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- Schild, R., et al.
(författare)
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Disparities in treatment and outcome of kidney replacement therapy in children with comorbidities: an ESPN/ERA Registry study
- 2023
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Ingår i: Clinical Kidney Journal. - : Oxford University Press (OUP). - 2048-8505 .- 2048-8513. ; 16:4, s. 745-755
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Tidskriftsartikel (refereegranskat)abstract
- Background Data on comorbidities in children on kidney replacement therapy (KRT) are scarce. Considering their high relevance for prognosis and treatment, this study aims to analyse the prevalence and implications of comorbidities in European children on KRT. Methods We included data from patients <20 years of age when commencing KRT from 2007 to 2017 from 22 European countries within the European Society of Paediatric Nephrology/European Renal Association Registry. Differences between patients with and without comorbidities in access to kidney transplantation (KT) and patient and graft survival were estimated using Cox regression. Results Comorbidities were present in 33% of the 4127 children commencing KRT and the prevalence has steadily increased by 5% annually since 2007. Comorbidities were most frequent in high-income countries (43% versus 24% in low-income countries and 33% in middle-income countries). Patients with comorbidities had a lower access to transplantation {adjusted hazard ratio [aHR] 0.67 [95% confidence interval (CI) 0.61-0.74]} and a higher risk of death [aHR 1.79 (95% CI 1.38-2.32)]. The increased mortality was only seen in dialysis patients [aHR 1.60 (95% CI 1.21-2.13)], and not after KT. For both outcomes, the impact of comorbidities was stronger in low-income countries. Graft survival was not affected by the presence of comorbidities [aHR for 5-year graft failure 1.18 (95% CI 0.84-1.65)]. Conclusions Comorbidities have become more frequent in children on KRT and reduce their access to transplantation and survival, especially when remaining on dialysis. KT should be considered as an option in all paediatric KRT patients and efforts should be made to identify modifiable barriers to KT for children with comorbidities. Lay Summary Kidney transplantation (KT) is considered the optimal treatment for children who suffer from permanent kidney failure, because it leads to a lower mortality and higher quality of life compared with dialysis. Children on dialysis frequently suffer from diseases of other organs (comorbidities) that can directly lower their life expectancy and could potentially represent a barrier for transplantation, posing an additional disease burden for these children. In this study we looked at data from a large multinational registry for children with kidney failure who require kidney replacement. Using these data, we studied whether these children suffered from comorbidities and whether these impact their life expectancy or their access to KT. We found that more and more children with kidney failure suffer from comorbidities when starting kidney replacement therapy. We also found that these children have a lower access to KT and a higher mortality on dialysis compared with children without comorbidities, especially in low-income countries. After KT, children with comorbidities have a similar mortality and graft survival compared with children without comorbidities. We concluded that reduced access to a kidney transplant might represent a modifiable barrier to KT in children with comorbidities, especially in low-resource countries. We suggest that children with comorbidities in need for kidney replacement therapy should be rapidly evaluated for eligibility for KT.
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- Bath, PMW, et al.
(författare)
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Baseline characteristics of the 4011 patients recruited into the ‘Efficacy of Nitric Oxide in Stroke’ (ENOS) trial
- 2014
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Ingår i: International journal of stroke : official journal of the International Stroke Society. - : SAGE Publications. - 1747-4949. ; 9:6, s. 711-720
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Tidskriftsartikel (refereegranskat)abstract
- High blood pressure is common in acute stroke and associated with a worse functional outcome. Many patients who present with acute stroke are taking prescribed antihypertensive therapy before their stroke. Aims ENOS tested whether lowering blood pressure and continuing pre-stroke antihypertensive therapy are each safe and effective. Methods This study is an international multi-centre prospective randomized single-blind blinded-endpoint parallel-group partial-factorial controlled trial of transdermal glyceryl trinitrate (a nitric oxide donor, given for seven-days) vs. no glyceryl trinitrate, and of continuing vs. stopping (temporarily for seven-days) pre-stroke antihypertensive drugs if relevant, in patients with acute ischaemic stroke or intracerebral haemorrhage and high systolic blood pressure (140–220 mmHg). Results Recruitment ran from July 2001 to October 2013. Four thousand eleven patients [2097 (52·3%) in the continue/stop arm] were recruited from 173 sites across 23 countries in 5 continents (Asia 14%, Continental Europe 16%, UK 64%). Baseline characteristics include: mean age 70 (standard deviation 12) years; male 57%; mean time from stroke to recruitment 26 ( 13 ) h; mean severity (Scandinavian Stroke Scale) 34 ( 13 ) of 58; mean blood pressure 167 ( 19 )/90 ( 13 ) mmHg; ischaemic stroke 83%; and intracerebral haemorrhage 16%. The main trial results will be presented in May 2014. The results will also be presented in updated Cochrane systematic reviews and included in individual patient data meta-analyses of all relevant randomized controlled trials. Conclusion ENOS is a large completed international trial of blood pressure management in acute stroke and includes patients representative of many stroke services worldwide.
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| 5. |
- Hart, R. G., et al.
(författare)
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Rivaroxaban for Stroke Prevention after Embolic Stroke of Undetermined Source
- 2018
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Ingår i: New England Journal of Medicine. - 0028-4793 .- 1533-4406. ; 378:23, s. 2191-2201
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND Embolic strokes of undetermined source represent 20% of ischemic strokes and are associated with a high rate of recurrence. Anticoagulant treatment with rivaroxaban, an oral factor Xa inhibitor, may result in a lower risk of recurrent stroke than aspirin. We compared the efficacy and safety of rivaroxaban (at a daily dose of 15 mg) with aspirin (at a daily dose of 100 mg) for the prevention of recurrent stroke in patients with recent ischemic stroke that was presumed to be from cerebral embolism but without arterial stenosis, lacune, or an identified cardioembolic source. The primary efficacy outcome was the first recurrence of ischemic or hemorrhagic stroke or systemic embolism in a time-to-event analysis; the primary safety outcome was the rate of major bleeding. A total of 7213 participants were enrolled at 459 sites; 3609 patients were randomly assigned to receive rivaroxaban and 3604 to receive aspirin. Patients had been followed for a median of 11 months when the trial was terminated early because of a lack of benefit with regard to stroke risk and because of bleeding associated with rivaroxaban. The primary efficacy outcome occurred in 172 patients in the rivaroxaban group (annualized rate, 5.1%) and in 160 in the aspirin group (annualized rate, 4.8%) (hazard ratio, 1.07; 95% confidence interval [CI], 0.87 to 1.33; P=0.52). Recurrent ischemic stroke occurred in 158 patients in the rivaroxaban group (annualized rate, 4.7%) and in 156 in the aspirin group (annualized rate, 4.7%). Major bleeding occurred in 62 patients in the rivaroxaban group (annualized rate, 1.8%) and in 23 in the aspirin group (annualized rate, 0.7%) (hazard ratio, 2.72; 95% CI, 1.68 to 4.39; P<0.001). Rivaroxaban was not superior to aspirin with regard to the prevention of recurrent stroke after an initial embolic stroke of undetermined source and was associated with a higher risk of bleeding.
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- Appleton, JP, et al.
(författare)
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It is safe to use transdermal glyceryl trinitrate to lower blood pressure in patients with acute ischaemic stroke with carotid stenosis
- 2019
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Ingår i: Stroke and vascular neurology. - : BMJ. - 2059-8696 .- 2059-8688. ; 4:1, s. 28-35
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Tidskriftsartikel (refereegranskat)abstract
- There is concern that blood pressure (BP) lowering in acute stroke may compromise cerebral perfusion and worsen outcome in the presence of carotid stenosis. We assessed the effect of glyceryl trinitrate (GTN) in patients with carotid stenosis using data from the Efficacy of Nitric Oxide in Stroke (ENOS) Trial.MethodsENOS randomised 4011 patients with acute stroke and raised systolic BP (140–220 mm Hg) to transdermal GTN or no GTN within 48 hours of onset. Those on prestroke antihypertensives were also randomised to stop or continue their medication for 7 days. The primary outcome was the modified Rankin Scale (mRS) at day 90. Ipsilateral carotid stenosis was split: <30%; 30–<50%; 50–<70%; ≥70%. Data are ORs with 95% CIs adjusted for baseline prognostic factors.Results2023 (60.5%) ischaemic stroke participants had carotid imaging. As compared with <30%, ≥70% ipsilateral stenosis was associated with an unfavourable shift in mRS (worse outcome) at 90 days (OR 1.88, 95% CI 1.44 to 2.44, p<0.001). Those with ≥70% stenosis who received GTN versus no GTN had a favourable shift in mRS (OR 0.56, 95% CI 0.34 to 0.93, p=0.024). In those with 50–<70% stenosis, continuing versus stopping prestroke antihypertensives was associated with worse disability, mood, quality of life and cognition at 90 days. Clinical outcomes did not differ across bilateral stenosis groups.ConclusionsFollowing ischaemic stroke, severe ipsilateral carotid stenosis is associated with worse functional outcome at 90 days. GTN appears safe in ipsilateral or bilateral carotid stenosis, and might improve outcome in severe ipsilateral carotid stenosis.
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- Bereczki, E, et al.
(författare)
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Corrigendum
- 2019
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Ingår i: Brain : a journal of neurology. - : Oxford University Press (OUP). - 1460-2156. ; 142:6, s. e24-
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Tidskriftsartikel (refereegranskat)
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- Bereczki, E., et al.
(författare)
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Synaptic proteins in CSF relate to Parkinson's disease stage markers
- 2017
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Ingår i: Npj Parkinsons Disease. - : Springer Science and Business Media LLC. - 2373-8057. ; 3
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Tidskriftsartikel (refereegranskat)abstract
- Recent findings of morphological and functional changes in Parkinson's disease brains have shown altered synapse formation, but their role in cognitive decline is still an area under exploration. Here we measured the concentration of three key synaptic proteins, Rab3A, SNAP25 and neurogranin by enzyme-linked immunosorbent assay, in cerebrospinal fluid from a total of 139 participants (87 controls and 52 Parkinson's disease patients out of which 30 were drug-naive) and explored their associations with motor and cognitive symptoms. Associations with motor disease stage (assessed by Hoehn and Yahr scale) and cognitive performance (assessed by the Montreal Cognitive Assessment scores) were explored. An overall increase in the concentration of SNAP25 was found in Parkinson's disease patients (p = 0.032). Increased neurogranin levels were found in the drug naive patients subgroup (p = 0.023). Significant associations were observed between increased concentration of neurogranin and cognitive impairment in total Parkinson's disease group (p = 0.017), as well as in the drug naive (p = 0.021) and with motor disease stage (p = 0.041). There were no significant disease-driven changes observed in the concentration of Rab3a. Concentrations SNAP25 and neurogranin were increased in cerebrospinal fluid of Parkinson's disease patients in a disease specific manner and related to cognitive and motor symptom severity. Future longitudinal studies should explore whether cerebrospinal fluid synaptic proteins can predict cognitive decline in Parkinson's disease.
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| 20. |
- Bereczki, E., et al.
(författare)
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Synaptic proteins predict cognitive decline in Alzheimer's disease andLewy body dementia
- 2016
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Ingår i: Alzheimer's & Dementia. - : Wiley. - 1552-5260 .- 1552-5279. ; 12:11, s. 1149-1158
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Tidskriftsartikel (refereegranskat)abstract
- Introduction Our objective was to compare the levels of three synaptic proteins involved in different steps of the synaptic transmission: Rab3A, SNAP25, and neurogranin, in three common forms of dementia: Alzheimer's disease (AD), dementia with Lewy bodies (DLB), and Parkinson's disease dementia. Methods A total of 129 postmortem human brain samples were analyzed in brain regional specific manner exploring their associations with morphologic changes and cognitive decline. Results We have observed robust changes reflecting synaptic dysfunction in all studied dementia groups. There were significant associations between the rate of cognitive decline and decreased levels of Rab3 in DLB in the inferior parietal lobe and SNAP25 in AD in the prefrontal cortex. Of particular note, synaptic proteins significantly discriminated between dementia cases and controls with over 90% sensitivity and specificity. Discussion Our findings suggest that the proposition that synaptic markers can predict cognitive decline in AD, should be extended to Lewy body diseases. © 2016 The Alzheimer's Association
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- Hart, Robert G., et al.
(författare)
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Rivaroxaban for secondary stroke prevention in patients with embolic strokes of undetermined source : Design of the NAVIGATE ESUS randomized trial
- 2016
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Ingår i: European Stroke Journal. - : SAGE Publications. - 2396-9873 .- 2396-9881. ; 1:3, s. 146-154
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Tidskriftsartikel (refereegranskat)abstract
- Background: Embolic strokes of undetermined source comprise up to 20% of ischemic strokes. The stroke recurrence rate is substantial with aspirin, widely used for secondary prevention. The New Approach riVaroxaban Inhibition of Factor Xa in a Global trial versus ASA to prevenT Embolism in Embolic Stroke of Undetermined Source international trial will compare the efficacy and safety of rivaroxaban, an oral factor Xa inhibitor, versus aspirin for secondary prevention in patients with recent embolic strokes of undetermined source. Main hypothesis: In patients with recent embolic strokes of undetermined source, rivaroxaban 15 mg once daily will reduce the risk of recurrent stroke (both ischemic and hemorrhagic) and systemic embolism (primary efficacy outcome) compared with aspirin 100 mg once daily. Design: Double-blind, randomized trial in patients with embolic strokes of undetermined source, defined as nonlacunar cryptogenic ischemic stroke, enrolled between seven days and six months from the qualifying stroke. The planned sample size of 7000 participants will be recruited from approximately 480 sites in 31 countries between 2014 and 2017 and followed for a mean of about two years until at least 450 primary efficacy outcome events have occurred. The primary safety outcome is major bleeding. Two substudies assess (1) the relative effect of treatments on MRI-determined covert brain infarcts and (2) the biological underpinnings of embolic strokes of undetermined source using genomic and biomarker approaches. Summary: The New Approach riVaroxaban Inhibition of Factor Xa in a Global trial versus ASA to prevenT Embolism in Embolic Stroke of Undetermined Source trial is evaluating the benefits and risks of rivaroxaban for secondary stroke prevention in embolic strokes of undetermined source patients. Main results are anticipated in 2018.
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| 24. |
- Kasner, Scott E., et al.
(författare)
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Characterization of Patients with Embolic Strokes of Undetermined Source in the NAVIGATE ESUS Randomized Trial
- 2018
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Ingår i: Journal of Stroke and Cerebrovascular Diseases. - : Elsevier BV. - 1052-3057. ; 27:6, s. 1673-1682
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Tidskriftsartikel (refereegranskat)abstract
- Background: The New Approach Rivaroxaban Inhibition of Factor Xa in a Global Trial vs. ASA to Prevent Embolism in Embolic Stroke of Undetermined Source (NAVIGATE-ESUS) trial is a randomized phase-III trial comparing rivaroxaban versus aspirin in patients with recent ESUS. Aims: We aimed to describe the baseline characteristics of this large ESUS cohort to explore relationships among key subgroups. Methods: We enrolled 7213 patients at 459 sites in 31 countries. Prespecified subgroups for primary safety and efficacy analyses included age, sex, race, global region, stroke or transient ischemic attack prior to qualifying event, time to randomization, hypertension, and diabetes mellitus. Results: Mean age was 66.9 ± 9.8 years; 24% were under 60 years. Older patients had more hypertension, coronary disease, and cancer. Strokes in older subjects were more frequently cortical and accompanied by radiographic evidence of prior infarction. Women comprised 38% of participants and were older than men. Patients from East Asia were oldest whereas those from Latin America were youngest. Patients in the Americas more frequently were on aspirin prior to the qualifying stroke. Acute cortical infarction was more common in the United States, Canada, and Western Europe, whereas prior radiographic infarctions were most common in East Asia. Approximately forty-five percent of subjects were enrolled within 30 days of the qualifying stroke, with earliest enrollments in Asia and Eastern Europe. Conclusions: NAVIGATE-ESUS is the largest randomized trial comparing antithrombotic strategies for secondary stroke prevention in patients with ESUS. The study population encompasses a broad array of patients across multiple continents and these subgroups provide ample opportunities for future research.
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- Sharma, Mukul, et al.
(författare)
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Safety and efficacy of factorXIa inhibition with milvexian for secondary stroke prevention (AXIOMATIC-SSP) : a phase 2, international, randomised, double-blind, placebo-controlled, dose-finding trial
- 2024
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Ingår i: LANCET NEUROLOGY. - 1474-4422 .- 1474-4465. ; 23:1, s. 46-59
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Tidskriftsartikel (refereegranskat)abstract
- Background People with factor XI deficiency have lower rates of is chaemic stroke than the general population and infrequent spontaneous bleeding, suggesting that factor XI has a more important role in thrombosis than in haemostasis. Milvexian, an oral small-molecule inhibitor of activated factor XI, added to standard antiplatelet therapy, might reduce the risk of non-cardioembolic ischaemic stroke without increasing the risk of bleeding. We aimed to estimate the dose-response of milvexian for recurrent ischaemic cerebral events and major bleeding in patients with recent ischaemic stroke or transient ischaemic attack (TIA).Methods AXIOMATIC-SSP was a phase 2, randomised, double-blind, placebo-controlled, dose-finding trial done at 367 hospitals in 27 countries. Eligible participants aged 40 years or older, with acute (<48 h) ischaemic stroke or high-risk TIA, were randomly assigned by a web-based interactive response system in a 1:1:1:1:1:2 ratio to receive one of five doses of milvexian (25 mg once daily, 25 mg twice daily, 50 mg twice daily, 100 mg twice daily, or 200 mg twice daily) or matching placebo twice daily for 90 days. All participants received clopidogrel 75 mg daily for the first 21 days and aspirin 100 mg daily for the first 90 days. Investigators, site staff, and participants were masked to treatment assignment. The primary efficacy endpoint was the composite of ischaemic stroke or incident covert brain infarct on MRI at 90 days, assessed in all participants allocated to treatment who completed a follow-up MRI brain scan, and the primary analysis assessed the dose-response relationship with Multiple Comparison Procedure-Modelling (MCP-MOD). The main safety outcome was major bleeding at 90 days, assessed in all participants who received at least one dose of the study drug. This trial is registered with ClinicalTrials.gov (NCT03766581) and the EU Clinical Trials Register (2017-005029-19).Findings Between Jan 27, 2019, and Dec 24, 2021, 2366 participants were randomly allocated to placebo (n=691); milvexian 25 mg once daily (n=328); or twice-daily doses of milvexian 25 mg (n=318), 50 mg (n=328), 100 mg (n=310), or 200 mg (n=351). The median age of participants was 71 (IQR 62-77) years and 859 (36%) were female. At 90 days, the estimates of the percentage of participants with either symptomatic ischaemic stroke or covert brain infarcts were 168 (902% CI 145-191) for placebo, 167 (148-186) for 25 mg milvexian once daily, 166 (148-183) for 25 mg twice daily, 156 (139-175) for 50 mg twice daily, 154 (134-176) for 100 mg twice daily, and 153 (128-197) for 200 mg twice daily. No significant dose-response was observed among the five milvexian doses for the primary composite efficacy outcome. Model-based estimates of the relative risk with milvexian compared with placebo were 099 (902% CI 091-105) for 25 mg once daily, 099 (087-111) for 25 mg twice daily, 093 (078-111) for 50 mg twice daily, 092 (075-113) for 100 mg twice daily, and 091 (072-126) for 200 mg twice daily. No apparent dose-response was observed for major bleeding (four [1%] of 682 participants with placebo, two [1%] of 325 with milvexian 25 mg once daily, two [1%] of 313 with 25 mg twice daily, five [2%] of 325 with 50 mg twice daily, five [2%] of 306 with 100 mg twice daily, and five [1%] of 344 with 200 mg twice daily). Five treatment-emergent deaths occurred, four of which were considered unrelated to the study drug by the investigator.Interpretation Factor XIa inhibition with milvexian, added to dual antiplatelet therapy, did not substantially reduce the composite outcome of symptomatic ischaemic stroke or covert brain infarction and did not meaningfully increase the risk of major bleeding. Findings from our study have informed the design of a phase 3 trial of milvexian for the prevention of ischaemic stroke in patients with acute ischaemic stroke or TIA.
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