Grade B, LOE Moderate)</td><td>Nil</td></tr></tbody></table>

SVD: small vessel disease; VWMH: white matter hyperintensities on MRI; CMB: cerebral microbleeds; CAA: cerebral amyloid angiopathy; BP: blood pressure; OAC: oral anticoagulation; PFO: patent foramen ovale; AIS: acute ischaemic stroke; IVT: intravenous thrombolysis.
<table><caption>**Table I. (Continued)**</caption><thead><tr><th>Name of guideline</th><th>Date pub</th><th>Key findings related to acute phase treatment of SVD related stroke</th><th>Key findings related to secondary prevention of SVD related stroke</th><th>Key findings when presence SVD influences other treatments</th></tr></thead><tbody><tr><td>Canadian Stroke Best Practice Recommendations – acute management<sup>25</sup><br>UK-based guidelines</td><td>2022</td><td>Nil</td><td>Nil</td><td>Nil</td></tr><tr><td>Royal College of Physicians – National clinical guideline for stroke<sup>26</sup></td><td>2016</td><td>Nil</td><td>Mentioning the SPSS3 trial that suggests targeting a systolic BP of below 130 mmHg in patients with recent lacunar stroke</td><td>Reminding that pre-existing SVD should be assessed when evaluating the association between statin use and cerebral haemorrhage</td></tr><tr><td>NICE guideline – Stroke and transient ischaemic attack in over 16s: diagnosis and initial management: https://www.nice.org.uk/guidance/NG128</td><td>2019</td><td>Nil</td><td>Nil</td><td>Nil</td></tr><tr><td>Australia/New Zealand Australian and New Zealand Clinical Guidelines for Stroke Management – Acute stroke management<sup>27</sup></td><td>2021</td><td>Mentions a substudy of WAKE-UP which was able to show a very similar benefit of alteplase in the lacunar subgroup compared to non-lacunar patients, providing reassurance that lacunar stroke patients do indeed benefit from thrombolysis.</td><td>Secondary prevention with antihypertensives in patients with recent lacunar stroke is safe and effective.</td><td>CMBs at brain MRI do not contraindicate i.v. thrombolysis</td></tr><tr><td>Australian and New Zealand Clinical Guidelines for Stroke Management – Secondary prevention<sup>27</sup></td><td>2021</td><td>Nil</td><td>Antiplatelet treatment (without specific drug preference) is effective for secondary lacunar stroke prevention</td><td>Patients with lacunar stroke should not undergo PFO closure</td></tr><tr><td>Asian countries Chinese Stroke Association guidelines for clinical management of cerebrovascular disorders: executive summary and 2019 update of clinical management of ischaemic cerebrovascular diseases<sup>28</sup><br>Also see Chinese guideline for diagnosis and treatment of cerebral small vessel disease 2020.<sup>29</sup></td><td>2020</td><td>At present, it is recommended to manage blood pressure, and use of aspirin, clopidogrel or cilostazol (class I, level of evidence B). The blood pressure of patients should be closely monitored (class IIa, level of evidence B). Control of systolic and diastolic pressure is the key factor to control the incidence and progression of cerebral small vessel disease (class IIa, level of evidence B). It is necessary to monitor the 24 hours ambulatory blood pressure in patients with cerebral small vessel disease. When conditions permit, it is best to detect changes in blood pressure during head upright tilt test (class I, level of evidence B).</td><td>Nil</td><td>Routine use of MRI to identify intracranial microhaemorrhage, which can affect decisions to IV thrombolysis, is not recommended (class III, level of evidence B). Prethrombolytic MRI examination showed that IV thrombolysis was reasonable in patients with a number of (I–10) cerebral microbleeds (class IIa, level of evidence B). Prethrombolytic MRI examination showed that IV thrombolysis was associated with an increased risk of symptomatic intracerebral haemorrhage in patients with a number of (>10) cerebral microbleeds, and the clinical benefit is not clear. If there may be significant potential benefits, IV thrombolysis may be reasonable (class IIa, level of evidence B).</td></tr><tr><td>Japanese Stroke Guidelines<sup>30</sup></td><td>2021</td><td>Nil</td><td>In patients who experience ischemic stroke or TIA, without bilateral severe carotid artery stenosis and occlusion of major intracranial artery, who present with lacunar infarction, or undergoing antithrombotic therapy, as lower target value of blood pressure is favourable if possible, a target value of &lt;130/80 mmHg for antihypertensive therapy is reasonable (Grade B, LOE Moderate)</td><td>Nil</td></tr></tbody></table>

SVD: small vessel disease; VWMH: white matter hyperintensities on MRI; CMB: cerebral microbleeds; CAA: cerebral amyloid angiopathy; BP: blood pressure; OAC: oral anticoagulation; PFO: patent foramen ovale; AIS: acute ischaemic stroke; IVT: intravenous thrombolysis.
Summary of aetiologic work-up to be considered in suspected or presumed lacunar ischaemic stroke (Panel 2): All patients presenting with a suspected or presumed lacunar ischaemic stroke should undergo brain imaging, neck artery imaging (carotid ultrasound/CTA/MRA), screening for AF, and other routine stroke examinations (BP, blood glucose, lipids, markers of renal function, etc) may be considered to identify treatable causes of the stroke, relevant comorbidities and preventable causes of future stroke. Echocardiography and cerebral artery imaging may be indicated and additional tests (e.g. ambulatory ECG monitoring) further warranted depending on age and initial findings (e.g. fundus examination in diabetes or hypertension).

In the acute situation, CT or MR brain imaging is usually performed although CT does not show the acute small subcortical infarct in around 50% of cases within the first 6 h.³¹ Diagnostic algorithms have been suggested.¹¹ CT angiography of cerebral arteries may detect atherosclerotic changes including lesions at the origin of small penetrating arteries. CT perfusion, if performed routinely, should be examined closely since it may show a perfusion defect in a relevant brain region.³² MRI is very useful instead of or in addition to CT, when the relevant sequences are included (including DW-MRI, FLAIR, SWI, T1 and T2) since it has higher sensitivity for recent small subcortical as well as cortical infarcts and is often well tolerated in patients with lacunar ischaemic stroke. If not available acutely, then MRI is still worth performing up to a few weeks later, although the interpretation may be complicated since some small subcortical infarcts can disappear subacutely.³³

Cognitive evaluation should be considered in all patients with suspected/presumed lacunar ischaemic stroke in view of the high rate of cognitive impairment⁵ and to provide a baseline. Progression of cSVD may manifest as cognitive decline rather than recurrent stroke or dependency. Practical routine screening tools can include MMSE, MoCA and Trail Making test. A more comprehensive assessment by a neuropsychologist may be needed by patients of working age, or if a specific deficit or complaint is identified. Screening for neuropsychiatric symptoms (i.e. depression, apathy) should also be considered since these symptoms are relatively common, the tests provide a baseline and cSVD progression may manifest through fluctuation in neuropsychiatric symptoms.³⁴

# Methods

## Composition and approval of the Module Working Group

These guidelines were initiated by the ESO. Two chairpersons (Arne Lindgren and Joanna Wardlaw) were selected to assemble and coordinate the Guideline Module Working Group (MWG). The final group contained 17 experts (12 senior members and 5 fellows) plus a methodologist. The

ESO Guideline Board and Executive Committee reviewed the intellectual and financial disclosures of all MWG members and approved the composition of the group. The full details of all MWG members and their disclosures are included in Supplemental Table 1.

## Development and approval of clinical questions

This guideline was prepared according to the ESO standard operating procedures (SOP),³⁵ which are based on the Grading of Recommendations, Assessment, Development and Evaluations (GRADE) framework.³⁶ Supplemental Table 2 describes outcome grading. While recognising that many patients presenting with stroke also have pre-existing changes of cSVD on brain imaging, the MWG identified clinical lacunar ischaemic stroke as the most important topic to address in this guideline, deferring the topic of ‘other stroke subtypes with cSVD on imaging’ to a future guideline in view of the complexity of including both in one guideline. The MWG also identified that acute treatment (arbitrarily defined as ‘usually implemented within the first 24–48 h after symptom onset’), progressive lacunar stroke and secondary prevention were of great clinical interest, with some overlap between them. In the acute phase the clinical diagnosis of lacunar ischaemic stroke is often not completely clear, and we therefore used the term *suspected acute lacunar ischaemic stroke* for these situations. In contrast we used the term *lacunar ischaemic stroke* for the more long-term situations where secondary prevention becomes a priority. Interventions included thrombolysis and ‘other’ (i.e. novel) agents for acute treatment and progressive stroke; antiplatelet and antihypertensive agents for acute treatment, progressive stroke and secondary prevention; and lipid lowering and lifestyle interventions and other agents for secondary prevention. Common outcomes included recurrent ischaemic stroke, dependency, death, cognitive impairment or dementia, haemorrhagic stroke, Major Adverse Cardiovascular Event (MACE), mobility or gait disorder, and mood disorders. Questions were formatted using the PICO approach (Population, Intervention, Comparator and Outcome), generating 10 PICO questions in total (five acute, including progressive, and five secondary prevention, as summarised in Table 8) and reviewed by two external reviewers as well as members of the ESO Guideline board and Executive Committee. The outcomes were rated by members of the MWG as: critical, important or of limited importance according to GRADE criteria. The final decision on outcomes used a Delphi approach. Results of the outcomes rating for each PICO question are included in the Supplemental Table 2.

## Literature search

For each PICO question, search terms were developed by the MWG and guideline methodologist (SH). Where a
Summary of aetiologic work-up to be considered in suspected or presumed lacunar ischaemic stroke (Panel 2): All patients presenting with a suspected or presumed lacunar ischaemic stroke should undergo brain imaging, neck artery imaging (carotid ultrasound/CTA/MRA), screening for AF, and other routine stroke examinations (BP, blood glucose, lipids, markers of renal function, etc) may be considered to identify treatable causes of the stroke, relevant comorbidities and preventable causes of future stroke. Echocardiography and cerebral artery imaging may be indicated and additional tests (e.g. ambulatory ECG monitoring) further warranted depending on age and initial findings (e.g. fundus examination in diabetes or hypertension).

In the acute situation, CT or MR brain imaging is usually
performed although CT does not show the acute small sub-
cortical infarct in around 50% of cases within the first 6 h.³¹
Diagnostic algorithms have been suggested.¹¹ CT angiogra-
phy of cerebral arteries may detect atherosclerotic changes
including lesions at the origin of small penetrating arteries.
CT perfusion, if performed routinely, should be examined
closely since it may show a perfusion defect in a relevant
brain region.³² MRI is very useful instead of or in addition
to CT, when the relevant sequences are included (including
DW-MRI, FLAIR, SWI, T1 and T2) since it has higher sen-
sitivity for recent small subcortical as well as cortical
infarcts and is often well tolerated in patients with lacunar
ischaemic stroke. If not available acutely, then MRI is still
worth performing up to a few weeks later, although the
interpretation may be complicated since some small sub-
cortical infarcts can disappear subacutely.³³

Cognitive evaluation should be considered in all patients
with suspected/presumed lacunar ischaemic stroke in view
of the high rate of cognitive impairment⁵ and to provide a
baseline. Progression of cSVD may manifest as cognitive
decline rather than recurrent stroke or dependency. Practical
routine screening tools can include MMSE, MoCA and
Trail Making test. A more comprehensive assessment by a
neuropsychologist may be needed by patients of working
age, or if a specific deficit or complaint is identified.
Screening for neuropsychiatric symptoms (i.e. depression,
apathy) should also be considered since these symptoms are
relatively common, the tests provide a baseline and cSVD
progression may manifest through fluctuation in neuropsy-
chiatric symptoms.³⁴

**Methods**

Composition and approval of the Module
Working Group

These guidelines were initiated by the ESO. Two chairper-
sons (Arne Lindgren and Joanna Wardlaw) were selected to
assemble and coordinate the Guideline Module Working
Group (MWG). The final group contained 17 experts (12
senior members and 5 fellows) plus a methodologist. The

ESO Guideline Board and Executive Committee reviewed
the intellectual and financial disclosures of all MWG mem-
bers and approved the composition of the group. The full
details of all MWG members and their disclosures are
included in Supplemental Table 1.

Development and approval of clinical questions

This guideline was prepared according to the ESO standard
operating procedures (SOP),³⁵ which are based on the
Grading of Recommendations, Assessment, Development
and Evaluations (GRADE) framework.³⁶ Supplemental
Table 2 describes outcome grading. While recognising that
many patients presenting with stroke also have pre-existing
changes of cSVD on brain imaging, the MWG identified
clinical lacunar ischaemic stroke as the most important
topic to address in this guideline, deferring the topic of
‘other stroke subtypes with cSVD on imaging’ to a future
guideline in view of the complexity of including both in
one guideline. The MWG also identified that acute treat-
ment (arbitrarily defined as ‘usually implemented within
the first 24–48 h after symptom onset’), progressive lacunar
stroke and secondary prevention were of great clinical
interest, with some overlap between them. In the acute
phase the clinical diagnosis of lacunar ischaemic stroke is
often not completely clear, and we therefore used the term
suspected acute lacunar ischaemic stroke for these situa-
tions. In contrast we used the term lacunar ischaemic stroke
for the more long-term situations where secondary preven-
tion becomes a priority. Interventions included thromboly-
sis and ‘other’ (i.e. novel) agents for acute treatment and
progressive stroke; antiplatelet and antihypertensive agents
for acute treatment, progressive stroke and secondary pre-
vention; and lipid lowering and lifestyle interventions and
other agents for secondary prevention. Common outcomes
included recurrent ischaemic stroke, dependency, death,
cognitive impairment or dementia, haemorrhagic stroke,
Major Adverse Cardiovascular Event (MACE), mobility or
gait disorder, and mood disorders. Questions were format-
ted using the PICO approach (Population, Intervention,
Comparator and Outcome), generating 10 PICO questions
in total (five acute, including progressive, and five second-
ary prevention, as summarised in Table 8) and reviewed by
two external reviewers as well as members of the ESO
Guideline board and Executive Committee. The outcomes
were rated by members of the MWG as: critical, important
or of limited importance according to GRADE criteria. The
final decision on outcomes used a Delphi approach. Results
of the outcomes rating for each PICO question are included
in the Supplemental Table 2.

Literature search

For each PICO question, search terms were developed by
the MWG and guideline methodologist (SH). Where a
validated search strategy was available, this was used or
adapted. Where there was a recent relevant systematic
review on the question of interest, the corresponding search
strategy and results were used and updated as necessary.
Search strategies are described in Supplemental Appendix.

The search was performed by the ESO Guideline meth-
odologist (SH). The following databases: Medline, Embase
and Cochrane databases were searched from inception to
November 2022. Reference lists of review articles, trials
papers, the authors' personal reference libraries, conference
proceedings and previous guidelines were also searched for
additional relevant records.

Search results were loaded into the web-based Covidence
platform (Health Innovation, Melbourne, Australia) for
assessment by the MWG. Two or more MWG members
were assigned to independently screen the titles and
abstracts of publications registered in Covidence and then
assess the full text of studies determined to be potentially
relevant. All disagreements were resolved by discussion
between the two reviewers or by a third MWG member.

We prioritised randomised controlled trials (RCTs) but
where data were limited, we also considered health registry
data analyses, large observational studies and systematic
reviews or meta-analyses of observational studies. We con-
sidered only studies in humans. We excluded publications
with only conference abstracts available.

All PRISMA diagrams summarising the search findings
are available in the Supplement PRISMA diagrams.

Data analysis

Data extraction was performed by the MWG fellows and
members (and the methodologist for PICO 3/7), using a
pre-designed data extraction template. The ESO methodol-
ogist performed appropriate meta-analyses. Any discrep-
ancy during data extraction stage was resolved by
discussion. In the case that relevant data were not reported
in an eligible study, we attempted to contact the correspond-
ing author or co-authors of the study. If no answer was
received, data were considered as missing.

Due to the expectation of high heterogeneity, random-
effects meta-analyses were conducted using Review
Manager (RevMan) software (Cochrane) version 5.4.3.
Statistical heterogeneity across studies was assessed using
the I² statistic, and classified as moderate (≥30%), substan-
tial (≥50%) or considerable (≥75%).³⁷

Where appropriate, we performed outcome analyses
based on stroke outcome subtypes any stroke, ischaemic
stroke and haemorrhagic stroke; and severity (major
adverse cardiovascular events). Where suitable, we grouped
the trials into those with acute phase results (approximately
within 2–4 weeks after stroke onset), and those with long-
term results (treatment administered for more than 4 weeks).

Where appropriate, network meta-analysis was con-
ducted to compare multiple interventions simultaneously

for each outcome.³⁸ Network meta-analysis was conducted
only for PICO 6 which was found to be feasible based on
abundance of available evidence, transitivity assumption,
network connectivity, inconsistency or incoherence assess-
ment (node-splitting approach).³⁹ Evidence of incoherence
in the entire network was assessed using the design-by-
treatment model.⁴⁰ Assuming a common heterogeneity
parameter, network meta-analysis was performed with a
frequentist framework using a multivariate meta-analysis
estimated by restricted maximum likelihood to assess the
comparative effectiveness.⁴¹,⁴² We considered ‘placebo’ as
the reference group across the networks. Network meta-
analysis was performed using STATA version 15.1.

Evaluation of the quality of evidence and
formulation of recommendations

The risk of bias of each included randomised trial was
assessed with the Cochrane RoB2 tool by the ESO method-
ologist and MWG member independently.⁴³ Any discrep-
ancy or confusion in RoB judgement was discussed with a
third MWG member.⁴⁴

The results of data analysis were imported into the
GRADEpro Guideline Development Tool (McMaster
University, 2015; developed by Evidence Prime, Inc.). For
each PICO question, and each outcome, the following were
considered: risk of bias based on the type of available evi-
dence (randomised or observational studies); considera-
tions on inconsistency of results; indirectness of evidence,
imprecision of results, and other possible bias. GRADE
evidence profiles/summary of findings tables were gener-
ated and used to prepare recommendations. ‘Evidence-
based Recommendations’ were based on the GRADE
methodology. The direction, strength and formulation of
the recommendations were determined according to the
GRADE evidence profiles and the ESO-SOP.³⁵,³⁶

Finally, Expert Consensus Statements were added par-
ticularly whenever the PICO group considered that there
was insufficient evidence available to provide Evidence-
based Recommendations and practical guidance is needed
for routine clinical practice. The Expert Consensus
Statements were based on voting by all expert MWG mem-
bers (summarised in Supplemental Table 3). Importantly,
these Expert Consensus Statements should not be regarded
as Evidence-based Recommendations, since they only
reflect the opinion of the writing group.

Drafting of the document, revision and approval

Each PICO question was addressed in distinct sections, in
line with the updated ESO SOP.³⁵

First, ‘Analysis of current evidence’ summarised current
pathophysiological considerations followed by a summary
and discussion of the results of the identified RCTs and
other studies.
validated search strategy was available, this was used or
adapted. Where there was a recent relevant systematic
review on the question of interest, the corresponding search
strategy and results were used and updated as necessary.
Search strategies are described in Supplemental Appendix.

The search was performed by the ESO Guideline meth-
odologist (SH). The following databases: Medline, Embase
and Cochrane databases were searched from inception to
November 2022. Reference lists of review articles, trials
papers, the authors' personal reference libraries, conference
proceedings and previous guidelines were also searched for
additional relevant records.

Search results were loaded into the web-based Covidence
platform (Health Innovation, Melbourne, Australia) for
assessment by the MWG. Two or more MWG members
were assigned to independently screen the titles and
abstracts of publications registered in Covidence and then
assess the full text of studies determined to be potentially
relevant. All disagreements were resolved by discussion
between the two reviewers or by a third MWG member.

We prioritised randomised controlled trials (RCTs) but
where data were limited, we also considered health registry
data analyses, large observational studies and systematic
reviews or meta-analyses of observational studies. We con-
sidered only studies in humans. We excluded publications
with only conference abstracts available.

All PRISMA diagrams summarising the search findings
are available in the Supplement PRISMA diagrams.

Data analysis

Data extraction was performed by the MWG fellows and
members (and the methodologist for PICO 3/7), using a
pre-designed data extraction template. The ESO methodol-
ogist performed appropriate meta-analyses. Any discrep-
ancy during data extraction stage was resolved by
discussion. In the case that relevant data were not reported
in an eligible study, we attempted to contact the correspond-
ing author or co-authors of the study. If no answer was
received, data were considered as missing.

Due to the expectation of high heterogeneity, random-
effects meta-analyses were conducted using Review
Manager (RevMan) software (Cochrane) version 5.4.3.
Statistical heterogeneity across studies was assessed using
the I² statistic, and classified as moderate (≥30%), substan-
tial (≥50%) or considerable (≥75%).³⁷

Where appropriate, we performed outcome analyses
based on stroke outcome subtypes any stroke, ischaemic
stroke and haemorrhagic stroke; and severity (major
adverse cardiovascular events). Where suitable, we grouped
the trials into those with acute phase results (approximately
within 2–4 weeks after stroke onset), and those with long-
term results (treatment administered for more than 4 weeks).

Where appropriate, network meta-analysis was con-
ducted to compare multiple interventions simultaneously

for each outcome.³⁸ Network meta-analysis was conducted
only for PICO 6 which was found to be feasible based on
abundance of available evidence, transitivity assumption,
network connectivity, inconsistency or incoherence assess-
ment (node-splitting approach).³⁹ Evidence of incoherence
in the entire network was assessed using the design-by-
treatment model.⁴⁰ Assuming a common heterogeneity
parameter, network meta-analysis was performed with a
frequentist framework using a multivariate meta-analysis
estimated by restricted maximum likelihood to assess the
comparative effectiveness.⁴¹,⁴² We considered ‘placebo’ as
the reference group across the networks. Network meta-
analysis was performed using STATA version 15.1.

Evaluation of the quality of evidence and
formulation of recommendations

The risk of bias of each included randomised trial was
assessed with the Cochrane RoB2 tool by the ESO method-
ologist and MWG member independently.⁴³ Any discrep-
ancy or confusion in RoB judgement was discussed with a
third MWG member.⁴⁴

The results of data analysis were imported into the
GRADEpro Guideline Development Tool (McMaster
University, 2015; developed by Evidence Prime, Inc.). For
each PICO question, and each outcome, the following were
considered: risk of bias based on the type of available evi-
dence (randomised or observational studies); considera-
tions on inconsistency of results; indirectness of evidence,
imprecision of results, and other possible bias. GRADE
evidence profiles/summary of findings tables were gener-
ated and used to prepare recommendations. ‘Evidence-
based Recommendations’ were based on the GRADE
methodology. The direction, strength and formulation of
the recommendations were determined according to the
GRADE evidence profiles and the ESO-SOP.³⁵,³⁶

Finally, Expert Consensus Statements were added par-
ticularly whenever the PICO group considered that there
was insufficient evidence available to provide Evidence-
based Recommendations and practical guidance is needed
for routine clinical practice. The Expert Consensus
Statements were based on voting by all expert MWG mem-
bers (summarised in Supplemental Table 3). Importantly,
these Expert Consensus Statements should not be regarded
as Evidence-based Recommendations, since they only
reflect the opinion of the writing group.

Drafting of the document, revision and approval

Each PICO question was addressed in distinct sections, in
line with the updated ESO SOP.³⁵

First, ‘Analysis of current evidence’ summarised current
pathophysiological considerations followed by a summary
and discussion of the results of the identified RCTs and
other studies.
Second, ‘Additional information’ was added when more details on the studies referred to in the first section were needed to provide information on key subgroup analyses of the included studies, on ongoing or future RCTs, and on other studies which can provide important clinical guidance on the topic.

Third, an ‘Expert Consensus Statement’ paragraph was added when the MWG considered that insufficient evidence was available to provide evidence-based recommendations for situations in which practical guidance is needed for everyday clinical practice.

The Guideline document was reviewed several times by all MWG members and modified using a Delphi approach until consensus was reached. The final submitted document was peer-reviewed by two external reviewers, two members of the ESO Guideline Board and one member of the Executive Committee.

# Results

## PICO 1:

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?

### Analysis of current evidence

The use of intravenous thrombolysis in patients with lacunar stroke has been debated over the years, for three reasons.⁴⁵ Firstly, lacunar strokes are mild in many instances, and this may raise the suspicion of an unclear benefit over side effects, particularly the risk of bleeding. Secondly, thrombosis in the perforating arteriole is not identified routinely in lacunar stroke because the affected vessel is too small to be visualised in vivo. Thirdly, patients with lacunar stroke usually have other features of small vessel disease (SVD) (e.g. white matter hyperintensities and microbleeds) that are associated with an increased haemorrhagic risk, whether or not linked with thrombolysis.³¹ Additionally, amongst neurologically milder strokes, in a routine clinical setting, the diagnosis of the ischaemic stroke subtype can be difficult in the hyperacute or acute time window, although use of diagnostic algorithms¹¹ and CT perfusion³² may help, particularly in the absence of MRI. In the first 24–48 h after stroke onset, approximately 15% of clinical lacunar syndromes are due to a cortical infarct on brain imaging and about 15%–20% of neurologically mild cortical syndromes are due to a recent small subcortical infarct.¹⁰ A further point to note is that dependency is a less frequent outcome of lacunar⁴⁶ than of other more severe stroke

subtypes and therefore functional outcome using the often dichotomised mRS 0–2 versus mRS 3–6 may not be the most sensitive measure of outcome when assessing the effects of acute treatments such as thrombolysis, and an alternative for lacunar ischaemic stroke trials may be to use mRS 0–1 versus 2–6 instead. This notwithstanding, up to 2014, observational and limited randomised trial data had suggested that thrombolysis is an effective treatment in acute lacunar stroke, and that while the presence of cSVD increases the risk of intracerebral haemorrhage during thrombolysis, it did not represent an absolute exclusion criterion.⁴⁵

Our literature search retrieved 897 papers (Supplement PRISMA diagram). 851 non-duplicate studies were screened, of which 47 were assessed for eligibility. Two trials were identified by independent searching. Finally, five RCTs were relevant to the review of which three could be meta-analysed (Supplemental Table 4).

Only one outcome, good functional outcome, that is recognised to have limitations in assessing outcome after lacunar stroke, is available for more than two trials. The risk of bias is low but the sample size is small (521 patients is smaller than the National Institute of Neurological Disorders and Stroke (NINDS) trial and all the European Cooperative Acute Stroke Study (ECASS) trials), the certainty is very low, and the confidence intervals are very wide. Data on SICH and death are extremely limited.

Three trials of intravenous alteplase versus control included patients with lacunar stroke where the outcome data for the lacunar patients could be extracted: NINDS,⁴⁷ IST-3,⁴⁸,⁴⁹ and Wake-up.⁵⁰ One trial, Enhanced Control of Hypertension and Thrombolysis Stroke Study, (ENCHANTED) tested low versus standard dose of alteplase and provided data on lacunar stroke.⁵¹ In another RCT in patients with mild stroke, the Potential of rtPA for Ischaemic Strokes With Mild Symptoms (PRISMS) trial,⁵² 35% of patients had lacunar stroke but the results were not published by stroke subtype.

The original NINDS trial⁴⁷ (total n=624) included a small subsample (n=81) of patients with lacunar stroke, of whom 51 were randomised to alteplase and 30 to placebo within 3 h from symptoms onset.

In the IST-3, n=3035, 168 patients with lacunar stroke within 6 h from symptoms onset were randomised to alteplase 0.9 mg/kg and 164 to placebo.⁴⁸ A secondary analysis considered patients randomised within 3 h of stroke who were NIHSS ≤5, with pretreatment blood pressure <185/110 mmHg, and no other alteplase exclusion criteria. 106/3035 met the restricted criteria in whom allocation to alteplase was associated with an increase in Oxfordshire Handicap Score (OHS) 0–2 (84% alteplase vs 65% control; (OR 3.31, 95% CI 1.24, 8.79) and a favourable shift in OHS distribution (OR 2.38, 95% CI 1.17, 4.85). There was no significant effect of alteplase on OHS 0–1 (60% vs 51%; OR 1.92, 95% CI 0.83, 4.43).⁴⁹
Second, ‘Additional information’ was added when more details on the studies referred to in the first section were needed to provide information on key subgroup analyses of the included studies, on ongoing or future RCTs, and on other studies which can provide important clinical guidance on the topic.

Third, an ‘Expert Consensus Statement’ paragraph was added when the MWG considered that insufficient evidence was available to provide evidence-based recommendations for situations in which practical guidance is needed for everyday clinical practice.

The Guideline document was reviewed several times by all MWG members and modified using a Delphi approach until consensus was reached. The final submitted document was peer-reviewed by two external reviewers, two members of the ESO Guideline Board and one member of the Executive Committee.

# Results

## PICO 1:

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?

### Analysis of current evidence

The use of intravenous thrombolysis in patients with lacunar stroke has been debated over the years, for three reasons.⁴⁵ Firstly, lacunar strokes are mild in many instances, and this may raise the suspicion of an unclear benefit over side effects, particularly the risk of bleeding. Secondly, thrombosis in the perforating arteriole is not identified routinely in lacunar stroke because the affected vessel is too small to be visualised in vivo. Thirdly, patients with lacunar stroke usually have other features of small vessel disease (SVD) (e.g. white matter hyperintensities and microbleeds) that are associated with an increased haemorrhagic risk, whether or not linked with thrombolysis.³¹ Additionally, amongst neurologically milder strokes, in a routine clinical setting, the diagnosis of the ischaemic stroke subtype can be difficult in the hyperacute or acute time window, although use of diagnostic algorithms¹¹ and CT perfusion³² may help, particularly in the absence of MRI. In the first 24–48 h after stroke onset, approximately 15% of clinical lacunar syndromes are due to a cortical infarct on brain imaging and about 15%–20% of neurologically mild cortical syndromes are due to a recent small subcortical infarct.¹⁰ A further point to note is that dependency is a less frequent outcome of lacunar⁴⁶ than of other more severe stroke

subtypes and therefore functional outcome using the often dichotomised mRS 0–2 versus mRS 3–6 may not be the most sensitive measure of outcome when assessing the effects of acute treatments such as thrombolysis, and an alternative for lacunar ischaemic stroke trials may be to use mRS 0–1 versus 2–6 instead. This notwithstanding, up to 2014, observational and limited randomised trial data had suggested that thrombolysis is an effective treatment in acute lacunar stroke, and that while the presence of cSVD increases the risk of intracerebral haemorrhage during thrombolysis, it did not represent an absolute exclusion criterion.⁴⁵

Our literature search retrieved 897 papers (Supplement PRISMA diagram). 851 non-duplicate studies were screened, of which 47 were assessed for eligibility. Two trials were identified by independent searching. Finally, five RCTs were relevant to the review of which three could be meta-analysed (Supplemental Table 4).

Only one outcome, good functional outcome, that is recognised to have limitations in assessing outcome after lacunar stroke, is available for more than two trials. The risk of bias is low but the sample size is small (521 patients is smaller than the National Institute of Neurological Disorders and Stroke (NINDS) trial and all the European Cooperative Acute Stroke Study (ECASS) trials), the certainty is very low, and the confidence intervals are very wide. Data on SICH and death are extremely limited.

Three trials of intravenous alteplase versus control included patients with lacunar stroke where the outcome data for the lacunar patients could be extracted: NINDS,⁴⁷ IST-3⁴⁸,⁴⁹ and Wake-up.⁵⁰ One trial, Enhanced Control of Hypertension and Thrombolysis Stroke Study, (ENCHANTED) tested low versus standard dose of alteplase and provided data on lacunar stroke.⁵¹ In another RCT in patients with mild stroke, the Potential of rtPA for Ischaemic Strokes With Mild Symptoms (PRISMS) trial,⁵² 35% of patients had lacunar stroke but the results were not published by stroke subtype.

The original NINDS trial⁴⁷ (total n=624) included a small subsample (n=81) of patients with lacunar stroke, of whom 51 were randomised to alteplase and 30 to placebo within 3 h from symptoms onset.

In the IST-3, n=3035, 168 patients with lacunar stroke within 6 h from symptoms onset were randomised to alteplase 0.9 mg/kg and 164 to placebo.⁴⁸ A secondary analysis considered patients randomised within 3 h of stroke who were NIHSS ≤5, with pretreatment blood pressure <185/110 mmHg, and no other alteplase exclusion criteria. 106/3035 met the restricted criteria in whom allocation to alteplase was associated with an increase in Oxfordshire Handicap Score (OHS) 0–2 (84% alteplase vs 65% control; (OR 3.31, 95% CI 1.24, 8.79) and a favourable shift in OHS distribution (OR 2.38, 95% CI 1.17, 4.85). There was no significant effect of alteplase on OHS 0–1 (60% vs 51%; OR 1.92, 95% CI 0.83, 4.43).⁴⁹
The Wake-up trial⁵⁰ enrolled patients with wake up stroke or unknown time of symptom onset with a DWI-FLAIR mismatch indicating salvageable tissue amongst which were included 108 patients with lacunar ischaemic stroke, of whom 55 were randomised to alteplase, 53 to placebo.

The ENCHANTED trial⁵¹ enrolled a subgroup of 241 patients with lacunar stroke within 4.5 h from symptoms onset treated with alteplase 0.6 mg/kg and 249 randomised to alteplase 0.9 mg/kg.

PRISMS included 35% lacunar stroke, 29% undetermined type (some of which may have been lacunar) and 29% large artery atherosclerosis or cardioembolic. However, results were not presented by subtype and therefore cannot be included in the meta-analysis. Worth noting is the overall neutral result for all patients and the excess of haemorrhages in the alteplase group.

The duration of follow-up was 90 days for all except the IST3 trial which was 6 months.

The main drug evaluated was alteplase in a standard 0.9 mg/kg dose (in ENCHANTED a comparison of different doses was available).

A meta-analysis of three trials (NINDS, IST-3, Wake-up) on good functional outcomes was possible (Table 2, Figure 1). Some data were available on SICH and death, but this was not meta-analysable since events were too sparse. We provide a narrative summary of available outcomes. There were no data on recurrent ischaemic stroke, MACE, cognitive impairment or dementia, mobility or mood disorders.

**Functional outcome.** Three trials have evaluated the effect of thrombolysis with alteplase 0.9 mg/kg on functional outcome, total *n* = 521. Allocation to alteplase was associated with non-significantly higher odds of good functional outcome defined as mRS 0–1 in NINDS and Wake up and as Oxford Handicap Scale 0–2 in IST-3 (*p* = 0.33) (Figure 1).

**Symptomatic intracranial haemorrhage (SICH).** In Wake-up, 1/55 lacunar stroke patients allocated alteplase had SICH compares with none of 53 patients allocated placebo. Data were not provided in SICH for lacunar stroke patients in NINDS or IST-3.

In ENCHANTED, none of 241 lacunar stroke patients allocated 0.6 mg/kg alteplase had SICH versus 1/249 patients allocated 0.9 mg/kg alteplase. For any ICH, there were 11/241 (4.6%) ICH in the low dose and 7/249 (2.8%) ICH in the standard dose groups, aOR 1.50, 95% CI 0.56, 3.99.

**Death.** Data amongst patients with lacunar stroke allocated alteplase versus no alteplase were available from WAKE-up: 1/55 patients allocated alteplase versus 0/53 allocated no alteplase died within 90 days.

<table><caption>**Table 2.** PICO I: GRADE evidence profile table for alteplase compared to placebo for good functional outcome in patients with lacunar stroke.</caption><thead><tr><th rowspan="2">No of studies</th><th rowspan="2">Study design</th><th rowspan="2">Risk of bias</th><th rowspan="2">Inconsistency</th><th rowspan="2">Indirectness</th><th rowspan="2">Imprecision</th><th rowspan="2">Other considerations</th><th colspan="2">No of patients</th><th colspan="2">Effect</th><th rowspan="2">Certainty</th><th rowspan="2">Importance</th></tr><tr><th>Alteplase</th><th>Placebo</th><th>Relative (95% CI)</th><th>Absolute (95% CI)</th></tr></thead><tbody><tr><td>3</td><td>Good Functional Outcome (defined as mRS scores 0–1; Oxford Handicap Score 0–2)<br/>Randomised controlled trials</td><td>Not serious</td><td>Serious<sup>a</sup></td><td>Serious</td><td>Very serious<sup>b</sup></td><td>None</td><td>163/274 (59.5%)</td><td>139/247 (56.3%)</td><td>OR 1.36 (0.73, 2.55)</td><td>74 more per 1000 (from 78 fewer to 204 more)</td><td>⊕○○○ Very Low</td><td>CRITICAL</td></tr></tbody></table>

CI: confidence interval; OR: odds ratio.

aHigh heterogeneity (I²=59%).

bLow sample size and confidence interval crosses the clinical decision threshold.
The Wake-up trial⁵⁰ enrolled patients with wake up stroke or unknown time of symptom onset with a DWI-FLAIR mismatch indicating salvageable tissue amongst which were included 108 patients with lacunar ischaemic stroke, of whom 55 were randomised to alteplase, 53 to placebo.

The ENCHANTED trial⁵¹ enrolled a subgroup of 241 patients with lacunar stroke within 4.5 h from symptoms onset treated with alteplase 0.6 mg/kg and 249 randomised to alteplase 0.9 mg/kg.

PRISMS included 35% lacunar stroke, 29% undetermined type (some of which may have been lacunar) and 29% large artery atherosclerosis or cardioembolic. However, results were not presented by subtype and therefore cannot be included in the meta-analysis. Worth noting is the overall neutral result for all patients and the excess of haemorrhages in the alteplase group.

The duration of follow-up was 90 days for all except the IST3 trial which was 6 months.

The main drug evaluated was alteplase in a standard 0.9 mg/kg dose (in ENCHANTED a comparison of different doses was available).

A meta-analysis of three trials (NINDS, IST-3, Wake-up) on good functional outcomes was possible (Table 2, Figure 1). Some data were available on SICH and death, but this was not meta-analysable since events were too sparse. We provide a narrative summary of available outcomes. There were no data on recurrent ischaemic stroke, MACE, cognitive impairment or dementia, mobility or mood disorders.

**Functional outcome.** Three trials have evaluated the effect of thrombolysis with alteplase 0.9 mg/kg on functional outcome, total *n* = 521. Allocation to alteplase was associated with non-significantly higher odds of good functional outcome defined as mRS 0–1 in NINDS and Wake up and as Oxford Handicap Scale 0–2 in IST-3 (*p* = 0.33) (Figure 1).

**Symptomatic intracranial haemorrhage (SICH).** In Wake-up, 1/55 lacunar stroke patients allocated alteplase had SICH compares with none of 53 patients allocated placebo. Data were not provided in SICH for lacunar stroke patients in NINDS or IST-3.

In ENCHANTED, none of 241 lacunar stroke patients allocated 0.6 mg/kg alteplase had SICH versus 1/249 patients allocated 0.9 mg/kg alteplase. For any ICH, there were 11/241 (4.6%) ICH in the low dose and 7/249 (2.8%) ICH in the standard dose groups, aOR 1.50, 95% CI 0.56, 3.99.

**Death.** Data amongst patients with lacunar stroke allocated alteplase versus no alteplase were available from WAKE-up: 1/55 patients allocated alteplase versus 0/53 allocated no alteplase died within 90 days.

<table><caption>**Table 2.** PICO I: GRADE evidence profile table for alteplase compared to placebo for good functional outcome in patients with lacunar stroke.</caption><thead><tr><th rowspan="2">No of studies</th><th rowspan="2">Study design</th><th rowspan="2">Risk of bias</th><th rowspan="2">Inconsistency</th><th rowspan="2">Indirectness</th><th rowspan="2">Imprecision</th><th rowspan="2">Other considerations</th><th colspan="2">No of patients</th><th colspan="2">Effect</th><th rowspan="2">Certainty</th><th rowspan="2">Importance</th></tr><tr><th>Alteplase</th><th>Placebo</th><th>Relative (95% CI)</th><th>Absolute (95% CI)</th></tr></thead><tbody><tr><td>3</td><td>Good Functional Outcome (defined as mRS scores 0–1; Oxford Handicap Score 0–2)<br/>Randomised controlled trials</td><td>Not serious</td><td>Serious<sup>a</sup></td><td>Serious</td><td>Very serious<sup>b</sup></td><td>None</td><td>163/274 (59.5%)</td><td>139/247 (56.3%)</td><td>OR 1.36 (0.73, 2.55)</td><td>74 more per 1000 (from 78 fewer to 204 more)</td><td>⊕○○○ Very Low</td><td>CRITICAL</td></tr></tbody></table>

CI: confidence interval; OR: odds ratio.

aHigh heterogeneity (I²=59%).

bLow sample size and confidence interval crosses the clinical decision threshold.
<figure><img src="image_5.png" /><figcaption>**Figure 1.** The effect of alteplase versus placebo on favourable functional outcome (OHS 0–2 in IST-3)/excellent functional outcome (mRS 0–1 in NINDS and Wake-up trials) in patients with acute lacunar ischaemic stroke.</figcaption></figure>

In ENCHANTED, 1/241 patients with lacunar stroke allocated low dose alteplase and 2/249 lacunar strokes allocated standard dose alteplase died within 90 days, aOR 0.44, 95% CI 0.03, 5.71.

## Additional information

In ENCHANTED,⁵¹ 490 patients with lacunar stroke were compared to 2098 patients with non-lacunar stroke. Compared with patients with non-lacunar stroke, patients with lacunar stroke had better functional outcomes on either dose of alteplase (mRS 2–6, adjusted OR 0.60, 95% CI 0.47, 0.77), presumably reflecting that outcomes are better in general after mild than more severe stroke. Outcomes with low dose versus standard dose of alteplase did not differ (mRS 2–6, aOR 1.04, 95% CI 0.87, 1.24). In general, lower dose of alteplase reduced the risk of SICH across all patients (although no significant effect was seen in the lacunar stroke, Supplemental Table 4).

The PRISMS trial⁵² randomised 313 patients with NIHSS ≤5 to receive 0.9 mg/kg alteplase (n=156) or 325 mg oral aspirin (n=157) within 3 h of onset of whom 37% of patients had a lacunar stroke. The planned sample size was 948 but the trial stopped early due to slow enrolment. The primary outcome was favourable outcome (mRS 0–1) at 90 days, seen in 122 patients (78.2%) allocated alteplase versus 128 patients 81.5% allocated aspirin (adjusted absolute risk difference −1.1%, 95% CI −9.4%, 7.3%). There were 5 SICH (3.2%) in patients allocated alteplase versus none in patients allocated aspirin, absolute risk difference 3.3%, 95% CI 0.8%, 7.4%. Details on death as an outcome for the whole sample, as well as specific information on outcomes for patients with lacunar stroke, were not reported.

The Antiplatelet versus R-tPA for Acute Mild Ischaemic Stroke (ARAMIS) trial, published in 2023,⁵³ randomised 760 patients with minor non-disabling stroke to alteplase 0.9 mg/kg versus dual antiplatelet therapy (DAPT) with aspirin and clopidogrel within 4.5 h of onset, of whom 166 (21.1%) were classified as small vessel occlusion. The primary outcome was excellent functional outcome (mRS <2) which for patients with lacunar infarct/small artery occlusion was achieved in 83/87 allocated DAPT

and 73/79 allocated alteplase, risk difference 3.0%, 95% CI −4.3%, 10.3%, in favour of DAPT. The result for the whole trial was similar, 346/369 DAPT and 320/350 allocated alteplase had excellent functional outcome, an adjusted risk difference of 2.3%, 95% CI −1.6%, 6.1%, *p* < 0.001 for non-inferiority in favour of DAPT. In the whole trial, SICH (1 DAPT, 3 alteplase) and any bleeding (6 DAPT, 19 alteplase) were infrequent and not reported for the lacunar subgroup.

The Austrian Stroke Unit Registry⁵⁴ records patients admitted to Stroke Units in Austria. In a retrospective analysis of patients with lacunar or non lacunar stroke who received alteplase or not (401 each), matched for NIHSS, prestroke mRS and other risk factors, patients with lacunar stroke who received alteplase had better functional outcome at 3 months than patients with lacunar stroke who did not receive alteplase (*p* < 0.001). SICH occurred in 1% of patients who received alteplase and 0.2% of those not given alteplase.

Marcelinus et al.⁵⁵ retrospectively analysed patients with lacunar ischaemic stroke from a stroke registry of the neurology department of first Affiliated Hospital of Zhengzhou University from January 2013 to December 2020. They used propensity score matching to compare patients who received alteplase versus those who did not. The primary outcome was favourable functional outcome at 3 months after stroke onset, defined by attaining a score of ≤2 points on the modified Rankin scale (mRS). 132 of 717 patients were identified of whom 44 pairs of alteplase–no alteplase were successfully matched. After propensity matching, the patients who received alteplase were more likely to have a favourable outcome at 3-month follow-up (OR=0.247, 95% CI 0.074, 0.830, *p*=0.024). There was one case of asymptomatic ICH in alteplase-treated patients.

The available trials and sample with data on lacunar ischaemic stroke do not provide any data on risk of SICH according to cSVD burden. Data from IST3 found that SICH was increased with severe WMH and old infarcts but there was still benefit of alteplase.³¹ Observational analyses also show that SICH risk is increased in patients with severe WMH and old infarcts and should be balanced against the likelihood of benefit from thrombolysis.⁵⁶
<figure><img src="image_5.png" /><figcaption>**Figure 1.** The effect of alteplase versus placebo on favourable functional outcome (OHS 0–2 in IST-3)/excellent functional outcome (mRS 0–1 in NINDS and Wake-up trials) in patients with acute lacunar ischaemic stroke.</figcaption></figure>

In ENCHANTED, 1/241 patients with lacunar stroke allocated low dose alteplase and 2/249 lacunar strokes allocated standard dose alteplase died within 90 days, aOR 0.44, 95% CI 0.03, 5.71.

## Additional information

In ENCHANTED,⁵¹ 490 patients with lacunar stroke were compared to 2098 patients with non-lacunar stroke. Compared with patients with non-lacunar stroke, patients with lacunar stroke had better functional outcomes on either dose of alteplase (mRS 2–6, adjusted OR 0.60, 95% CI 0.47, 0.77), presumably reflecting that outcomes are better in general after mild than more severe stroke. Outcomes with low dose versus standard dose of alteplase did not differ (mRS 2–6, aOR 1.04, 95% CI 0.87, 1.24). In general, lower dose of alteplase reduced the risk of SICH across all patients (although no significant effect was seen in the lacunar stroke, Supplemental Table 4).

The PRISMS trial⁵² randomised 313 patients with NIHSS ≤5 to receive 0.9 mg/kg alteplase (n=156) or 325 mg oral aspirin (n=157) within 3 h of onset of whom 37% of patients had a lacunar stroke. The planned sample size was 948 but the trial stopped early due to slow enrolment. The primary outcome was favourable outcome (mRS 0–1) at 90 days, seen in 122 patients (78.2%) allocated alteplase versus 128 patients 81.5% allocated aspirin (adjusted absolute risk difference −1.1%, 95% CI −9.4%, 7.3%). There were 5 SICH (3.2%) in patients allocated alteplase versus none in patients allocated aspirin, absolute risk difference 3.3%, 95% CI 0.8%, 7.4%. Details on death as an outcome for the whole sample, as well as specific information on outcomes for patients with lacunar stroke, were not reported.

The Antiplatelet versus R-tPA for Acute Mild Ischaemic Stroke (ARAMIS) trial, published in 2023,⁵³ randomised 760 patients with minor non-disabling stroke to alteplase 0.9 mg/kg versus dual antiplatelet therapy (DAPT) with aspirin and clopidogrel within 4.5 h of onset, of whom 166 (21.1%) were classified as small vessel occlusion. The primary outcome was excellent functional outcome (mRS <2) which for patients with lacunar infarct/small artery occlusion was achieved in 83/87 allocated DAPT

and 73/79 allocated alteplase, risk difference 3.0%, 95% CI −4.3%, 10.3%, in favour of DAPT. The result for the whole trial was similar, 346/369 DAPT and 320/350 allocated alteplase had excellent functional outcome, an adjusted risk difference of 2.3%, 95% CI −1.6%, 6.1%, *p* < 0.001 for non-inferiority in favour of DAPT. In the whole trial, SICH (1 DAPT, 3 alteplase) and any bleeding (6 DAPT, 19 alteplase) were infrequent and not reported for the lacunar subgroup.

The Austrian Stroke Unit Registry⁵⁴ records patients admitted to Stroke Units in Austria. In a retrospective analysis of patients with lacunar or non lacunar stroke who received alteplase or not (401 each), matched for NIHSS, prestroke mRS and other risk factors, patients with lacunar stroke who received alteplase had better functional outcome at 3 months than patients with lacunar stroke who did not receive alteplase (*p* < 0.001). SICH occurred in 1% of patients who received alteplase and 0.2% of those not given alteplase.

Marcelinus et al.⁵⁵ retrospectively analysed patients with lacunar ischaemic stroke from a stroke registry of the neurology department of first Affiliated Hospital of Zhengzhou University from January 2013 to December 2020. They used propensity score matching to compare patients who received alteplase versus those who did not. The primary outcome was favourable functional outcome at 3 months after stroke onset, defined by attaining a score of ≤2 points on the modified Rankin scale (mRS). 132 of 717 patients were identified of whom 44 pairs of alteplase–no alteplase were successfully matched. After propensity matching, the patients who received alteplase were more likely to have a favourable outcome at 3-month follow-up (OR=0.247, 95% CI 0.074, 0.830, *p*=0.024). There was one case of asymptomatic ICH in alteplase-treated patients.

The available trials and sample with data on lacunar ischaemic stroke do not provide any data on risk of SICH according to cSVD burden. Data from IST3 found that SICH was increased with severe WMH and old infarcts but there was still benefit of alteplase.³¹ Observational analyses also show that SICH risk is increased in patients with severe WMH and old infarcts and should be balanced against the likelihood of benefit from thrombolysis.⁵⁶
Current clinical guidelines on thrombolytic treatment¹⁹ (Table 1) do not provide specific recommendations on subtypes of ischaemic stroke.

In summary, the MWG noted that the data on alteplase in lacunar ischaemic stroke was very limited, that lacunar ischaemic stroke is difficult to identify clinically or with CT brain scanning (as used in most trials) in the acute phase, that dependency (the main outcome measure in trials of thrombolysis) is infrequent after lacunar stroke giving limited power to detect effects, and that the confidence

intervals overlapped the line of no effect. In general, the trend was in the direction of benefit from alteplase, and consistent with the overall results of trials of alteplase versus control across all stroke severities and subtypes.¹⁹ For this reason, the MWG provided a cautiously worded Evidence-based Recommendation, voted on two Expert Consensus Statements concerning use of rt-PA in lacunar stroke, and concurred cautiously that patients with lacunar ischaemic stroke should be managed as per current guidelines on use of thrombolysis in ischaemic stroke.¹⁹

<figure><img src="image_6.png" /></figure>

PICO 1 Risk of bias assessment for good functional outcome

**Evidence-based Recommendation**

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.

Quality of evidence: Very Low ⊕

Strength of recommendation: Weak for intervention ↑?

**Expert consensus statement 1**

Twelve of 12 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.

**Expert consensus statement 2**

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.

**PICO 2:**

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?

This PICO addresses antiplatelet treatment; anticoagulant treatment is covered in PICO 4 (progressive lacunar stroke) and PICO 5 (other treatments).

**Analysis of current evidence**

We performed a combined literature search for PICO 2 and PICO 6 (Supplemental Table 5; Supplement PRISMA diagrams) and identified 3 acute antiplatelet treatment trials.

These were heterogeneous regarding intervention or timing of outcome evaluation and therefore no meta-analysis was possible.

**Aspirin versus placebo.** The Chinese Acute Stroke Trial (CAST) included patients with ischaemic stroke within 48 h from the event onset. Patients were randomised to receive either aspirin 160 mg or placebo.⁵⁷ Patients were followed up to 4 weeks. In the subgroup of patients with lacunar
Current clinical guidelines on thrombolytic treatment¹⁹ (Table 1) do not provide specific recommendations on subtypes of ischaemic stroke.

In summary, the MWG noted that the data on alteplase in lacunar ischaemic stroke was very limited, that lacunar ischaemic stroke is difficult to identify clinically or with CT brain scanning (as used in most trials) in the acute phase, that dependency (the main outcome measure in trials of thrombolysis) is infrequent after lacunar stroke giving limited power to detect effects, and that the confidence

intervals overlapped the line of no effect. In general, the trend was in the direction of benefit from alteplase, and consistent with the overall results of trials of alteplase versus control across all stroke severities and subtypes.¹⁹ For this reason, the MWG provided a cautiously worded Evidence-based Recommendation, voted on two Expert Consensus Statements concerning use of rt-PA in lacunar stroke, and concurred cautiously that patients with lacunar ischaemic stroke should be managed as per current guidelines on use of thrombolysis in ischaemic stroke.¹⁹

<figure><img src="image_6.png" /></figure>

PICO 1 Risk of bias assessment for good functional outcome

**Evidence-based Recommendation**

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.

Quality of evidence: Very Low ⊕

Strength of recommendation: Weak for intervention ↑?

**Expert consensus statement 1**

Twelve of 12 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.

**Expert consensus statement 2**

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.

## PICO 2:

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?

This PICO addresses antiplatelet treatment; anticoagulant treatment is covered in PICO 4 (progressive lacunar stroke) and PICO 5 (other treatments).

## Analysis of current evidence

We performed a combined literature search for PICO 2 and PICO 6 (Supplemental Table 5; Supplement PRISMA diagrams) and identified 3 acute antiplatelet treatment trials.

These were heterogeneous regarding intervention or timing of outcome evaluation and therefore no meta-analysis was possible.

**Aspirin versus placebo.** The Chinese Acute Stroke Trial (CAST) included patients with ischaemic stroke within 48 h from the event onset. Patients were randomised to receive either aspirin 160 mg or placebo.⁵⁷ Patients were followed up to 4 weeks. In the subgroup of patients with lacunar
stroke, aspirin was not superior to placebo in preventing a composite of any stroke, myocardial infarction and death (RR 0.89, 95% CI 0.66, 1.21).⁵⁸

The International Stroke Trial (IST)⁵⁹ used a factorial design to examine treatment with heparin 5000 IU or 12500 IU twice daily or no heparin, as well as aspirin 300 mg daily or no aspirin. There were two primary outcomes: death within 14 days, and death or dependency at 6 months. The trial found a trend towards better primary outcome in the aspirin group (death at 14 days 9.0% vs 9.4% and death or dependency at 6 months 62.2% vs 63.5%, (2p=0.07)). When analysing additional outcomes, the authors found that death at 14 days (2.8% vs 3.9% (2p < 0.001)) as well as a reduction of death or non-fatal recurrent stroke (11.3% vs 12.4% (2p=0.02)) were significantly better for the aspirin group and the authors concluded that their study and the Chinese Acute Stroke Trial (CAST)⁵⁷ suggest that aspirin should be started as early as possible after acute ischaemic stroke onset.⁵⁹ In a lacunar stroke subgroup analysis, there were 1112 primary events among 2308 patients in the aspirin group and 1116 primary events among 2308 patients in the control group for being dead or dependent at 6 months (corresponding to OR 0.99, 95% CI 0.88, 1.11).⁵⁹

**Intensive antiplatelet therapy versus standard therapy.** The Triple Antiplatelets for Reducing Dependency after Ischaemic Stroke (TARDIS) trial⁶⁰ compared the combined administration of three antiplatelets with either aspirin and dipyridamole in combination denoted as 'Intensive anti-platelet therapy', or clopidogrel alone denoted as 'Guideline-based antiplatelet therapy'. Patients were included within 48h of stroke/TIA onset and received one of these treatments for 30 days. Primary outcome was defined as the combined incidence and severity of any recurrent stroke (ischaemic or haemorrhagic; assessed using the modified Rankin Scale) or TIA within 90 days. The trial was stopped early because of an increase of major bleedings in the intensive treatment group without a reduction of the primary outcome.⁶⁰ Among the 1556 patients receiving intensive antiplatelet therapy, 646 (42%) had a previous lacunar ischaemic stroke and among the 1540 patients receiving Guideline therapy 642 (42%) had a previous lacunar ischaemic stroke according to the Oxfordshire Community Stroke Project (OCSP) classification. For the subgroup of patients with lacunar ischaemic stroke, there was no difference in the primary outcome at 90 days (OR 1.0, 95% CI 0.6, 1.5).

**Cilostazol versus no antithrombotic treatment.** No trial with specific results for patients with suspected acute lacunar ischaemic stroke was identified. Some additional information is provided in PICO 5.

**Cilostazol versus other antiplatelet agents.** No trial with specific results for patients with suspected acute lacunar ischaemic stroke was identified. Some additional information is provided in PICO 5.

**Dual antiplatelet therapy.** The CHANCE⁶¹ and POINT⁶² trials found effect but did not specifically report results for patients with lacunar ischaemic stroke in their primary reports. However, it is not uncommon that there is a substantial proportion of patients with lacunar/small vessel stroke in clinical trials.⁵⁷,⁵⁹,⁶³ CHANCE subsequently reported a subgroup analysis,⁶⁴ with no detected difference in the primary efficacy outcome between single small subcortical infarction patients without or with parental artery disease (considered to be related to atherosclerosis), but this may be due to insufficient power and that the definition of small vessel disease was not equal to that of lacunar ischaemic stroke.

## Additional information

The CHANCE-2 trial included patients with minor stroke or transient ischaemic attack within 24h of symptom onset and carring CYP2C19 loss-of-function alleles, for treatment with either ticagrelor+aspirin or clopidogrel+aspirin for 90 days.⁶⁵ A recently published subgroup analysis results showed that for 1750 patients with small-vessel occlusion ischaemic stroke, the primary outcome new stroke within 90 days occurred in 5.3% overall, and was less frequent among those administered ticagrelor+aspirin (3.6%) versus 7.0% of those administered clopidogrel+aspirin (OR 0.51, 95% CI 0.33, 0.79, p=0.002).⁶⁶ The stroke recurrence rates were higher among the 1696 participants with large artery atherosclerosis (10.2% overall) with no difference in the recurrence rate between those allocated ticagrelor-aspirin (9.8%) versus those allocated clopidogrel-aspirin (10.7%; OR 0.86, 95% CI 0.63, 1.18, p=0.34). Based on this secondary analysis of a subgroup, it has been suggested that DAPT with ticagrelor-aspirin initiated very early and maintained for 90 days after stroke onset may perhaps be beneficial in patients with lacunar ischaemic stroke.⁶⁷

The Method Working Group discussed whether to include an Expert Consensus Statement with specific recommendations on short-term DAPT in patients with presumed lacunar ischaemic stroke. After these discussions the group reached an agreement to not include a specific Expert Consensus Statement regarding early short-term DAPT because of (1) inclusion also of TIA patients in the previous trials as shown in the Table immediately below, (2) the paucity of specific data for lacunar ischaemic stroke in previous trials shown in the Table immediately below (none of these trials reported specific outcome details on lacunar ischaemic stroke), (3) the early stroke recurrence rate is lower for lacunar ischaemic stroke than for other subtypes of ischaemic stroke,⁴ and (4) because the pathogenetic mechanism in lacunar ischaemic stroke may usually be non-atherosclerotic and non-embolic,³ antiplatelet treatment may not be as effective as in other subtypes of ischaemic stroke.

The MWG recognise that the amount and level of evidence for short-term DAPT in lacunar ischaemic stroke
stroke, aspirin was not superior to placebo in preventing a composite of any stroke, myocardial infarction and death (RR 0.89, 95% CI 0.66, 1.21).⁵⁸

The International Stroke Trial (IST)⁵⁹ used a factorial design to examine treatment with heparin 5000 IU or 12500 IU twice daily or no heparin, as well as aspirin 300 mg daily or no aspirin. There were two primary outcomes: death within 14 days, and death or dependency at 6 months. The trial found a trend towards better primary outcome in the aspirin group (death at 14 days 9.0% vs 9.4% and death or dependency at 6 months 62.2% vs 63.5%, (2p=0.07)). When analysing additional outcomes, the authors found that death at 14 days (2.8% vs 3.9% (2p < 0.001)) as well as a reduction of death or non-fatal recurrent stroke (11.3% vs 12.4% (2p=0.02)) were significantly better for the aspirin group and the authors concluded that their study and the Chinese Acute Stroke Trial (CAST)⁵⁷ suggest that aspirin should be started as early as possible after acute ischaemic stroke onset.⁵⁹ In a lacunar stroke subgroup analysis, there were 1112 primary events among 2308 patients in the aspirin group and 1116 primary events among 2308 patients in the control group for being dead or dependent at 6 months (corresponding to OR 0.99, 95% CI 0.88, 1.11).⁵⁹

**Intensive antiplatelet therapy versus standard therapy.** The Triple Antiplatelets for Reducing Dependency after Ischaemic Stroke (TARDIS) trial⁶⁰ compared the combined administration of three antiplatelets with either aspirin and dipyridamole in combination denoted as 'Intensive anti-platelet therapy', or clopidogrel alone denoted as 'Guideline-based antiplatelet therapy'. Patients were included within 48 h of stroke/TIA onset and received one of these treatments for 30 days. Primary outcome was defined as the combined incidence and severity of any recurrent stroke (ischaemic or haemorrhagic; assessed using the modified Rankin Scale) or TIA within 90 days. The trial was stopped early because of an increase of major bleedings in the intensive treatment group without a reduction of the primary outcome.⁶⁰ Among the 1556 patients receiving intensive antiplatelet therapy, 646 (42%) had a previous lacunar ischaemic stroke and among the 1540 patients receiving Guideline therapy 642 (42%) had a previous lacunar ischaemic stroke according to the Oxfordshire Community Stroke Project (OCSP) classification. For the subgroup of patients with lacunar ischaemic stroke, there was no difference in the primary outcome at 90 days (OR 1.0, 95% CI 0.6, 1.5).

**Cilostazol versus no antithrombotic treatment.** No trial with specific results for patients with suspected acute lacunar ischaemic stroke was identified. Some additional information is provided in PICO 5.

**Cilostazol versus other antiplatelet agents.** No trial with specific results for patients with suspected acute lacunar ischaemic stroke was identified. Some additional information is provided in PICO 5.

**Dual antiplatelet therapy.** The CHANCE⁶¹ and POINT⁶² trials found effect but did not specifically report results for patients with lacunar ischaemic stroke in their primary reports. However, it is not uncommon that there is a substantial proportion of patients with lacunar/small vessel stroke in clinical trials.⁵⁷,⁵⁹,⁶³ CHANCE subsequently reported a subgroup analysis,⁶⁴ with no detected difference in the primary efficacy outcome between single small subcortical infarction patients without or with parental artery disease (considered to be related to atherosclerosis), but this may be due to insufficient power and that the definition of small vessel disease was not equal to that of lacunar ischaemic stroke.

## Additional information

The CHANCE-2 trial included patients with minor stroke or transient ischaemic attack within 24 h of symptom onset and carring CYP2C19 loss-of-function alleles, for treatment with either ticagrelor+aspirin or clopidogrel+aspirin for 90 days.⁶⁵ A recently published subgroup analysis results showed that for 1750 patients with small-vessel occlusion ischaemic stroke, the primary outcome new stroke within 90 days occurred in 5.3% overall, and was less frequent among those administered ticagrelor+aspirin (3.6%) versus 7.0% of those administered clopidogrel+aspirin (OR 0.51, 95% CI 0.33, 0.79, *p*=0.002).⁶⁶ The stroke recurrence rates were higher among the 1696 participants with large artery atherosclerosis (10.2% overall) with no difference in the recurrence rate between those allocated ticagrelor-aspirin (9.8%) versus those allocated clopidogrel-aspirin (10.7%; OR 0.86, 95% CI 0.63, 1.18, *p*=0.34). Based on this secondary analysis of a subgroup, it has been suggested that DAPT with ticagrelor-aspirin initiated very early and maintained for 90 days after stroke onset may perhaps be beneficial in patients with lacunar ischaemic stroke.⁶⁷

The Method Working Group discussed whether to include an Expert Consensus Statement with specific recommendations on short-term DAPT in patients with presumed lacunar ischaemic stroke. After these discussions the group reached an agreement to not include a specific Expert Consensus Statement regarding early short-term DAPT because of (1) inclusion also of TIA patients in the previous trials as shown in the Table immediately below, (2) the paucity of specific data for lacunar ischaemic stroke in previous trials shown in the Table immediately below (none of these trials reported specific outcome details on lacunar ischaemic stroke), (3) the early stroke recurrence rate is lower for lacunar ischaemic stroke than for other subtypes of ischaemic stroke,⁴ and (4) because the pathogenetic mechanism in lacunar ischaemic stroke may usually be non-atherosclerotic and non-embolic,³ antiplatelet treatment may not be as effective as in other subtypes of ischaemic stroke.

The MWG recognise that the amount and level of evidence for short-term DAPT in lacunar ischaemic stroke
<table><thead><tr><th>Trial</th><th>Proportion of patients with lacunar mechanism</th><th>Proportion of patients with TIA</th></tr></thead><tbody><tr><td>FASTER<sup>68</sup></td><td>25.3%-36.1%</td><td>At least 39%</td></tr><tr><td>CHANCE<sup>61</sup></td><td>Not reported,*</td><td>27.9%</td></tr><tr><td>POINT<sup>62</sup></td><td>Not reported</td><td>43.2%</td></tr><tr><td>THALES<sup>69</sup></td><td>Not reported</td><td>9%</td></tr></tbody></table>

*Liu et al.⁷⁰ reported that among the total of 5170 subjects in CHANCE, a subgroup of 1089 underwent MR angiography, where 56% had intracranial large vessel stenosis (ICAS) and that there was no treatment effect interaction when comparing ICAS versus other (where the majority might be suspected to be small vessel disease), (p = 0.52).

is rather low and new data on suspected lacunar ischaemic stroke are becoming available which may clarify the use of dual antiplatelet drugs short-term after suspected acute lacunar ischaemic stroke. For the above reasons, the Expert Consensus Statement is worded very cautiously, and presently no solid recommendations can be given.

The ESO expedited recommendation for the use of short-term dual antiplatelet therapy early after minor stroke and high-risk TIA does not specifically mention lacunar ischaemic stroke or small vessel disease,⁷¹ but, although we found little evidence to support short-term DAPT specifically in lacunar ischaemic stroke, we also found no evidence contradicting the suggestion to follow these recommendations. It should also be noted that in the acute phase within 24 h after stroke onset it is often difficult to diagnose with certainty that the ischaemic stroke is indeed a lacunar ischaemic stroke, further adding to the support for using the previously published ESO recommendations.⁷¹

As there are no additional data suggesting that patients with lacunar ischaemic stroke should be treated differently than the current recommendations for acute antiplatelet treatment for ischaemic stroke⁷¹ it may therefore be reasonable to use dual antiplatelet therapy short term according to the CHANCE and POINT trials' protocols.

**Evidence-based Recommendation**

In patients with suspected acute lacunar ischaemic stroke, there is continued uncertainty about a specific combination of antiplatelet therapy over monotherapy.

Quality of evidence: Very low ⊕

Strength of recommendation: -

**Expert Consensus Statement**

Twelve of 12 MWG members agree with the statement that in patients with suspected lacunar ischaemic stroke, initiation of antiplatelet therapy should be started as soon as possible after stroke onset.

**PICO 3:**

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?

**Analysis of current evidence**

Five randomised controlled trials (RCTs) have assessed the impact of immediate antihypertensive treatment compared to avoiding this intervention in patients with acute ischaemic stroke, with secondary analyses on acute lacunar ischaemic stroke patients: CATIS,⁷² SCAST,⁷³ ENOS,⁷⁴ VENTURE⁷⁵ and ENCHANTED⁷⁶ (Table 3; Supplemental Table 6; Supplement PRISMA diagrams). While lower SBP after acute stroke has been associated with better outcome in several observational studies,⁷⁷,⁷⁸ and lower risk of symptomatic intracerebral haemorrhage in a trial and registry setting,⁷⁹,⁸⁰ an important concern is that rapid BP reductions might worsen cerebral ischaemia through hypoperfusion with compromised autoregulation and collateral flow.⁸¹ While none of these trials was specifically addressing this question in patients with acute lacunar ischaemic stroke, all have reported some secondary analysis results in this subgroup of patients, encompassing haemorrhagic stroke, major adverse cardiovascular events (MACE), dependency, depression and death. No subgroup information is available for the other outcomes (recurrent ischaemic stroke, cognitive impairment or dementia, mobility or gait).

The China Antihypertensive Trial in Acute Ischaemic Stroke (CATIS) trial is a single-blind, blinded end-points randomised clinical trial, conducted among 4071 patients with non-thrombolysed ischaemic stroke within 48 h of onset and elevated systolic blood pressure (SBP, 140–220 mmHg), recruited in China.⁷² Patients were randomly assigned to receive antihypertensive treatment (N=2038, aimed at lowering systolic blood pressure by 10%–25% within the first 24 h after randomisation, achieving BP less than 140/90 mmHg within 7 days, and maintaining this level during hospitalisation) or to discontinue all antihypertensive medications (control) during hospitalisation (N=2033). Mean time from stroke onset to randomisation was 15 h. Among these patients, 417 and 385 had lacunar ischaemic stroke in the antihypertensive treatment and control arm respectively. BP lowering was achieved with either intravenous angiotensin receptor inhibitors (ACEi) (first line), oral calcium channel antagonists (CCB) (second line), or oral diuretics. Mean SBP was reduced more drastically within 24 h in the antihypertensive treatment group than in the control group (absolute difference –9.1 mmHg; *p* < 0.001).

Overall, the primary and secondary composite outcomes of death and major disability (mRS 3–6) at 14 days or hospital discharge and 3-month respectively did not differ between treatment groups (*p* = 0.98 and 0.93).
<table><thead><tr><th>Trial</th><th>Proportion of patients with lacunar mechanism</th><th>Proportion of patients with TIA</th></tr></thead><tbody><tr><td>FASTER<sup>68</sup></td><td>25.3%-36.1%</td><td>At least 39%</td></tr><tr><td>CHANCE<sup>61</sup></td><td>Not reported,*</td><td>27.9%</td></tr><tr><td>POINT<sup>62</sup></td><td>Not reported</td><td>43.2%</td></tr><tr><td>THALES<sup>69</sup></td><td>Not reported</td><td>9%</td></tr></tbody></table>

*Liu et al.⁷⁰ reported that among the total of 5170 subjects in CHANCE, a subgroup of 1089 underwent MR angiography, where 56% had intracranial large vessel stenosis (ICAS) and that there was no treatment effect interaction when comparing ICAS versus other (where the majority might be suspected to be small vessel disease), (p = 0.52).

is rather low and new data on suspected lacunar ischaemic stroke are becoming available which may clarify the use of dual antiplatelet drugs short-term after suspected acute lacunar ischaemic stroke. For the above reasons, the Expert Consensus Statement is worded very cautiously, and presently no solid recommendations can be given.

The ESO expedited recommendation for the use of short-term dual antiplatelet therapy early after minor stroke and high-risk TIA does not specifically mention lacunar ischaemic stroke or small vessel disease,⁷¹ but, although we found little evidence to support short-term DAPT specifically in lacunar ischaemic stroke, we also found no evidence contradicting the suggestion to follow these recommendations. It should also be noted that in the acute phase within 24 h after stroke onset it is often difficult to diagnose with certainty that the ischaemic stroke is indeed a lacunar ischaemic stroke, further adding to the support for using the previously published ESO recommendations.⁷¹

As there are no additional data suggesting that patients with lacunar ischaemic stroke should be treated differently than the current recommendations for acute antiplatelet treatment for ischaemic stroke⁷¹ it may therefore be reasonable to use dual antiplatelet therapy short term according to the CHANCE and POINT trials' protocols.

**Evidence-based Recommendation**

In patients with suspected acute lacunar ischaemic stroke, there is continued uncertainty about a specific combination of antiplatelet therapy over monotherapy.

Quality of evidence: Very low ⊕

Strength of recommendation: -

**Expert Consensus Statement**

Twelve of 12 MWG members agree with the statement that in patients with suspected lacunar ischaemic stroke, initiation of antiplatelet therapy should be started as soon as possible after stroke onset.

**PICO 3:**

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?

**Analysis of current evidence**

Five randomised controlled trials (RCTs) have assessed the impact of immediate antihypertensive treatment compared to avoiding this intervention in patients with acute ischaemic stroke, with secondary analyses on acute lacunar ischaemic stroke patients: CATIS,⁷² SCAST,⁷³ ENOS,⁷⁴ VENTURE⁷⁵ and ENCHANTED⁷⁶ (Table 3; Supplemental Table 6; Supplement PRISMA diagrams). While lower SBP after acute stroke has been associated with better outcome in several observational studies,⁷⁷,⁷⁸ and lower risk of symptomatic intracerebral haemorrhage in a trial and registry setting,⁷⁹,⁸⁰ an important concern is that rapid BP reductions might worsen cerebral ischaemia through hypoperfusion with compromised autoregulation and collateral flow.⁸¹ While none of these trials was specifically addressing this question in patients with acute lacunar ischaemic stroke, all have reported some secondary analysis results in this subgroup of patients, encompassing haemorrhagic stroke, major adverse cardiovascular events (MACE), dependency, depression and death. No subgroup information is available for the other outcomes (recurrent ischaemic stroke, cognitive impairment or dementia, mobility or gait).

The China Antihypertensive Trial in Acute Ischaemic Stroke (CATIS) trial is a single-blind, blinded end-points randomised clinical trial, conducted among 4071 patients with non-thrombolysed ischaemic stroke within 48 h of onset and elevated systolic blood pressure (SBP, 140–220 mmHg), recruited in China.⁷² Patients were randomly assigned to receive antihypertensive treatment (N=2038, aimed at lowering systolic blood pressure by 10%–25% within the first 24 h after randomisation, achieving BP less than 140/90 mmHg within 7 days, and maintaining this level during hospitalisation) or to discontinue all antihypertensive medications (control) during hospitalisation (N=2033). Mean time from stroke onset to randomisation was 15 h. Among these patients, 417 and 385 had lacunar ischaemic stroke in the antihypertensive treatment and control arm respectively. BP lowering was achieved with either intravenous angiotensin receptor inhibitors (ACEi) (first line), oral calcium channel antagonists (CCB) (second line), or oral diuretics. Mean SBP was reduced more drastically within 24 h in the antihypertensive treatment group than in the control group (absolute difference –9.1 mmHg; *p* < 0.001).

Overall, the primary and secondary composite outcomes of death and major disability (mRS 3–6) at 14 days or hospital discharge and 3-month respectively did not differ between treatment groups (*p* = 0.98 and 0.93).
<table><caption>**Table 3.** GRADE evidence profile for PICO3 – In patients with lacunar stroke, does immediate antihypertensive treatment (considering agent and BP target), compared to avoiding this intervention, reduce functional outcome, MACE and other outcomes?</caption><thead><tr><th rowspan="2">Certainty assessment</th><th rowspan="2">No of studies</th><th rowspan="2">Study design</th><th rowspan="2">Risk of bias</th><th rowspan="2">Inconsist-ency</th><th rowspan="2">Indirect-ness</th><th rowspan="2">Imprec-ision</th><th rowspan="2">Other considerations</th><th colspan="2">No of patients</th><th colspan="2">Effect</th><th rowspan="2">Certainty</th><th rowspan="2">Importance</th></tr><tr><th>Interv-ention</th><th>Compara-tor</th><th>Odds Ratio (95% CI)</th><th>Absolute (95% CI)</th></tr></thead><tbody><tr><td rowspan="2">Functional Outcome</td><td rowspan="2">4 Randomised trials</td><td rowspan="2">Not serious</td><td rowspan="2">Not serious</td><td rowspan="2">Not serious</td><td rowspan="2">Serious<sup>a</sup></td><td rowspan="2">None</td><td rowspan="2">NR</td><td rowspan="2">NR</td><td rowspan="2">OR 0.98 (0.74, 1.28)*<br>OR 0.99 (0.78, 1.27)**</td><td rowspan="2">I fewer per 1000<br>(from I fewer to I fewer)**<sup>**</sup></td><td rowspan="2">&oplus;&oplus;&oplus;○<br>Moderate</td><td rowspan="2">&oplus;&oplus;&oplus;○<br>CRITICAL</td><td rowspan="2"></td></tr><tr><td>2 Randomised trials</td><td>Not serious</td><td>Not serious</td><td>Not serious</td><td>None</td><td>25/321 (7.8%)</td><td>21/359 (5.8%)</td><td>OR 1.33 (0.73, 2.44)</td><td>18 more per 1000<br>(from 15 fewer to 73 more)</td><td>CRITICAL</td></tr><tr><td>Shift in mRS distribution</td><td>2 Randomised trials</td><td>Not serious</td><td>Not serious</td><td>Not serious</td><td>Serious<sup>a</sup></td><td>None</td><td>-/634</td><td>-/613</td><td>OR 0.98 (0.72, 1.34)*<br>OR 0.94 (0.80, 1.10)**</td><td>I fewer per 1000<br>(from I fewer to I fewer)<br>0 fewer per 1000<br>(from 0 fewer to 0 fewer)</td><td>CRITICAL</td><td>Moderate</td><td></td></tr></tbody></table>

CI: confidence interval; OR: odds ratio; a Confidence interval crosses the clinical decision threshold.

\*Represents odds ratio for continuing anti-hypertensives (ENOS).

\*\*Represents odds ratio for transdermal glyceryl trinitrate (ENOS).

\*\*\*Represents identical absolute 95% CI for both \* and \*\*

The Angiotensin-receptor blocker candesartan for treatment of acute stroke (SCAST) trial is a randomised, placebo-controlled, double-blind trial where patients with acute stroke (ischaemic or haemorrhagic) and SBP≥140 mmHg were randomised within 30 h of symptom onset to receive candesartan or placebo for 7 days, with doses increasing from 4 mg on day 1 to 16 mg on days 3 to 7.⁷³ Mean time from stroke onset to randomisation was 18 h. In total, 2029 patients from Northern Europe were included in the intention-to-treat analysis (1017 in the candesartan and 1012 in the placebo group), of whom 588 with lacunar ischaemic stroke (279 in the candesartan group and 309 in the placebo group), defined based on OCSP criteria. The average achieved SBP difference between randomised groups during the 7-day treatment period was of 5 mmHg.

Overall, at 6 months, the risk of the composite vascular endpoint (vascular death, myocardial infarction, or stroke) did not differ between treatment groups (p=0.52), while analysis of functional outcome (shift in modified Rankin Scale (mRS) using ordinal logistic regression) suggested a nominally significant (p=0.048) higher risk of poor outcome in the candesartan group (not significant after multiple testing correction at p≤0.025).

The Efficacy of Nitric Oxide in Stroke (ENOS) trial is a partial-factorial trial where patients admitted to hospital with an acute ischaemic or haemorrhagic stroke and raised SBP (systolic 140–220 mmHg) were randomly assigned, within 48 h of stroke onset, to 7 days of transdermal glyceryl trinitrate (GTN, 5 mg per day) or to no GTN (control group).⁷⁴ A subset of patients who were taking antihypertensive drugs before their stroke were also randomly assigned to continue or stop taking these drugs. Mean time from stroke onset to randomisation was 26 h. In total, 4011 patients (80% from Europe, 14% from Asia) were included (2000 assigned to the GTN group and 2011 to the no GTN group), of whom 1397 with lacunar ischaemic stroke (695 in the GTN group and 702 in the no GTN group), defined based on OCSP criteria. Mean SBP was significantly reduced on day 1 in patients allocated to GTN compared with controls (difference −7.0 mmHg, p<0.0001), and on day 7 in patients allocated to continue antihypertensive drugs compared with patients randomised to stop them (difference −9.5 mmHg, p<0.0001).

Overall, at 3 months, the primary outcome (shift in mRS using ordinal logistic regression) did not differ in either treatment comparison. GTN had no significant effects on any of the secondary outcomes. Patients who continued their BP-lowering drugs were significantly more likely to have died in hospital, be dead or disabled (Barthel index <60) and had significantly lower cognition scores at day 90 than were those who stopped treatment.⁷⁴

The Valsartan Efficacy oN modesT blood pressUre REduction in acute ischaemic stroke (VENTURE) study group⁷⁵ performed a randomised, open-label, blinded-end-point trial examining whether lowering BP with valsartan
<table><caption>**Table 3.** GRADE evidence profile for PICO3 – In patients with lacunar stroke, does immediate antihypertensive treatment (considering agent and BP target), compared to avoiding this intervention, reduce functional outcome, MACE and other outcomes?</caption><thead><tr><th rowspan="2">Certainty assessment</th><th rowspan="2">No of studies</th><th rowspan="2">Study design</th><th rowspan="2">Risk of bias</th><th rowspan="2">Inconsist-ency</th><th rowspan="2">Indirect-ness</th><th rowspan="2">Imprec-ision</th><th rowspan="2">Other considerations</th><th colspan="2">No of patients</th><th colspan="2">Effect</th><th rowspan="2">Certainty</th><th rowspan="2">Importance</th></tr><tr><th>Interv-ention</th><th>Compara-tor</th><th>Odds Ratio (95% CI)</th><th>Absolute (95% CI)</th></tr></thead><tbody><tr><td rowspan="2">Functional Outcome</td><td rowspan="2">4 Randomised trials</td><td rowspan="2">Not serious</td><td rowspan="2">Not serious</td><td rowspan="2">Not serious</td><td rowspan="2">Serious<sup>a</sup></td><td rowspan="2">None</td><td rowspan="2">NR</td><td rowspan="2">NR</td><td rowspan="2">OR 0.98 (0.74,1.28),<sup>*</sup><br/>OR 0.99 (0.78, 1.27)<sup>**</sup></td><td rowspan="2">I fewer per 1000<br/>(from I fewer to I fewer)<sup>***</sup></td><td rowspan="2">&oplus;&oplus;&oplus;○<br/>Moderate</td><td rowspan="2">&oplus;&oplus;&oplus;○<br/>CRITICAL</td><td rowspan="2"></td></tr><tr><td>2 Randomised trials</td><td>Not serious</td><td>Not serious</td><td>Not serious</td><td>25/321<br/>(7.8%)</td><td>21/359<br/>(5.8%)</td><td>OR 1.33<br/>(0.73, 2.44)</td><td>18 more per 1000<br/>(from 15 fewer to 73 more)</td><td>CRITICAL</td></tr><tr><td>Shift in mRS distribution</td><td>2 Randomised trials</td><td>Not serious</td><td>Not serious</td><td>Not serious</td><td>Serious<sup>a</sup></td><td>None</td><td>-/634</td><td>-/613</td><td>OR 0.98<br/>(0.72, 1.34),<sup>*</sup><br/>OR 0.94<br/>(0.80, 1.10)<sup>**</sup></td><td>I fewer per 1000<br/>(from I fewer to I fewer)<br/>0 fewer per 1000<br/>(from 0 fewer to 0 fewer)</td><td>CRITICAL</td><td>Moderate</td><td></td></tr></tbody></table>

CI: confidence interval; OR: odds ratio; a Confidence interval crosses the clinical decision threshold.

\*Represents odds ratio for continuing anti-hypertensives (ENOS).

\*\*Represents odds ratio for transdermal glyceryl trinitrate (ENOS).

\*\*\*Represents identical absolute 95% CI for both \* and \*\*

The Angiotensin-receptor blocker candesartan for treatment of acute stroke (SCAST) trial is a randomised, placebo-controlled, double-blind trial where patients with acute stroke (ischaemic or haemorrhagic) and SBP≥140 mmHg were randomised within 30 h of symptom onset to receive candesartan or placebo for 7 days, with doses increasing from 4 mg on day 1 to 16 mg on days 3 to 7.<sup>73</sup> Mean time from stroke onset to randomisation was 18 h. In total, 2029 patients from Northern Europe were included in the intention-to-treat analysis (1017 in the candesartan and 1012 in the placebo group), of whom 588 with lacunar ischaemic stroke (279 in the candesartan group and 309 in the placebo group), defined based on OCSP criteria. The average achieved SBP difference between randomised groups during the 7-day treatment period was of 5 mmHg.

Overall, at 6 months, the risk of the composite vascular endpoint (vascular death, myocardial infarction, or stroke) did not differ between treatment groups (p=0.52), while analysis of functional outcome (shift in modified Rankin Scale (mRS) using ordinal logistic regression) suggested a nominally significant (p=0.048) higher risk of poor outcome in the candesartan group (not significant after multiple testing correction at p≤0.025).

The Efficacy of Nitric Oxide in Stroke (ENOS) trial is a partial-factorial trial where patients admitted to hospital with an acute ischaemic or haemorrhagic stroke and raised SBP (systolic 140–220 mmHg) were randomly assigned, within 48 h of stroke onset, to 7 days of transdermal glyceryl trinitrate (GTN, 5 mg per day) or to no GTN (control group).<sup>74</sup> A subset of patients who were taking antihypertensive drugs before their stroke were also randomly assigned to continue or stop taking these drugs. Mean time from stroke onset to randomisation was 26 h. In total, 4011 patients (80% from Europe, 14% from Asia) were included (2000 assigned to the GTN group and 2011 to the no GTN group), of whom 1397 with lacunar ischaemic stroke (695 in the GTN group and 702 in the no GTN group), defined based on OCSP criteria. Mean SBP was significantly reduced on day 1 in patients allocated to GTN compared with controls (difference −7.0 mmHg, p<0.0001), and on day 7 in patients allocated to continue antihypertensive drugs compared with patients randomised to stop them (difference −9.5 mmHg, p<0.0001).

Overall, at 3 months, the primary outcome (shift in mRS using ordinal logistic regression) did not differ in either treatment comparison. GTN had no significant effects on any of the secondary outcomes. Patients who continued their BP-lowering drugs were significantly more likely to have died in hospital, be dead or disabled (Barthel index <60) and had significantly lower cognition scores at day 90 than were those who stopped treatment.<sup>74</sup>

The Valsartan Efficacy oN modesT blood pressUre REduction in acute ischaemic stroke (VENTURE) study group<sup>75</sup> performed a randomised, open-label, blinded-end-point trial examining whether lowering BP with valsartan
versus placebo could improve death or dependency after acute ischaemic stroke. Out of 393 subjects included in the trial overall, 44% of participants had lacunar ischaemic stroke. Mean time from stroke onset to randomisation was 12 h.

Overall, this trial failed to achieve the intended target in the valsartan group (defined as a 15% decrease from baseline or to 145 mmHg), (SBP 146.8 mmHg in the valsartan group vs 147.1 mmHg in the control group on the second day. The difference in primary outcome, death or dependency at 90 days, between the treatment and control groups (24.6% vs 22.6%) was not statistically significant. However, reducing BP with valsartan during this acute period was associated with an elevated risk of early neurological deterioration (END) during the first 7 days (secondary outcome).

The Enhanced Control of Hypertension and Thrombolysis Stroke Study (ENCHANTED) assessed intensive blood pressure (BP) lowering compared with guideline-recommended BP lowering, in patients treated with alteplase for acute ischaemic stroke.⁷⁶ The design was a partial-factorial, open-label, blinded-endpoint trial of thrombolysis-eligible patients (age ≥ 18 years) with acute ischaemic stroke and SBP ≥ 150 mmHg. Eligible patients were randomly assigned within 6 h of stroke onset to receive intensive (target SBP 130–140 mmHg within 1 h) or guideline (target SBP < 180 mmHg) BP lowering treatment over 72 h. Mean time from stroke onset to randomisation was 3 h. In total, 2196 patients (74% Asian) were included in the intention-to-treat analysis (1081 in the intensive group and 1115 in the guideline group), of whom 623 with lacunar ischaemic stroke (333 in the intensive group and 290 in the guideline group), defined based on TOAST criteria. The average achieved SBP difference between randomised groups was of 6 mmHg, much smaller than the envisaged 15 mmHg.

Overall, at 3 months, intensive BP lowering compared with current guideline-recommended BP management after IV alteplase therapy was not associated with a significant difference in functional recovery, as assessed by a shift in the distribution of mRS scores. It was associated with a significant reduction in the incidence of intracranial haemorrhage.⁷⁶

*Dependency, early neurological deterioration and death.* In the CATIS trial,⁷² a secondary subgroup analysis for the primary outcome (combination of death and major disability (mRS 3–6) at 14 days or hospital discharge) showed a trend (*p*=0.06) towards interaction with ischaemic stroke subtypes. Although not significant, lacunar stroke was the only stroke subtype for which antihypertensive treatment tended to be associated with lower risk of mRS 3–6 (Supplemental Table 6).

In the SCAST trial,⁷³ there was a significant trend towards a better functional outcome (mRS, ordinal logistic regression) with candesartan in patients with total anterior circulation ischaemic stroke (TACI) and partial anterior circulation ischaemic stroke (PACI), than in patients with lacunar

infarction (LACI, *p* value for trend = 0.02).⁸² The difference was no longer significant in the adjusted analysis, and, overall, there was no heterogeneity of treatment effect between the subgroups (*p*=0.11)⁸² (Supplemental Table 6).

In the ENOS trial,⁷⁴ the neutral effect on functional outcome (shift in 3-months mRS score distribution) of early BP lowering by transdermal glyceryl trinitrate was comparable across acute ischaemic stroke subtypes, with a neutral effect in lacunar ischaemic stroke specifically (OR 0.99, 95% CI 0.82, 1.19; Supplemental Table 6). Secondary outcomes in lacunar ischaemic stroke patients are not reported.

In the VENTURE trial,⁷⁵ the neutral efficacy outcomes did not differ in subgroups stratified by ischaemic stroke subtypes (P interaction 0.62 for death or dependency and 0.90 for MACE).

In the ENCHANTED trial,⁷⁶ in secondary analyses published as part of the main trial results, no significant heterogeneity of the treatment effect on the main outcome (shift on 3-month mRS score) was observed across ischaemic stroke subtypes classified on the basis of clinician diagnosis based on TOAST criteria (*p* for interaction 0.90)⁷⁶ (Supplemental Table 6).⁷⁶ Subsequently, as there was concern that this approach may have over-estimated the frequency of lacunar ischaemic stroke, classification as lacunar ischaemic stroke was reassessed by a combination of clinical and centrally adjudicated imaging findings.⁸³ This analysis comprised 454 patients with definite/probable lacunar ischaemic stroke (definite 155; probable 299) and 1178 patients with definite/probable non-lacunar ischaemic stroke, who all received intravenous alteplase. The overall treatment effect of intensive BP reduction versus guideline-recommended BP management on functional, safety and other clinical outcomes were comparable to the main results of the ENCHANTED trial (Supplemental Table 6). There was no heterogeneity of treatment effect on primary and other outcomes across the subgroups of lacunar and non-lacunar AIS, (all *p*:s for interaction ≥ 0.19).

*Haemorrhagic stroke.* In the ENCHANTED trial,⁷⁶ in the secondary analysis where the classification as lacunar ischaemic stroke was reassessed by a combination of clinical and centrally adjudicated imaging findings,⁸³ there was no significant difference on any outcomes by randomisation in the lacunar ischaemic stroke subgroup. (Supplemental Table 6).⁸³

*MACE.* In the SCAST trial,⁷³ for the composite vascular endpoint (vascular death, myocardial infarction or stroke) there were no differences in treatment effect for either subgroup (*p*=0.28),⁸² (Supplemental Table 6).

*Post-stroke depression.* In the prespecified substudy⁸⁴ of the CATIS⁷² trial, a total of 642 patients with acute ischaemic stroke within 48 h of onset and elevated systolic BP at 7 sites of CATIS were included. Patients were randomly
versus placebo could improve death or dependency after acute ischaemic stroke. Out of 393 subjects included in the trial overall, 44% of participants had lacunar ischaemic stroke. Mean time from stroke onset to randomisation was 12 h.

Overall, this trial failed to achieve the intended target in the valsartan group (defined as a 15% decrease from baseline or to 145 mmHg), (SBP 146.8 mmHg in the valsartan group vs 147.1 mmHg in the control group on the second day. The difference in primary outcome, death or dependency at 90 days, between the treatment and control groups (24.6% vs 22.6%) was not statistically significant. However, reducing BP with valsartan during this acute period was associated with an elevated risk of early neurological deterioration (END) during the first 7 days (secondary outcome).

The Enhanced Control of Hypertension and Thrombolysis Stroke Study (ENCHANTED) assessed intensive blood pressure (BP) lowering compared with guideline-recommended BP lowering, in patients treated with alteplase for acute ischaemic stroke.⁷⁶ The design was a partial-factorial, open-label, blinded-endpoint trial of thrombolysis-eligible patients (age ≥ 18 years) with acute ischaemic stroke and SBP ≥ 150 mmHg. Eligible patients were randomly assigned within 6 h of stroke onset to receive intensive (target SBP 130–140 mmHg within 1 h) or guideline (target SBP < 180 mmHg) BP lowering treatment over 72 h. Mean time from stroke onset to randomisation was 3 h. In total, 2196 patients (74% Asian) were included in the intention-to-treat analysis (1081 in the intensive group and 1115 in the guideline group), of whom 623 with lacunar ischaemic stroke (333 in the intensive group and 290 in the guideline group), defined based on TOAST criteria. The average achieved SBP difference between randomised groups was of 6 mmHg, much smaller than the envisaged 15 mmHg.

Overall, at 3 months, intensive BP lowering compared with current guideline-recommended BP management after IV alteplase therapy was not associated with a significant difference in functional recovery, as assessed by a shift in the distribution of mRS scores. It was associated with a significant reduction in the incidence of intracranial haemorrhage.⁷⁶

*Dependency, early neurological deterioration and death.* In the CATIS trial,⁷² a secondary subgroup analysis for the primary outcome (combination of death and major disability (mRS 3–6) at 14 days or hospital discharge) showed a trend (*p*=0.06) towards interaction with ischaemic stroke subtypes. Although not significant, lacunar stroke was the only stroke subtype for which antihypertensive treatment tended to be associated with lower risk of mRS 3–6 (Supplemental Table 6).

In the SCAST trial,⁷³ there was a significant trend towards a better functional outcome (mRS, ordinal logistic regression) with candesartan in patients with total anterior circulation ischaemic stroke (TACI) and partial anterior circulation ischaemic stroke (PACI), than in patients with lacunar

infarction (LACI, *p* value for trend = 0.02).⁸² The difference was no longer significant in the adjusted analysis, and, overall, there was no heterogeneity of treatment effect between the subgroups (*p*=0.11)⁸² (Supplemental Table 6).

In the ENOS trial,⁷⁴ the neutral effect on functional outcome (shift in 3-months mRS score distribution) of early BP lowering by transdermal glyceryl trinitrate was comparable across acute ischaemic stroke subtypes, with a neutral effect in lacunar ischaemic stroke specifically (OR 0.99, 95% CI 0.82, 1.19; Supplemental Table 6). Secondary outcomes in lacunar ischaemic stroke patients are not reported.

In the VENTURE trial,⁷⁵ the neutral efficacy outcomes did not differ in subgroups stratified by ischaemic stroke subtypes (P interaction 0.62 for death or dependency and 0.90 for MACE).

In the ENCHANTED trial,⁷⁶ in secondary analyses published as part of the main trial results, no significant heterogeneity of the treatment effect on the main outcome (shift on 3-month mRS score) was observed across ischaemic stroke subtypes classified on the basis of clinician diagnosis based on TOAST criteria (*p* for interaction 0.90)⁷⁶ (Supplemental Table 6).⁷⁶ Subsequently, as there was concern that this approach may have over-estimated the frequency of lacunar ischaemic stroke, classification as lacunar ischaemic stroke was reassessed by a combination of clinical and centrally adjudicated imaging findings.⁸³ This analysis comprised 454 patients with definite/probable lacunar ischaemic stroke (definite 155; probable 299) and 1178 patients with definite/probable non-lacunar ischaemic stroke, who all received intravenous alteplase. The overall treatment effect of intensive BP reduction versus guideline-recommended BP management on functional, safety and other clinical outcomes were comparable to the main results of the ENCHANTED trial (Supplemental Table 6). There was no heterogeneity of treatment effect on primary and other outcomes across the subgroups of lacunar and non-lacunar AIS, (all *p*:s for interaction ≥ 0.19).

*Haemorrhagic stroke.* In the ENCHANTED trial,⁷⁶ in the secondary analysis where the classification as lacunar ischaemic stroke was reassessed by a combination of clinical and centrally adjudicated imaging findings,⁸³ there was no significant difference on any outcomes by randomisation in the lacunar ischaemic stroke subgroup. (Supplemental Table 6).⁸³

*MACE.* In the SCAST trial,⁷³ for the composite vascular endpoint (vascular death, myocardial infarction or stroke) there were no differences in treatment effect for either subgroup (*p*=0.28),⁸² (Supplemental Table 6).

*Post-stroke depression.* In the prespecified substudy⁸⁴ of the CATIS⁷² trial, a total of 642 patients with acute ischaemic stroke within 48 h of onset and elevated systolic BP at 7 sites of CATIS were included. Patients were randomly
<figure><img src="image_7.png" /><figcaption>**Figure 2.** Meta-analysis of immediate antihypertensive therapy in suspected lacunar ischaemic stroke on functional outcome (mRS 3-6 vs 0-2), (a) continuing versus stopping antihypertensive treatment and (b) transdermal GTN versus no GTN.</figcaption></figure>

assigned to receive antihypertensive treatment (n=318) or to the control group (n=324). The primary outcome was depression (Hamilton Rating Scale for Depression score ≥8) at 3-month post-treatment follow-up. There were 102 lacunar stroke patients (defined according to TOAST criteria) in the antihypertensive group and 104 lacunar stroke patients in the control group. The number of events (Hamilton Rating Scale for Depression score ≥8) was slightly higher in the antihypertensive group than in the control group (OR 1.42, 95% CI 0.82, 2.46). There was no heterogeneity of treatment effect on post-stroke depression across stroke subtypes (p=0.07).

In summary, there is no evidence that immediate antihypertensive treatment, compared to avoiding this intervention, may be more beneficial in patients with suspected acute lacunar ischaemic stroke than in acute ischaemic stroke patients overall, in whom the absence of benefit has already been demonstrated and reflected in guidelines, with which we concur.⁸⁵

Time to treatment may have an effect and varies across RCTs (6–48 h), but in trials with longer time windows analyses stratified on time to treatment are not available in patients with lacunar ischaemic stroke.

Results of the aforementioned trials may also have been diluted by the modest difference in BP reduction between the intervention and control groups in most trials.

Most RCTs excluded patients with extremely elevated systolic blood pressure (>220 mmHg), or do not provide

separate results in the subgroup in patients with lacunar ischaemic stroke and SBP >220 mmHg.

## Meta-analyses

Few data were available to conduct meta-analyses.

Primary meta-analyses were conducted in acute lacunar ischaemic stroke patients without thrombolysis only. Indeed, optimal BP management may be different in patients undergoing reperfusion therapy and those who are not. Of note, we did include in this meta-analysis two studies that included a small percentage (<12%) of patients who underwent thrombolysis (ENOS,⁷⁴ SCAST⁸²), although subgroup results in lacunar ischaemic stroke without thrombolysis weren't available.

In a meta-analysis combining CATIS,⁷² SCAST,⁸² VENTURE⁷⁵ and ENOS immediate antihypertensive treatment (using a defined dose of Candesartan, Valsartan, transdermal glyceryl trinitrate or targeting a BP <140/90 mg with ACEi, CCB, or diuretics), compared to avoiding this intervention was not associated with a better functional outcome: OR 0.98, 95% CI 0.74, 1.28, for mRS 3–6, Figure 2.

In a meta-analysis combining SCAST⁸² and VENTURE,⁷⁵ immediate antihypertensive treatment, compared to avoiding this intervention was not associated with a lower risk of MACE: HR 1.33, 95% CI 0.73, 2.44, Figure 3.

As recanalisation may theoretically be less critical in lacunar ischaemic stroke compared to ischaemic stroke
<figure><img src="image_7.png" /><figcaption>**Figure 2.** Meta-analysis of immediate antihypertensive therapy in suspected lacunar ischaemic stroke on functional outcome (mRS 3-6 vs 0-2), (a) continuing versus stopping antihypertensive treatment and (b) transdermal GTN versus no GTN.</figcaption></figure>

assigned to receive antihypertensive treatment (n=318) or to the control group (n=324). The primary outcome was depression (Hamilton Rating Scale for Depression score ≥8) at 3-month post-treatment follow-up. There were 102 lacunar stroke patients (defined according to TOAST criteria) in the antihypertensive group and 104 lacunar stroke patients in the control group. The number of events (Hamilton Rating Scale for Depression score ≥8) was slightly higher in the antihypertensive group than in the control group (OR 1.42, 95% CI 0.82, 2.46). There was no heterogeneity of treatment effect on post-stroke depression across stroke subtypes (p=0.07).

In summary, there is no evidence that immediate antihypertensive treatment, compared to avoiding this intervention, may be more beneficial in patients with suspected acute lacunar ischaemic stroke than in acute ischaemic stroke patients overall, in whom the absence of benefit has already been demonstrated and reflected in guidelines, with which we concur.⁸⁵

Time to treatment may have an effect and varies across RCTs (6–48 h), but in trials with longer time windows analyses stratified on time to treatment are not available in patients with lacunar ischaemic stroke.

Results of the aforementioned trials may also have been diluted by the modest difference in BP reduction between the intervention and control groups in most trials.

Most RCTs excluded patients with extremely elevated systolic blood pressure (>220 mmHg), or do not provide

separate results in the subgroup in patients with lacunar ischaemic stroke and SBP >220 mmHg.

## Meta-analyses

Few data were available to conduct meta-analyses.

Primary meta-analyses were conducted in acute lacunar ischaemic stroke patients without thrombolysis only. Indeed, optimal BP management may be different in patients undergoing reperfusion therapy and those who are not. Of note, we did include in this meta-analysis two studies that included a small percentage (<12%) of patients who underwent thrombolysis (ENOS,⁷⁴ SCAST⁸²), although subgroup results in lacunar ischaemic stroke without thrombolysis weren't available.

In a meta-analysis combining CATIS,⁷² SCAST,⁸² VENTURE⁷⁵ and ENOS immediate antihypertensive treatment (using a defined dose of Candesartan, Valsartan, transdermal glyceryl trinitrate or targeting a BP <140/90 mg with ACEi, CCB, or diuretics), compared to avoiding this intervention was not associated with a better functional outcome: OR 0.98, 95% CI 0.74, 1.28, for mRS 3–6, Figure 2.

In a meta-analysis combining SCAST⁸² and VENTURE,⁷⁵ immediate antihypertensive treatment, compared to avoiding this intervention was not associated with a lower risk of MACE: HR 1.33, 95% CI 0.73, 2.44, Figure 3.

As recanalisation may theoretically be less critical in lacunar ischaemic stroke compared to ischaemic stroke
<figure><img src="image_8.png" /><figcaption>**Figure 3.** Meta-analysis of immediate antihypertensive therapy in suspected lacunar ischaemic stroke on MACE.</figcaption></figure>

<figure><img src="image_9.png" /><figcaption>**Figure 4.** Meta-analysis of immediate antihypertensive therapy in suspected lacunar ischaemic stroke, subgroup analysis comparing with versus without thrombolytic treatment on functional outcome (mRS 3-6 vs 0-2), (a) continuing versus stopping antihypertensive treatment and (b) transdermal GTN versus no GTN.</figcaption></figure>

with large vessel occlusion, in particular with a lower risk of broad hypoperfusion related to BP lowering,⁸³ we also conducted pragmatic meta-analyses combining studies with and without thrombolysis.

In a meta-analysis combining CATIS,⁷² SCAST,⁸² VENTURE,⁷⁵ ENCHANTED,⁸³ and ENOS⁷⁴ immediate antihypertensive treatment (using a defined dose of Candesartan, Valsartan, targeting a BP <140/90 mg or a SBP 130–140mmHg), compared to avoiding this intervention was not associated with a better functional outcome: OR 0.99, 95% CI 0.82, 1.21, for mRS 3–6, Figure 4.

In a meta-analysis combining ENOS⁷⁴ and ENCHANTED,⁷⁶ immediate antihypertensive treatment (using transdermal glyceryl trinitrate or targeting a SBP 130–140mmHg), compared to avoiding this intervention was also not associated with a better functional outcome

measured by the shift in mRS score distribution: OR (continuing anti-hypertensives): 0.98, 95% CI 0.72, 1.34; OR (transdermal glyceryl trinitrate): 0.94, 95% CI 0.80, 1.10, for unfavourable shift (Figure 5).

## Additional information

Previous meta-analyses of RCTs have focused on BP lowering in acute ischaemic stroke at large only.

A meta-analysis of 18 RCTs assessing the impact of BP lowering drugs in acute ischaemic stroke on mortality, found no evidence of a beneficial effect⁸⁵: OR 1.00, 95% CI 0.84, 1.19, *p* = 0.98, *I*² = 35%. Similarly, a meta-analysis of 12 RCTs assessing the impact of BP lowering drugs in acute ischaemic stroke on improved functional outcome (mRS 0–2) at 3–6 months following symptom onset found
<figure><img src="image_8.png" /><figcaption>**Figure 3.** Meta-analysis of immediate antihypertensive therapy in suspected lacunar ischaemic stroke on MACE.</figcaption></figure>

<figure><img src="image_9.png" /><figcaption>**Figure 4.** Meta-analysis of immediate antihypertensive therapy in suspected lacunar ischaemic stroke, subgroup analysis comparing with versus without thrombolytic treatment on functional outcome (mRS 3-6 vs 0-2), (a) continuing versus stopping antihypertensive treatment and (b) transdermal GTN versus no GTN.</figcaption></figure>

with large vessel occlusion, in particular with a lower risk of broad hypoperfusion related to BP lowering,⁸³ we also conducted pragmatic meta-analyses combining studies with and without thrombolysis.

In a meta-analysis combining CATIS,⁷² SCAST,⁸² VENTURE,⁷⁵ ENCHANTED,⁸³ and ENOS⁷⁴ immediate antihypertensive treatment (using a defined dose of Candesartan, Valsartan, targeting a BP <140/90 mg or a SBP 130–140mmHg), compared to avoiding this intervention was not associated with a better functional outcome: OR 0.99, 95% CI 0.82, 1.21, for mRS 3–6, Figure 4.

In a meta-analysis combining ENOS⁷⁴ and ENCHANTED,⁷⁶ immediate antihypertensive treatment (using transdermal glyceryl trinitrate or targeting a SBP 130–140mmHg), compared to avoiding this intervention was also not associated with a better functional outcome

measured by the shift in mRS score distribution: OR (continuing anti-hypertensives): 0.98, 95% CI 0.72, 1.34; OR (transdermal glyceryl trinitrate): 0.94, 95% CI 0.80, 1.10, for unfavourable shift (Figure 5).

## Additional information

Previous meta-analyses of RCTs have focused on BP lowering in acute ischaemic stroke at large only.

A meta-analysis of 18 RCTs assessing the impact of BP lowering drugs in acute ischaemic stroke on mortality, found no evidence of a beneficial effect⁸⁵: OR 1.00, 95% CI 0.84, 1.19, *p* = 0.98, *I*² = 35%. Similarly, a meta-analysis of 12 RCTs assessing the impact of BP lowering drugs in acute ischaemic stroke on improved functional outcome (mRS 0–2) at 3–6 months following symptom onset found
<figure><img src="image_10.png" /><figcaption>**Figure 5.** Meta-analysis of immediate antihypertensive therapy in suspected lacunar ischaemic stroke on functional outcome analysed using ordinal shift analysis of the mRS, (a) continuing versus stopping antihypertensive treatment and (b) transdermal GTN versus no GTN.</figcaption></figure>

no statistically significant difference between the use of any BP lowering drugs compared with control⁸⁵: OR 0.98, 95% CI 0.85, 1.12, *p*=0.72, *I*²=35%.

Most of these RCTs (except for those mentioned above) did not include subgroup analyses in patients with lacunar ischaemic stroke.⁸⁶⁻⁹⁷

Of note, a meta-analysis of two RCTs (RIGHT⁹⁸ and RIGHT-2⁹⁹) assessing the impact of hyperacute pre-hospital BP lowering with any vasodepressor drug showed no difference between transdermal GTN and placebo for the outcome of death at 3 months or functional outcome (mRS 3–6).⁸⁵ However no subtype-specific results for lacunar ischaemic stroke were reported, a challenge in the pre-hospital (pre-imaging) setting.

## Other guidelines

To our knowledge, no previous guideline has focused specifically on acute BP lowering in patients with lacunar ischaemic stroke. Recent guidelines on blood pressure management in acute ischaemic stroke at large are summarised below as a point of comparison:

The previously published ESO guideline (Table 1), with which we concur, suggests against routine BP lowering in the pre-hospital setting and in the first 24 h following symptom onset in hospitalised patients with any acute ischaemic stroke and BP<220/110 mmHg not treated with intravenous thrombolysis or mechanical thrombectomy (unless necessary for a comorbid condition). In patients with any acute ischaemic stroke undergoing intravenous thrombolysis it suggests maintaining BP below 185/110 mmHg before

bolus and below 180/105 mmHg after bolus, and for 24 h after alteplase infusion. The guideline also states that there is continued uncertainty over the benefits and risks (advantages/disadvantages) of continuing versus temporarily stopping previous blood pressure lowering therapy. Moreover, although the effects of blood pressure lowering in acute ischaemic stroke patients with SBP>220 mmHg are unknown, as such patients were excluded in most RCTs, careful blood pressure reduction (<15% SBP in 24 h) was deemed reasonable and likely to be safe in an Expert Consensus Statement.⁸⁵

The current US guidelines for acute ischaemic stroke regardless of stroke subtype are to allow patients to autoregulate blood pressure to maintain perfusion for 24 h, up to a SBP of 220 mmHg for patients who did not receive alteplase and 180 mmHg for those who received tPA.¹⁰⁰

The Chinese guidelines for BP management in the acute phase of ischaemic stroke do not provide any specific guideline for the lacunar ischaemic stroke subtype either.²⁸ For patients with BP <220/120 mmHg, who do not receive IV alteplase or endovascular treatment and do not have complications requiring emergency antihypertensive treatment, this guideline states that starting or restarting antihypertensive therapy within the first 48–72 h after AIS is not effective in preventing death or severe disability. For patients with BP ≥220/120 mmHg, who do not receive IV alteplase or endovascular treatment and do not have complications requiring emergency antihypertensive treatment, the effect of starting or restarting antihypertensive therapy within the first 48–72 h after AIS is uncertain. The
<figure><img src="image_10.png" /><figcaption>**Figure 5.** Meta-analysis of immediate antihypertensive therapy in suspected lacunar ischaemic stroke on functional outcome analysed using ordinal shift analysis of the mRS, (a) continuing versus stopping antihypertensive treatment and (b) transdermal GTN versus no GTN.</figcaption></figure>

no statistically significant difference between the use of any BP lowering drugs compared with control⁸⁵: OR 0.98, 95% CI 0.85, 1.12, *p*=0.72, *I*²=35%.

Most of these RCTs (except for those mentioned above) did not include subgroup analyses in patients with lacunar ischaemic stroke.⁸⁶⁻⁹⁷

Of note, a meta-analysis of two RCTs (RIGHT⁹⁸ and RIGHT-2⁹⁹) assessing the impact of hyperacute pre-hospital BP lowering with any vasodepressor drug showed no difference between transdermal GTN and placebo for the outcome of death at 3 months or functional outcome (mRS 3–6).⁸⁵ However no subtype-specific results for lacunar ischaemic stroke were reported, a challenge in the pre-hospital (pre-imaging) setting.

## Other guidelines

To our knowledge, no previous guideline has focused specifically on acute BP lowering in patients with lacunar ischaemic stroke. Recent guidelines on blood pressure management in acute ischaemic stroke at large are summarised below as a point of comparison:

The previously published ESO guideline (Table 1), with which we concur, suggests against routine BP lowering in the pre-hospital setting and in the first 24 h following symptom onset in hospitalised patients with any acute ischaemic stroke and BP<220/110 mmHg not treated with intravenous thrombolysis or mechanical thrombectomy (unless necessary for a comorbid condition). In patients with any acute ischaemic stroke undergoing intravenous thrombolysis it suggests maintaining BP below 185/110 mmHg before

bolus and below 180/105 mmHg after bolus, and for 24 h after alteplase infusion. The guideline also states that there is continued uncertainty over the benefits and risks (advantages/disadvantages) of continuing versus temporarily stopping previous blood pressure lowering therapy. Moreover, although the effects of blood pressure lowering in acute ischaemic stroke patients with SBP>220 mmHg are unknown, as such patients were excluded in most RCTs, careful blood pressure reduction (<15% SBP in 24 h) was deemed reasonable and likely to be safe in an Expert Consensus Statement.⁸⁵

The current US guidelines for acute ischaemic stroke regardless of stroke subtype are to allow patients to autoregulate blood pressure to maintain perfusion for 24 h, up to a SBP of 220 mmHg for patients who did not receive alteplase and 180 mmHg for those who received tPA.¹⁰⁰

The Chinese guidelines for BP management in the acute phase of ischaemic stroke do not provide any specific guideline for the lacunar ischaemic stroke subtype either.²⁸ For patients with BP <220/120 mmHg, who do not receive IV alteplase or endovascular treatment and do not have complications requiring emergency antihypertensive treatment, this guideline states that starting or restarting antihypertensive therapy within the first 48–72 h after AIS is not effective in preventing death or severe disability. For patients with BP ≥220/120 mmHg, who do not receive IV alteplase or endovascular treatment and do not have complications requiring emergency antihypertensive treatment, the effect of starting or restarting antihypertensive therapy within the first 48–72 h after AIS is uncertain. The
guideline states that it may be reasonable to reduce BP by 15% within the first 24h after stroke.²⁸

## Registry data

A large Korean multicentre stroke registry data on 3042 patients with acute lacunar ischaemic stroke and 97349 systolic blood pressure measurements, recently showed that the relationship of SBP levels with poor outcome (3-months mRS 2-6) after acute stroke was strongly time-dependent.¹⁰¹ Elevated SBP was associated with poor outcome in patients with acute lacunar ischaemic stroke, except in the very early phase of acute stroke (first 4h). At 1 and 4h after stroke onset, the relationship between SBP and poor outcome showed a non-linear association. The nadir (BP value with lowest percentage of poor outcome) was 155mmHg at 1h and 124mmHg at 4h. After this time period, from 4 to 72h after stroke onset, higher SBP was linearly associated with a poorer outcome, with the steepest slope observed at 16–24h from onset. After that the effect of SBP on poor outcomes seemed to diminish, in line with previous reports.¹⁰²,¹⁰³ These results suggest a complex time-dependent pattern of association between BP level in acute lacunar stroke patients and functional outcome. They may, at least in part, explain the lack of benefit of BP lowering in published clinical trials and could be informative for the design of future RCTs. Based on this registry data it was estimated that a 10mmHg reduction of SBP at the timepoints of 16–72h could improve the outcome by approximately 2%.¹⁰¹

### Evidence-based Recommendation 1

In hospitalised patients with suspected acute lacunar ischaemic stroke and BP <220/110 mmHg, not treated with intravenous thrombolysis, we suggest against the routine use of additional, immediate BP lowering agents in the hyperacute phase, unless this is necessary for a specific comorbid condition.

Quality of evidence: **Moderate** ⊕⊕⊕

Strength of recommendation: **Weak against intervention** ↓?

### Evidence-based Recommendation 2

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 24h after alteplase infusion.

Quality of evidence: **Very Low** ⊕

Strength of recommendation: **Weak for intervention** ↑?

### Evidence-based Recommendation 3

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.

Quality of evidence: **Very Low** ⊕

Strength of recommendation: -

## Expert Consensus Statement 1

Twelve of 12 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, immediate blood pressure lowering therapy should be avoided for at least 24h after symptom onset.

## Expert Consensus Statement 2

When antihypertensive drugs need to be used in patients with suspected acute lacunar ischaemic stroke undergoing intravenous thrombolysis and with BP >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.

## Expert Consensus Statement 3

Eleven of 12 MWG members agreed that in patients with suspected acute lacunar ischaemic stroke not treated with intravenous thrombolysis and blood pressure >220/120 mmHg, careful blood pressure reduction (<15% systolic blood reduction in 24h) is reasonable. No specific blood pressure lowering agent can be recommended.

PICO 3 Risk of bias of randomised controlled trials (outcome: functional, shift in mRS score distribution)

<figure><img src="image_11.png" /></figure>

## PICO 4:

In patients with suspected acute lacunar ischaemic stroke and progressive symptoms, does acute treatment with anti-platelets/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?

**Definition:** Most lacunar strokes present with a neurological deficit which improves steadily after onset.¹⁰⁴ However, progressive worsening of neurological, particularly motor, symptoms in the hours or days after initial symptom onset occurs in some patients with lacunar stroke syndromes leading to unexpectedly worse disability than is
guideline states that it may be reasonable to reduce BP by 15% within the first 24h after stroke.²⁸

## Registry data

A large Korean multicentre stroke registry data on 3042 patients with acute lacunar ischaemic stroke and 97349 systolic blood pressure measurements, recently showed that the relationship of SBP levels with poor outcome (3-months mRS 2-6) after acute stroke was strongly time-dependent.¹⁰¹ Elevated SBP was associated with poor outcome in patients with acute lacunar ischaemic stroke, except in the very early phase of acute stroke (first 4h). At 1 and 4h after stroke onset, the relationship between SBP and poor outcome showed a non-linear association. The nadir (BP value with lowest percentage of poor outcome) was 155mmHg at 1h and 124mmHg at 4h. After this time period, from 4 to 72h after stroke onset, higher SBP was linearly associated with a poorer outcome, with the steepest slope observed at 16–24h from onset. After that the effect of SBP on poor outcomes seemed to diminish, in line with previous reports.¹⁰²,¹⁰³

These results suggest a complex time-dependent pattern of association between BP level in acute lacunar stroke patients and functional outcome. They may, at least in part, explain the lack of benefit of BP lowering in published clinical trials and could be informative for the design of future RCTs. Based on this registry data it was estimated that a 10mmHg reduction of SBP at the timepoints of 16–72h could improve the outcome by approximately 2%.¹⁰¹

### Evidence-based Recommendation 1

In hospitalised patients with suspected acute lacunar ischaemic stroke and BP <220/110 mmHg, not treated with intravenous thrombolysis, we suggest against the routine use of additional, immediate BP lowering agents in the hyperacute phase, unless this is necessary for a specific comorbid condition.

Quality of evidence: **Moderate** ⊕⊕⊕

Strength of recommendation: **Weak against intervention** ↓?

### Evidence-based Recommendation 2

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 24h after alteplase infusion.

Quality of evidence: **Very Low** ⊕

Strength of recommendation: **Weak for intervention** ↑?

### Evidence-based Recommendation 3

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.

Quality of evidence: **Very Low** ⊕

Strength of recommendation: -

## Expert Consensus Statement 1

Twelve of 12 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, immediate blood pressure lowering therapy should be avoided for at least 24h after symptom onset.

## Expert Consensus Statement 2

When antihypertensive drugs need to be used in patients with suspected acute lacunar ischaemic stroke undergoing intravenous thrombolysis and with BP >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.

## Expert Consensus Statement 3

Eleven of 12 MWG members agreed that in patients with suspected acute lacunar ischaemic stroke not treated with intravenous thrombolysis and blood pressure >220/120 mmHg, careful blood pressure reduction (<15% systolic blood reduction in 24h) is reasonable. No specific blood pressure lowering agent can be recommended.

PICO 3 Risk of bias of randomised controlled trials (outcome: functional, shift in mRS score distribution)

<figure><img src="image_11.png" /></figure>

## PICO 4:

In patients with suspected acute lacunar ischaemic stroke and progressive symptoms, does acute treatment with anti-platelets/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?

**Definition:** Most lacunar strokes present with a neurological deficit which improves steadily after onset.¹⁰⁴ However, progressive worsening of neurological, particularly motor, symptoms in the hours or days after initial symptom onset occurs in some patients with lacunar stroke syndromes leading to unexpectedly worse disability than is
typical in lacunar stroke.¹⁰⁵ This deterioration is referred to variously as early neurological deterioration (END), progressive stroke, progressing stroke, stuttering onset, or capsular warning syndrome (CWS); we use the term 'progressive lacunar stroke'.

‘Progressive lacunar stroke’ is defined quite variably, including as an increase in NIHSS of ≥2 points within 72 h¹⁰⁶,¹⁰⁷ or ≥3 points in total and ≥2 points for limb paresis within 5 days,¹⁰⁸ or ≥4 in total,¹⁰⁹,¹¹⁰ or ≥2 by 48 h¹¹¹ or the seventh day after admission,¹¹² or ≥1 within 5 days of onset,¹¹³,¹¹⁴ or ≥1¹¹⁵,¹¹⁶ in the NIHSS, or ‘any persistent neurological worsening’.¹¹⁷ Capsular warning syndrome (‘capsular’ or ‘stroke warning syndrome’) is variously defined as ‘≥3¹¹⁸⁻¹²¹ or ≥2¹²² stereotyped episodes of lacunar symptoms within 24, 48, or 72 h, with complete neurological resolution between episodes’. ‘Stuttering’ or ‘fluctuating’ lacunar syndrome is defined as ‘neurologic deficit’ with periods of improvement and worsening (with or without full resolution).¹²³

Progressive or stuttering stroke and capsular warning syndrome should be differentiated from early recurrent stroke occurring in the first few days since the mechanism and treatment implications may be different. Progressive stroke is a gradual deterioration whereas early recurrent stroke causes a sudden deterioration in neurological status or different neurological symptoms (indicating different brain region) to those of the initial stroke.

*Frequency, risk factors, outcomes:* Stuttering onset, capsular warning syndrome or progressive worsening of symptoms occur in 20%–36% of patients with lacunar clinical syndrome in the hours to days after first symptom onset.¹⁰⁵,¹²⁴ Risk factors such as motor paresis,¹⁰⁵,¹⁰⁸ larger infarct volume,¹⁰⁸,¹²⁴ more severe stroke at admission,¹⁰¹ worse perfusion in the infarct,¹⁰⁵,¹⁰⁶ more proximal location in the internal capsule or basal ganglia and larger diameter¹⁰⁷,¹⁰⁸ seem fairly consistent between studies. Other risk factors such as male sex,¹⁰⁵,¹⁰⁸ or older age¹⁰⁸ are variable. It is not consistently associated with BP,¹⁰⁵ hypertension, or cardiac embolic sources¹⁰⁴,¹⁰⁵,¹²⁴ An apparent association with D-dimer, thrombin and fibrin formation¹²⁵ may suggest a stuttering thrombotic process. Progressive stroke is associated with worse functional outcomes possibly reflecting the frequent occurrence in patients with motor symptoms.¹⁰⁵,¹⁰⁹,¹¹⁷

The systematic literature search identified 567 titles/ abstracts, of which 45 were duplicates (Supplemental PRISMA diagrams). Of the remaining 522, 21 were selected for full text review and of these six were selected for extraction. Some additional papers were identified during searches for the other PICOs and further articles were identified in reviews or other sources.

This provided two randomised trials both testing anti-platelet drugs (cilostazol,¹⁰⁹ clopidogrel¹¹²), plus three prospective observational studies, 14 retrospective observational studies, two case series, one case report (Supplemental

Tables 7 and 8) and one review.¹⁰⁵ The two randomised trials were too different to perform a meta-analysis but we were able to calculate ORs for progressive stroke and mRS.

## Analysis of Current Evidence

*Randomised Trials:* We found two RCTs that assessed interventions to reduce progressive stroke that included patients with lacunar stroke, but unfortunately in both trials, lacunar stroke was a subset (albeit > 50%) of the population, and neither trial reported outcomes including mRS for the lacunar group alone (Supplemental Table 7, Table 4). There were therefore no published RCTs assessing directly the effect of any interventions in progressive lacunar ischaemic stroke on the stated PICO outcomes.

One pilot multicentre RCT¹⁰⁹ (Table 4a) in 55 sites in Japan, randomised 510 non-cardioembolic progressive stroke patients (mean age 63) including 343 with lacunar stroke subtype, to cilostazol versus no cilostazol, open label. All patients received Japanese guideline treatment including antiplatelet or an antithrombin agent. Cilostazol was started within 24 h and continued for 3 months. The outcome was the rate of progressive stroke defined as ≥4pt on NIHSS on day 3 and/or 5, and mRS 0–1 at 3 months, but the authors only reported the rate of progressive stroke in the lacunar subgroup, and we were unable to obtain additional information from the authors. In 343 patients with lacunar stroke, 7/154 (3.2%) allocated cilostazol and 9/175 (6.3%) allocated no cilostazol experienced progression (OR 0.869, 95% CI 0.304, 2.386, *p*=0.143). mRS 0–2 was reported for all 507 patients (of which lacunar made up 68%) did not differ between cilostazol and no cilostazol (221/251, 88.1%, vs 217/256. 84.8%, OR 1.32, 95% CI 0.79, 2.21). There were several sources of bias: the method of randomisation was not given, the trial was open label, it is unclear if follow-up was blinded, and the guideline treatment was heterogeneous.

The other RCT¹¹² (Supplemental Table 7, Table 4b) in Japan enrolled 54 patients with lacunar infarcts (n=29) or branch atheromatous disease (n=23) within 48 h of stroke and randomised 28 to argatroban, aspirin and clopidogrel (AAC) and 26 to argatroban and aspirin (AA) and therefore is a trial of clopidogrel versus no clopidogrel on a background of argatroban and aspirin. The outcomes were progressive stroke, defined as worsening of ≥2 NIHSS on the seventh day of admission, and mRS at 3 months, but neither outcome was reported for the lacunar stroke group alone. There were fewer progressive strokes in the AAC group than in the AA group (0 [0%] versus 4 [16%] *p*=0.04) but no difference in dependency (mRS 3–6) at 3 months (AAC 6 [21%] vs AA 8 [32%], *p*=0.53). Sources of bias included randomisation by sealed envelope, open label and follow-up by hospital staff (blinding not mentioned).

We found one entry in a trial registry (UMIN-CTR Clinical Trial) for a RCT of cilostazol + aspirin versus aspirin started within 48 h of symptom onset and continued for