Gary A. Ford

Introduction: Levodopa did not enhance early motor recovery at 3 months after stroke in the Enhancement of Stroke Rehabilitation with Levodopa (ESTREL) trial. However, whether levodopa modifies the time course of recovery, leading to a delayed benefit remains unclear. Here, we examined levodopa’s effects on the trajectories of motor recovery up to 6 months after stroke. Patients and methods: The ESTREL trial, a double-blind, randomised controlled clinical trial, compared a 39-day regimen of levodopa/carbidopa (100 mg/25 mg, 3×/day) to placebo alongside standardised task-oriented training. We longitudinally analysed Fugl-Meyer Motor Assessment (FMA) total scores (primary outcome), mRS and NIHSS (secondary outcomes) at baseline (0–7 days post stroke), 5 weeks, 3 and 6 months using linear mixed-effects models including timepoint, treatment allocation and their interaction. Results: In total, 576 of 610 (94%) participants (median age 73 years; 40% female) were analysed. FMA scores improved over time in both groups (P < .001), with no overall levodopa effect across visits (estimate 0.65 points, 95% CI, −3.3 to 4.6; P = .75). There was no indication that levodopa modified the recovery trajectory (χ2 = 0.52, df = 3, P = .91), and estimated levodopa–placebo differences in FMA changes across visit intervals were small, ranging from −0.7 to +0.8 points, with confidence intervals crossing zero. Secondary outcomes showed similar longitudinal improvement, without evidence of a treatment effect. Conclusion: In this post hoc analysis of ESTREL participants with repeated FMA assessments, motor impairment improved from the first days after stroke up to 6 months. Levodopa added to task-oriented inpatient rehabilitation did not improve motor recovery or alter its trajectory over this period. Clinical Trial Registration: NCT03735901, available at ClinicalTrials.gov: https://clinicaltrials.gov/study/NCT03735901?cond=NCT03735901&rank=1

Improving stroke recognition and promoting immediate action are critical to enhancing prehospital stroke care. For two decades, the FAST (Face, Arm, Speech, Time) mnemonic has been widely taught, yet it fails to capture many posterior circulation strokes. To address these limitations, BE FAST (adding Balance and Eye symptoms) was introduced but showed reduced recall for more common symptoms represented by FAST, likely due to common symptoms being placed after less common ones, thus weakening retention of the original FAST elements. To improve both detection and action, we propose FAST BEE —keeping FAST first and adding BE after FAST with an additional “E” for Emergency Medical Services (EMS) call. This structure reinforces the urgency of activating EMS by repeating the call‐to‐action within the mnemonic. We further introduce a novel FAST BEE cartoon as a visual tool to enhance learning, recall across diverse populations, and immediate action (EMS call) in public. Using the bee metaphor provides a memorable, engaging, and globally adaptable educational strategy in English‐speaking populations. FAST BEE offers a fresh, action‐oriented framework that builds on the familiarity of FAST, emphasizes immediate EMS activation, and holds promise to strengthen stroke action awareness worldwide. Further evaluation of effectiveness in various English‐speaking populations is needed.

BACKGROUND: After acute ischemic stroke, it is uncertain whether the time of atrial fibrillation (AF) diagnosis (before or after stroke) or AF subtype (paroxysmal or permanent) modifies the treatment effect of early versus delayed direct oral anticoagulant (DOAC) initiation. METHODS: OPTIMAS (Optimal Timing of Anticoagulation After Acute Ischemic Stroke) was a randomized, parallel-group, open-label trial with blinded outcome assessment. Participants with acute ischemic stroke and AF were randomized 1:1 to early (within 4 days) or delayed (day 7–14) DOAC initiation. The primary outcome was a composite of recurrent ischemic stroke, symptomatic intracranial hemorrhage, and systemic arterial embolism. In this trial subgroup analysis, the prespecified subgroup of interest was time of AF diagnosis, classified as before or after the qualifying stroke. We also investigated AF subtype classified as persistent or paroxysmal. We fitted mixed effects logistic regression models with interaction terms between each subgroup and treatment allocation. We also investigated associations between AF time of diagnosis or subtype and outcomes using multivariable logistic regression. RESULTS: We included 3619 participants (mean age 78.0±9.9 years; 45.3% women). For AF diagnosed before stroke, 37 of 918 (4.0%) participants allocated to early DOAC had a primary outcome event versus 32 of 920 (3.5%) allocated to delayed DOAC, odds ratio, 1.17 (95% CI, 0.72–1.89), while for AF diagnosed after stroke the respective primary outcome rates were 22 of 895 (2.5%) and 27 of 886 (3.0%; odds ratio, 0.79 [95% CI, 0.45–1.40], P _interaction =0.312). AF subtype did not modify the treatment effect, with odds ratios (95% CIs) for early versus late DOAC for persistent and paroxysmal AF of 1.06 (0.71–1.58) and 0.66 (0.25–1.72), respectively, P _interaction =0.377. AF time of diagnosis was not associated with outcome events. Compared with paroxysmal AF, persistent AF was independently associated with an increased risk of the primary outcome (adjusted odds ratio, 2.10 [95% CI, 1.19–3.68]). CONCLUSIONS: We found no evidence that AF time of diagnosis or subtype modify the effects of early DOAC treatment. Persistent AF was independently associated with approximately double the risk of the primary outcome compared with paroxysmal AF. REGISTRATION: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT03759938.

Introduction: Post-stroke fatigue (PSF) is common and impacts stroke rehabilitation. Dopaminergic treatment may have beneficial effects on PSF. This study investigated whether levodopa, compared with placebo, was associated with a lower frequency or severity of PSF during in-hospital rehabilitation. Patients and methods: Enhancement of Stroke Rehabilitation with Levodopa (ESTREL)-Fatigue was an exploratory analysis of secondary outcome data obtained in the multicentre, randomised, placebo-controlled ESTREL trial. Participants with acute stroke received levodopa 100 mg/carbidopa 25 mg or placebo 3 times daily for 39 days to enhance motor recovery. Participants who (i) reported fatigue at 5 weeks and who (ii) took at least 80% of the study medication were included in ESTREL-Fatigue. No adjustments for confounding were made. The primary endpoint was the presence of PSF at 5 weeks, defined as a T-score of ≥ 55 on the Patient-Reported Outcomes Measurement Information System (PROMIS) Fatigue-Short-form-4a. As secondary endpoints, T-score cutoffs of ≥ 60 (moderate fatigue) and ≥ 70 (severe fatigue) were used. Binary logistic regression was used to compare PSF at 5 weeks between treatment groups. Results are presented as odds ratios (ORs) with 95% CI. Results: A total of 456 of 505 (90.3%) participants were included (levodopa/placebo 235/221, median age 73 years, 41% female). Post-stroke fatigue at 5 weeks was present in 63/235 (26.8%) levodopa-treated participants and in 65/221 (29.4%) placebo-treated participants (OR: 0.88; 95% CI, 0.58–1.32; risk ratio 0.91; risk difference − 2.6%). For cutoffs of ≥ 60 and ≥ 70, ORs were 0.78 (95% CI, 0.43–1.41) and 0.8 (95% CI, 0.25–2.44), respectively. A sensitivity analysis as per intention-to-treat with all 610 randomised ESTREL participants also showed no significant difference in fatigue presence between levodopa and placebo groups (OR: 0.95; 95% CI, 0.65–1.39) and a sensitivity analysis using a mixed-effects logistic regression showed no evidence of centre-related clustering. Conclusion: In ESTREL-Fatigue, levodopa, compared to placebo, was not associated with less PSF during in-hospital rehabilitation.

Introduction: Post-stroke depression (PSD) frequently occurs after acute stroke and negatively affects rehabilitation. Dopamine has beneficial effects on motivation and emotional stability. In stroke patients, low dopamine levels are linked to PSD. This study investigated whether levodopa treatment during in-hospital rehabilitation impacts PSD compared to placebo. Patients and methods: ESTREL-Depression was a pre-planned analysis of the multicenter, randomized, double-blind, placebo-controlled ESTREL trial. Participants with an acute ischemic or hemorrhagic stroke were randomly assigned to receive either levodopa/carbidopa (100/25 mg) or placebo three times daily for 39 days. All ESTREL participants with (1) information about the presence or absence of depression at three months and (2) who took at least 80% of the study medication were eligible for the study. Participants with a history of depression were excluded. For the primary outcome, the presence of PSD was defined as having a T-score of ≥55 in the Patient-Reported Outcomes Measurement Information System short-form depression-4a 3 months after randomization. Binary logistic regression was performed to assess the effect of levodopa on PSD. Results: The study included 407 ESTREL participants (median age 72, 60% male), 209 receiving levodopa, and 198 receiving placebo. At 3 months, the frequency and odds of PSD did not differ between the levodopa group (26%) and the placebo group (28%) (OR = 0.93, 95% CI, 0.60–1.43). Conclusion: In the ESTREL-Depression study, treatment with levodopa had no impact on the occurrence of PSD. Clinical Trial Registration: ClinicalTrials.gov: NCT03735901 (https://clinicaltrials.gov/study/NCT03735901).

Background: Structured Medication Reviews (SMRs) were introduced into primary care in England for patients living with multiple long-term conditions (MLTCs), polypharmacy, increased frailty, in care homes or at risk of medicines-related harm. SMRs aim to optimise the therapeutic potential of medication and reduce medicine-related harms through holistic reviews. Aim: To explore the day-to-day work being undertaken with, and by, clinical pharmacists to implement, embed and integrate SMRs into practice, and consider how to optimise SMRs. Design and setting: Qualitative one-to-one interviews with clinical pharmacists undertaking SMRs and SMR service leaders/managers (SMR leads) in England between February 2023 and November 2024. Method: Participants were recruited as part of a wider evaluation of the roll-out of SMRs in England. Interview topic guides and qualitative data analysis were informed by Normalization Process Theory (NPT). Results: Eighteen clinical pharmacists and five SMR leads participated. Participants reported often having to explain the purpose of SMRs and clinical pharmacists’ roles to patients, partly due to patients not being informed about SMRs. Participants valued SMRs and expressed that trust-building and tailored consultations were important for optimising medications. Integration varied due to high workload, inconsistent leadership support, inadequate administrative/pharmacist technician resource and lack of training. However, participants described SMRs as valuable for identifying and addressing unmet needs and supporting holistic, person-centred care across MLTC pathways. Conclusion: The findings demonstrate the need for improved information on SMRs for patients and primary care teams, adequate and appropriate resource allocation, and enhanced support for consultation skills training to optimise medicines use. How this fits in: - SMRs were formally introduced to primary care in 2020 to address the challenges of managing polypharmacy in an ageing population with increasing patient complexity and MLTCs. - SMRs were introduced alongside the expansion of clinical pharmacist roles in General Practice as a comprehensive, person-centred review of all a patient’s medicines. - This qualitative evaluation examines the day-to-day work of implementing and embedding SMRs, highlighting challenges to implementation and integration. - Our findings reveal challenges to the sustainability of SMRs and identify opportunities for optimisation, including addressing pharmacists’ training needs and resource allocation for administrative and pharmacy technician support.

BACKGROUND: Patients with chronic kidney disease (CKD) are at increased risk of ischemic stroke (IS) and intracerebral hemorrhage, so the safety and efficacy of early direct oral anticoagulant (DOAC) initiation in those with CKD are of clinical relevance. METHODS: OPTIMAS (Optimal Timing of Anticoagulation After Acute Ischemic Stroke With Atrial Fibrillation) was a multicenter, randomized, parallel-group, open-label trial with blinded outcome assessment, recruiting patients with IS and atrial fibrillation from 100 UK hospitals between 2019 and 2024. Participants were randomized 1:1, stratified by stroke severity, to early (within 4 days of onset) or delayed (at days 7–14) DOAC initiation. CKD was defined as a past medical history of known CKD, collected according to trial protocol as part of the case report form. For this prespecified subgroup analysis, the trial cohorts were classified according to the presence or absence of CKD. Whether CKD modified the treatment effect of early DOAC initiation was determined by fitting mixed effects logistic regression models with interaction terms between CKD and treatment group. The primary outcome was a composite outcome of recurrent IS, symptomatic intracranial hemorrhage, and systemic arterial embolism. Key secondary outcomes included the individual components of the primary outcome and all-cause mortality. RESULTS: We included 3601 patients (mean age, 78±10 years; 45% female), 543 with CKD. There were 116 primary outcome events: 97 (3.2%) in the normal kidney function group and 19 (3.5%) in the CKD group. There was no difference between early and delayed DOAC initiation for the primary outcome in either the normal kidney function group (odds ratio, 1.01 [95% CI, 0.67–1.51]) or the CKD group (odds ratio, 0.90 [95% CI, 0.36–2.25]; P _interaction =0.822). Similarly, for the secondary outcomes, we detected no modification of the treatment effect according to CKD ( P _interaction values of 0.637, 0.386, and 0.107 for IS, symptomatic intracranial hemorrhage, and all-cause mortality, respectively). CONCLUSIONS: Our findings suggest that CKD does not modify the effects of early versus delayed DOAC initiation after acute IS. Based on these results, early DOAC initiation should not be withheld in patients with CKD. REGISTRATION: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT03759938.

Objectives: The present study aimed to evaluate the impact of structured medication reviews (SMRs), by examining the proportion of eligible patients who received a review in the first two years of the programme, and whether SMRs were associated with changes in prescribing. Design: Retrospective observational cohort study. Setting: Patients registered to primary care practices in England contributing data to the Oxford Clinical Informatics Digital Hub (ORCHID) were included between 1 ^st April 2020 and 30 ^th September 2022. Participants: De-identified data were extracted from the electronic health records of individuals registered to ORCHID practices aged ≥65 years, prescribed one or more medications and fulfilling the specific eligibility criteria for a SMR. Main outcome measures: The primary outcome was the proportion of patients who received a review. Further outcomes included the proportion of potentially inappropriate drug combinations corrected following an SMR. The association between SMRs and prescription changes and primary care contacts was examined by matching individuals who received an SMR to individuals who did not receive an SMR, according to age, sex and primary care practice using cumulative density sampling. Analyses were undertaken using adjusted logistic regression. Results: From a total of 635,698 eligible patients, 82,285 patients (12.94%, 95% confidence interval [CI] 12.86% to 13.02%) received at least one SMR during the study observation period. In those prescribed potentially inappropriate drug combinations prior to an SMR, between 12.5% and 40.0% were corrected up to three months later. In matched analyses, SMRs were associated with a significant increase new prescriptions of ACE inhibitors (adjusted odds ratio [aOR] 1.56, 95%CI 1.35-1.81), statins (aOR 1.78, 95%CI 1.57-2.02), inhaled corticosteroids (aOR 1.19 95%CI 1.05-1.36), opioids (aOR 1.31 95%CI 1.20-1.42), and antidepressants (aOR 1.45 95%CI 1.28-1.63). In those previously prescribed treatment, individuals receiving an SMR were significantly more likely stop ACE inhibitors (aOR 1.37, 95%CI 1.18-1.58), statins (aOR 1.35, 95%CI 1.17-1.56) and antidepressants (antidepressants aOR 1.37 95%CI 1.21-1.56). SMRs were associated with a significant increase in primary care contacts of 0.14 (95% CI 0.13 to 0.16; equivalent to 14 extra patient contacts for every 100 individuals receiving an SMR). Conclusions: SMRs were associated with starting new medications and stopping existing prescriptions compared to usual care. It was unclear if such activity was appropriate or represented improved patient care. Further work is needed to understand if these changes in prescribing improved patient outcomes. What is already known on this topic: Inappropriate polypharmacy can expose the most vulnerable patients to decreased quality of life and adverse drug events. Outside of trials, studies of pharmacist-led medication reviews undertaken in routine clinical practice have shown little impact on prescribing and patient-centred care. Structured medication reviews are a National Institute for Health and Care Excellence (NICE) approved clinical intervention to address complex or problematic polypharmacy and were introduced widely in the UK NHS in 2020. What this study adds: We found that one in eight eligible patients received a structured medication review during the first two years of the programme’s rollout in England. Structured medication reviews were associated with an increased likelihood of starting medication in those not previously prescribed treatment, and an increased likelihood of stopping medications in those with existing prescriptions. This analysis was limited by the data available within primary care electronic health records and so it is unclear if the observed changes in prescribing resulted in improvements in patient outcomes

Background: There are a lot of advances that may affect the way treatment is delivered prehospital, including mobile stroke units and point-of-care diagnostics. These have the potential to affect populations differently and therefore affect the distribution of health outcomes. Objectives: We aimed to address the following research questions: (1) Which geographic and socioeconomic inequalities have been included when evaluating access to acute stroke treatment (including reperfusion therapies)? (2) How have the identified measures been considered/assessed/calculated? (3) We also report any methodological approaches that have been proposed that might further improve the way in which acute stroke care interventions are analysed, specified relating to inequalities. Methods: PubMed and Scopus electronic databases were searched for studies that included participants who underwent acute stroke treatment and included quantitative measures of geographic and/or socioeconomic inequalities or inequities in accessing/receiving treatment. Results: Overall, sixty-six studies were included in the review. Fifty-nine included at least one measure of geographic inequalities or inequities while thirty-six included at least one measure of socioeconomic inequalities or inequities. Twenty-eight of these studies included both a geographic and socioeconomic measure of inequalities or inequities. There were no commonalities in the methods of defining, categorising and measuring the inequalities or inequities. No study provided their definition of inequality or inequity or stated any normative judgements they had made. Conclusions: It is vital that the evaluation of programmes like acute stroke care consider impacts on inequality and inequity. Researchers and policy makers should work together to determine relevant measures of inequality/inequity and the most appropriate methods of measuring and categorising them. In addition, researchers should make it clear within their work how they are defining inequality and inequity and what (if any) normative judgements have been made.