23 Feb 24. Featured Paper

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

Link to paper at European Stroke Organisation Journal

Authors

Joanna M Wardlaw, Hugues Chabriat, Frank-Erik de Leeuw, Stéphanie Debette, Martin Dichgans, Fergus Doubal, Hanna Jokinen, Aristeidis H Katsanos,  Rafaelle Ornello, Leonardo Pantoni,  Marco Passi, Aleksandra M Pavlovic,  Salvatore Rudilosso, Reinhold Schmidt, Julie Staals, Martin Taylor-Rowan, Salman Hussain, and Arne G Lindgren

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 disorders. We systematically reviewed the literature, assessed the evidence and where feasible formulated evidence-based recommendations, and expert concensus 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.

Recommendations for future research

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

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

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

Third, the data on aspirin and clopidogrel (conventional ‘strong’ antiplatelet drugs), antihypertensives and statins indicate somewhat limited effectiveness and suggest that there is little point in attempting further trials of these agents, although the combination of aspirin and dipyridamole or aspirin and ticagrelor in acute lacunar ischaemic stroke could be of interest. This is consistent with the intrinsic nature of the underlying non-atheromatous, non-cardioembolic SVD pathology. Rather, it could be more informative to focus on emerging, newer, or novel agents with relevant modes of action to try and find more effective interventions that tackle the intrinsic pathology.

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

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

Keywords

• European Stroke Organisation
• STRIVE-2
• Oxfordshire Community Stroke Project
• Clopidogrel 
• Dipyridamole