Philippe Lyrer - Academia.edu (original) (raw)

Papers by Philippe Lyrer

Circulation, 2021

Background: A proportion of patients with embolic stroke of undetermined source have silent atria... more Background: A proportion of patients with embolic stroke of undetermined source have silent atrial fibrillation (AF) or develop AF after the initial evaluation. Better understanding of the risk for development of AF is critical to implement optimal monitoring strategies with the goal of preventing recurrent stroke attributable to underlying AF. The RE-SPECT ESUS trial (Randomized, Double-Blind Evaluation in Secondary Stroke Prevention Comparing the Efficacy and Safety of the Oral Thrombin Inhibitor Dabigatran Etexilate Versus Acetylsalicylic Acid in Patients With Embolic Stroke of Undetermined Source) provides an opportunity to assess predictors for developing AF and associated recurrent stroke. Methods: RE-SPECT ESUS was a randomized, controlled trial (564 sites, 42 countries) assessing dabigatran versus aspirin for the prevention of recurrent stroke in patients with embolic stroke of undetermined source. Of 5390 patients enrolled and followed for a median of 19 months, 403 (7.5%) ...

OBJECTIVE: The project was conducted in order to identify genes and pathways involved in the path... more OBJECTIVE: The project was conducted in order to identify genes and pathways involved in the pathogenesis of cerebral small-vessel disease (SVD). BACKGROUND: SVD is a common condition in older people and contributes to the development of vascular dementia (VaD), and lacunar strokes. A limited number of studies of its genetic basis have been performed so far and the etiology of the disease remains elusive. DESIGN/METHODS: We analysed the gene expression of post-mortem brain specimen of the frontal cortex, thalamus and frontal white matter of 5 patients histopathologically diagnosed with SVD in comparison with 5 non-affected patients, using oligonucleotide-based microarray technology (Affymetrix® Genechips). Gene annotation and statistic analysis were performed using Partek® Genomics Suite. Genes with fold expression change (F) 1.5, and P RESULTS: Classification into functional groups revealed that genes differentially expressed in the three brain regions were involved in the ubiquitin-mediated proteolysis, cell adhesion, cell cycle, anti-oxidative and fatty acid metabolisms. Genes involved in apoptosis and platelet aggregation were found differently expressed in the cortex and thalamus. Genes involved in myelination, angiogenesis and vesicular transport were differently expressed specifically in the cortex, whereas the expression of genes involved in glycolysis and nitrogen metabolisms was different in the white matter. CONCLUSIONS: Brains of patients suffering from SVD revealed that, on a molecular level, chronic SVD follows patterns of neurodegenerative and metabolic disorders more than ischemic ones. These results may provide guide to potential neuroprotective strategies for prevention of SVD in patients at risk. Supported by: Swiss Heart Foundation; Research Found of the Neurological Clinic, University Hopital Basel. Disclosure: Dr. Ritz has nothing to disclose. Dr. Schaeren-Wiemers has nothing to disclose. Dr. Fluri has nothing to disclose. Dr. Bonati has nothing to disclose. Dr. Kloss has nothing to disclose. Dr. Grond-Ginsbach has nothing to disclose. Dr. Engelter has nothing to disclose. Dr. Tolnay has nothing to disclose. Dr. Lyrer has received personal compensation for activities with Boehringer Ingelheim and Bayer Healthcare as scientific advisory board member. Dr. Lyrer has received personal compensation in an editorial capacity for Springer Medizin Verlag, Switzerland. Dr. Lyrer has received research support from Dpharm Innovative Biopharmaceuticals Photothera, USA.

Annals of Neurology, May 13, 2023

Current Neurovascular Research, Jan 12, 2016

Cerebral small-vessel disease (SVD) is characterized by periventricular white matter (WM) changes... more Cerebral small-vessel disease (SVD) is characterized by periventricular white matter (WM) changes and general brain atrophy. SVD is prevalent in elderly individuals and is frequently associated with the development of vascular dementia (VaD). Studies of the molecular basis of SVD are sparse. We have to gain further insight into the pathogenic mechanisms of SVD. Therefore, we compared gene expression patterns in the brains of SVD and control patients, in order to identify cellular pathways changed in diseased brains. We compared the expression of mRNA transcripts in postmortem, macroscopically normal-appearing human brain tissues isolated from frontal, temporal and occipital cortical and subcortical regions in 5 SVD and 5 non-SVD control patients. Significant expression changes were determined by fold change F>1.2 in either direction, and p<0.05. We identified 228 genes differentially expressed in cortex (89 up-, 139 down-regulated) and 555 genes in WM (223 up-, 332 down-regulated) in SVD patients. Pathway analyses revealed that upregulated genes were associated with inflammation and apoptosis in WM, suggesting active cell death. Downregulated genes were associated with coagulation and fatty and amino acids metabolisms. In the cortex, down-regulated genes were principally associated with neuronal functions. Our data revealed widespread changes in the transcriptome profiles in the cortex and WM of human SVD brains, with a predominance of changes in WM. We provide for the first time a comprehensive view of the molecular alterations in human SVD brains that seem to contribute to the neuropathogenesis of SVD.

Stroke, Dec 1, 2022

Background: The probability to receive intravenous thrombolysis (IVT) for treatment of acute isch... more Background: The probability to receive intravenous thrombolysis (IVT) for treatment of acute ischemic stroke declines with increasing age and is consequently the lowest in very elderly patients. Safety concerns likely influence individual IVT treatment decisions. Using data from a large IVT registry, we aimed to provide more evidence on safety of IVT in the very elderly. Methods: In this prospective multicenter study from the TRISP (Thrombolysis in Ischemic Stroke Patients) registry, we compared patients ≥90 years with those <90 years using symptomatic intracranial hemorrhage (ECASS [European Cooperative Acute Stroke Study]-II criteria), death, and poor functional outcome in survivors (modified Rankin Scale score 3–5 for patients with prestroke modified Rankin Scale score ≤2 and modified Rankin Scale score 4–5 for patients prestroke modified Rankin Scale ≥3) at 3 months as outcomes. We calculated adjusted odds ratio with 95% CI using logistic regression models. Results: Of 16 974 eligible patients, 976 (5.7%) were ≥90 years. Patients ≥90 years had higher median National Institutes of Health Stroke Scale on admission (12 versus 8) and were more often dependent prior to the index stroke (prestroke modified Rankin Scale score of ≥3; 45.2% versus 7.4%). Occurrence of symptomatic intracranial hemorrhage (5.7% versus 4.4%, odds ratio adjusted 1.14 [0.83–1.57]) did not differ significantly between both groups. However, the probability of death (odds ratio adjusted 3.77 [3.14–4.53]) and poor functional outcome (odds ratio adjusted 2.63 [2.13–3.25]) was higher in patients aged ≥90 years. Results for the sample of centenarians (n=21) were similar. Conclusions: The probability of symptomatic intracranial hemorrhage after IVT in very elderly patients with stroke did not exceed that of their younger counterparts. The higher probability of death and poor functional outcome during follow-up in the very elderly seems not to be related to IVT treatment. Very high age itself should not be a reason to withhold IVT.

Journal of Neurology, Neurosurgery, and Psychiatry, Apr 8, 2022

Objective To investigate the aetiology, subsequent preventive strategies and outcomes of stroke d... more Objective To investigate the aetiology, subsequent preventive strategies and outcomes of stroke despite anticoagulation in patients with atrial fibrillation (AF). Methods We analysed consecutive patients with AF with an index imaging-proven ischaemic stroke despite vitamin K-antagonist (VKA) or direct oral anticoagulant (DOAC) treatment across 11 stroke centres. We classified stroke aetiology as: (i) competing stroke mechanism other than AF-related cardioembolism; (ii) insufficient anticoagulation (non-adherence or low anticoagulant activity measured with drug-specific assays); or, (iii) AF-related cardioembolism despite sufficient anticoagulation. We investigated subsequent preventive strategies with regard to the primary (composite of recurrent ischaemic stroke, intracranial haemorrhage, death) and secondary endpoint (recurrent ischaemic stroke) within 3 months after index stroke. Results Among 2946 patients (median age 81 years; 48% women; 43% VKA, 57% DOAC), stroke aetiology was competing mechanism in 713 patients (24%), insufficient anticoagulation in 934 (32%) and cardioembolism despite sufficient anticoagulation in 1299 (44%). We found high rates of the primary (27% of patients; completeness 91.6%) and secondary endpoint (4.6%; completeness 88.5%). Only DOAC (vs VKA) treatment after index stroke showed lower odds for both endpoints (primary: adjusted OR (aOR) (95% CI) 0.49 (0.32 to 0.73); secondary: 0.44 (0.24 to 0.80)), but not switching between different DOAC types. Adding antiplatelets showed higher odds for both endpoints (primary: aOR (95% CI) 1.99 (1.25 to 3.15); secondary: 2.66 (1.40 to 5.04)). Only few patients (1%) received left atrial appendage occlusion as additional preventive strategy. Conclusions Stroke despite anticoagulation comprises heterogeneous aetiologies and cardioembolism despite sufficient anticoagulation is most common. While DOAC were associated with better outcomes than VKA, adding antiplatelets was linked to worse outcomes in these high-risk patients. Our findings indicate that individualised and novel preventive strategies beyond the currently available anticoagulants are needed. Trial registration number ISRCTN48292829.

European Journal of Neurology, Mar 26, 2012

To examine whether thrombolysis for stroke attributable to cervical artery dissection (CeAD Strok... more To examine whether thrombolysis for stroke attributable to cervical artery dissection (CeAD Stroke) affects outcome and major haemorrhage rates. Methods: We used a multicentre CeAD Stroke database to compare CeAD Stroke patients treated with and without thrombolysis. Main outcome measures were favourable 3-month outcome (modified Rankin Scale 0-2) and Ômajor haemorrhageÕ [any intracranial haemorrhage (ICH) and major extracranial haemorrhage]. Adjusted odds ratios [OR (95% confidence intervals)] were calculated on the whole database and on propensity-matched groups. Results: Among 616 CeAD Stroke patients, 68 (11.0%) received thrombolysis; which was used in 55 (81%) intravenously. Thrombolyzed patients had more severe strokes (median NIHSS score 16 vs. 3; P < 0.001) and more often occlusion of the dissected artery (66.2% vs. 39.4%; P < 0.001). After adjustment for stroke severity and vessel occlusion, the likelihood for favourable outcome did not differ between the treatment groups [OR adjusted 0.95 (95% CI 0.45-2.00)]. The propensity matching score model showed that the odds to recover favourably were virtually identical for 64 thrombolyzed and 64 non-thrombolyzed-matched CeAD Stroke patients [OR 1.00 (0.49-2.00)]. Haemorrhages occurred in 4 (5.9%) thrombolyzed patients, all being asymptomatic ICHs. In the non-thrombolysis group, 3 (0.6%) patients had major haemorrhages [asymptomatic ICH (n = 2) and major extracranial haemorrhage (n = 1)]. Conclusion: As thrombolysis was neither independently associated with unfavourable outcome nor with an excess of symptomatic bleedings, our findings suggest thrombolysis should not be withheld in CeAD Stroke patients. However, the lack of any trend towards a benefit of thrombolysis may indicate the legitimacy to search for more efficient treatment options including mechanical revascularization strategies.

Stroke, Feb 1, 2020

Background: The optimal timepoint of starting DOAC after an acute ischemic stroke (IS) related to... more Background: The optimal timepoint of starting DOAC after an acute ischemic stroke (IS) related to atrial fibrillation (AF) remains unclear. We aimed to compare an early (≤ 5 days of IS) versus late (&gt;5 days of IS) DOAC-start. Methods: Individual patient data analysis of 7 European and Japanese prospective observational cohort studies. We included patients with IS or TIA related to non-valvular AF where a DOAC was started within 30 days. We excluded patients with an intracranial bleeding (ICH) after the index event but prior to DOAC-start. We compared the 30-day rates of recurrent IS and ICH between the groups of early versus late DOAC-start with a landmark analysis at day 5. Results: Overall, 2550 patients were included. Median age was 77 years (IQR 70-84). DOAC were started early in 1362 (53%) patients, late in 1188 (47%). In the whole cohort, 37 patients suffered from a recurrent IS (1.5%), 16 patients (43%) of whom before any DOAC was started. 6 patients (0.2%) had an ICH. In the early DOAC-start group, 23 patients (1.7%) suffered from a recurrent IS after DOAC-start and within 30 days; two patients (0.1%) suffered from ICH after DOAC-start. In the late DOAC-start group, 14 patients (1.2%) suffered from a recurrent IS before DOAC was started; 4 patients (0.3%) suffered from ICH after DOAC-start. In the comparison of late versus early DOAC-groups, no difference in the hazard ratios was observed for the endpoint of recurrent IS (HR = 1.15, 95%CI 0.48-2.73, p=0.76) and ICH (HR = 4.71, 95%CI 0.51-43.10, p=0.17). Conclusion: Our results do not corroborate the concern that early anticoagulation - at least when performed with DOACs - increases the risk of hemorrhagic transformation of the brain infarct compared to late anticoagulation. Given the seven times higher risk of recurrent IS - with almost half of recurrent IS occurring before any DOAC-start - an early DOAC-start after AF-related IS may be reasonable, if inclusion in the ongoing trials (the recommended option) is not possible.

Stroke, Mar 1, 2023

HAL is a multidisciplinary open access archive for the deposit and dissemination of scientific re... more HAL is a multidisciplinary 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.

European stroke journal, Nov 13, 2019

Introduction: Alterations in haemoglobin levels are frequent in stroke patients. The prognostic m... more Introduction: Alterations in haemoglobin levels are frequent in stroke patients. The prognostic meaning of anaemia and polyglobulia on outcomes in patients treated with intravenous thrombolysis is ambiguous. Patients and methods: In this prospective multicentre, intravenous thrombolysis register-based study, we compared haemoglobin levels on hospital admission with three-month poor outcome (modified Rankin Scale 3-6), mortality and symptomatic intracranial haemorrhage (European Cooperative Acute Stroke Study II-criteria (ECASS-II-criteria)). Haemoglobin level was used as continuous and categorical variable distinguishing anaemia (female: <12 g/dl; male: <13 g/dl) and polyglobulia (female: >15.5 g/dl; male: >17 g/dl). Anaemia was subdivided into mild and moderate/severe (female/male: <11 g/dl). Normal haemoglobin level (female: 12.0-15.5 g/dl, male: 13.0-17.0 g/dl) served as reference group. Unadjusted and adjusted odds ratios with 95% confidence intervals were calculated with logistic regression models. Results: Among 6866 intravenous thrombolysis-treated stroke patients, 5448 (79.3%) had normal haemoglobin level, 1232 (17.9%) anaemia-of those 903 (13.2%) had mild and 329 (4.8%) moderate/severe anaemia-and 186 (2.7%) polyglobulia. Anaemia was associated with poor outcome (OR adjusted 1.25 (1.05-1.48)) and mortality (OR adjusted 1.58 (1.27-1.95)). In anaemia subgroups, both mild and moderate/severe anaemia independently predicted poor outcome

Journal of Neurology, Neurosurgery, and Psychiatry, Oct 11, 2021

Objective: The optimal timing to start direct oral anticoagulants (DOAC) after an acute ischemic ... more Objective: The optimal timing to start direct oral anticoagulants (DOAC) after an acute ischemic stroke (AIS) related to atrial fibrillation (AF) remains unclear. We aimed to compare early (≤ days of AIS) versus late (>5 days of AIS) DOAC-start. Methods: This is an individual patient data pooled analysis of 8 prospective European and Japanese cohort studies. We included patients with AIS related to non-valvular AF where a DOAC was started within 30 days. Primary endpoints were 30-day rates of recurrent AIS and ICH. Results: A total of 2550 patients were included. DOACs was started early in 1362 (53%) patients, late in 1188 (47%). During 212 patient-years, 37 patients had a recurrent AIS (1.5%), 16 (43%) before a DOAC was started; 6 patients (0.2%) had an ICH, all after DOACstart. In the early DOAC-start group, 23 patients (1.7%) suffered from a recurrent AIS, while 2 patients (0.1%) had an ICH. In the late DOAC-start group, 14 patients (1.2%) suffered from a recurrent AIS; 4 patients (0.3%) suffered from ICH. In the propensity-score adjusted comparison of late versus early DOAC-start groups, there was no statistically significant difference in the hazard of recurrent AIS (aHR=1.2, 95%CI 0.5-2.9, p=0.69), ICH (aHR=6.0, 95%CI 0.6-56.3, p=0.12) or any stroke. Conclusions: Our results do not corroborate concerns that an early DOAC-start might excessively increase the risk of ICH. The seven-fold higher risk of recurrent AIS than ICH suggests that an early DOAC-start might be reasonable, supporting enrolment into randomized trials comparing an early versus late DOAC start.

Journal of Stroke

Background and Purpose Knowledge about different etiologies of non-traumatic intracerebral hemorr... more Background and Purpose Knowledge about different etiologies of non-traumatic intracerebral hemorrhage (ICH) and their outcomes is scarce.Methods We assessed prevalence of pre-specified ICH etiologies and their association with outcomes in consecutive ICH patients enrolled in the prospective Swiss Stroke Registry (2014 to 2019). Results We included 2,650 patients (mean±standard deviation age 72±14 years, 46.5% female, median National Institutes of Health Stroke Scale 8 [interquartile range, 3 to 15]). Etiology was as follows: hypertension, 1,238 (46.7%); unknown, 566 (21.4%); antithrombotic therapy, 227 (8.6%); cerebral amyloid angiopathy (CAA), 217 (8.2%); macrovascular cause, 128 (4.8%); other determined etiology, 274 patients (10.3%). At 3 months, 880 patients (33.2%) were functionally independent and 664 had died (25.1%). ICH due to hypertension had a higher odds of functional independence (adjusted odds ratio [aOR], 1.33; 95% confidence interval [CI], 1.00 to 1.77; P=0.05) and l...

Stroke, 2021

Background: We determined the frequency of different etiologies of non-traumatic intracerebral he... more Background: We determined the frequency of different etiologies of non-traumatic intracerebral hemorrhage (ICH) and their association with clinical characteristics and outcomes. Methods: We analyzed data from consecutive ICH patients enrolled in the prospective Swiss Stroke Registry (2014-2019). Etiology of ICH was determined according to prespecified, mutually exclusive categories. We assessed prevalence of ICH etiologies, their association with clinical characteristics, functional independence (modified Rankin Scale 0-2), mortality, recurrent ICH and ischemic stroke at 3 months. Results: We included 2584 patients (median age 72y, IQR 64-82, 46.6% female, median NIHSS 10; IQR 3-15). 2037 patients (80%) had hypertension and 553 (22.3%) were on anticoagulants. Distribution of etiologies was as follows: Hypertension (n=1216 patients; 47.1% of all / 56.3% of patients with hypertension), unknown etiology (n=542, 21.0%), antithrombotic therapy (n=225, 8.7% of all / 38% of patients on ant...

The goal of this work was to explore age- dependent differences in cervical artery dissection (Ce... more The goal of this work was to explore age- dependent differences in cervical artery dissection (CeAD). This study is based on the Cervical Artery Dissection and Ischemic Stroke Patients population comprising 983 con- secutive CeAD patients and 658 control patients with a non-CeAD ischemic stroke (IS), frequency-matched for age and gender. Patients were divided into three age cat- egories: B33 (for CeAD, n = 150), 34-54 (n = 688), and C55 (n = 145) years, and the youngest and oldest groups were compared. The youngest patients were mostly women and the oldest men. The frequency of internal carotid artery dissection (ICAD) versus vertebral artery dissection (VAD) increased with age from 44 to 75 %. This age-related shift remained significant after adjustment for sex. The fre- quency of a transient ischemic event as the CeAD symptom declined from 33 % in the youngest age group, to 19 % in the oldest. Vascular risk factors increased in frequency with advancing age in both groups, but for ...

The Lancet, 2021

Summary Background Among asymptomatic patients with severe carotid artery stenosis but no recent ... more Summary Background Among asymptomatic patients with severe carotid artery stenosis but no recent stroke or transient cerebral ischaemia, either carotid artery stenting (CAS) or carotid endarterectomy (CEA) can restore patency and reduce long-term stroke risks. However, from recent national registry data, each option causes about 1% procedural risk of disabling stroke or death. Comparison of their long-term protective effects requires large-scale randomised evidence. Methods ACST-2 is an international multicentre randomised trial of CAS versus CEA among asymptomatic patients with severe stenosis thought to require intervention, interpreted with all other relevant trials. Patients were eligible if they had severe unilateral or bilateral carotid artery stenosis and both doctor and patient agreed that a carotid procedure should be undertaken, but they were substantially uncertain which one to choose. Patients were randomly allocated to CAS or CEA and followed up at 1 month and then annually, for a mean 5 years. Procedural events were those within 30 days of the intervention. Intention-to-treat analyses are provided. Analyses including procedural hazards use tabular methods. Analyses and meta-analyses of non-procedural strokes use Kaplan-Meier and log-rank methods. The trial is registered with the ISRCTN registry, ISRCTN21144362. Findings Between Jan 15, 2008, and Dec 31, 2020, 3625 patients in 130 centres were randomly allocated, 1811 to CAS and 1814 to CEA, with good compliance, good medical therapy and a mean 5 years of follow-up. Overall, 1% had disabling stroke or death procedurally (15 allocated to CAS and 18 to CEA) and 2% had non-disabling procedural stroke (48 allocated to CAS and 29 to CEA). Kaplan-Meier estimates of 5-year non-procedural stroke were 2·5% in each group for fatal or disabling stroke, and 5·3% with CAS versus 4·5% with CEA for any stroke (rate ratio [RR] 1·16, 95% CI 0·86–1·57; p=0·33). Combining RRs for any non-procedural stroke in all CAS versus CEA trials, the RR was similar in symptomatic and asymptomatic patients (overall RR 1·11, 95% CI 0·91–1·32; p=0·21). Interpretation Serious complications are similarly uncommon after competent CAS and CEA, and the long-term effects of these two carotid artery procedures on fatal or disabling stroke are comparable. Funding UK Medical Research Council and Health Technology Assessment Programme.