[Smell the smoke before one sees the fire-The oligosymptomatic prodromal phase of neurodegenerative diseases]. / Den Rauch riechen, bevor man das Feuer sieht ­ die oligosymptomatische Prodromalphase neurodegenerativer Erkrankungen.

BACKGROUND: With the increasing development of disease-modifying causative treatment, the importance of early diagnosis and detection of asymptomatic or oligosymptomatic early stages of neurodegenerative diseases is increasing. OBJECTIVE: Presentation of early stages of neurodegenerative diseases, diagnostic procedures for the early detection and possible treatment consequences. MATERIAL AND METHODS: Selective literature search, discussion of basic research and expert recommendations. RESULTS: Many neurodegenerative diseases have a prodromal phase preceding the manifest disease that can be diagnosed with current criteria. In this prodromal phase, those affected are often oligosymptomatic but in some cases can already be identified using biomarkers. These developments are already taken into account in diagnostic criteria for some of these prodromal phases. The prodromal phase, in turn, is preceded by an asymptomatic phase which, however, already shows molecular changes and can be identified by biomarkers in some diseases. The early identification and stratification of patients is particularly important when planning studies for disease-modifying treatment, and biomarkers are already being used in clinical trials for this purpose. DISCUSSION: Biomarker-based identification of individuals in the prodromal phase of neurodegenerative diseases is already possible for some entities. People who show the first signs of a neurodegenerative disease can be referred to centers for clinical trials and observational studies.

SAFE-ROCK: A Phase I Trial of an Oral Application of the ROCK Inhibitor Fasudil to Assess Bioavailability, Safety, and Tolerability in Healthy Participants.

BACKGROUND: The intravenous (IV) formulation of Rho-kinase (ROCK) inhibitor fasudil has been approved for the treatment of subarachnoid haemorrhage since 1995. Additionally, fasudil has shown promising preclinical results for various chronic diseases, including neurodegenerative diseases such as amyotrophic lateral sclerosis, Parkinson's disease, and dementia, in which long-term intravenous (IV) administration might not be suitable. OBJECTIVE: The objective of this study was to assess the absolute bioavailability of oral, in comparison to IV, application of the approved formulation of fasudil (ERIL®) and to evaluate the safety and tolerability of the oral application of fasudil. METHODS: This was a phase I, single-center, open-label, randomized, two period cross-over clinical trial in healthy women and men. By applying a cross-over design, each subject served as their own control. Two treatments were investigated, separated by a wash out phase of at least 3 days. Oral fasudil was administered once on day 1 to assess pharmacokinetics and three times on day 2, at an interval of 8 ± 1 h, to assess safety and gastrointestinal tolerability. For pharmacometrics of IV fasudil, it was administered once on day 1. Plasma profiles of fasudil and its active metabolite hydroxyfasudil after oral or IV administration were measured by liquid chromatography electrospray tandem mass spectrometry. Tolerability was assessed as proportion of subjects without significant drug intolerance, and safety was assessed by the proportion of subjects without clinical or laboratory treatment-associated serious adverse events. Gastrointestinal safety was assessed by applying the gastrointestinal symptom rating scale (GSRS). RESULTS: Fourteen subjects aged 30-70 years were included in this trial. After oral administration, fasudil concentrations in blood were mostly very low [1.4 g/L; coefficient of variation (CV) 41.0%]. After IV application, the peak concentration was 100.6 µg/L (CV 74.2%); however, a high variance in peak concentrations were assessed for both treatments. The maximal concentrations of hydroxyfasudil in blood were similar after oral and IV treatment [111.6 µg/L (CV 24.1%) and 108.4 µg/L (CV 19.7%), respectively]. Exposure of hydroxyfasudil (assessed as AUC0-tz) differed between both treatments, with 449 µg × h/L after IV treatment and 309 µg × h/L after oral treatment. Therefore, the absolute bioavailability of hydroxyfasudil after the oral treatment was approximately 69% of the IV treatment. No serious adverse events (SAEs) occurred during this trial, and good tolerability of oral fasudil (90 mg/day) was documented. CONCLUSIONS: Oral fasudil was generally well tolerated in the studied population, and no safety concerns were identified. However, systemic bioavailability of oral hydroxyfasudil corresponded to 69%, and dose adjustments need to considered. The results presented here lay grounds for future trials of fasudil in chronic diseases, which require an oral long-term application. This trial was registered with EudraCT (no. 2019-001805-26).

Protocol for a randomized, placebo-controlled, double-blind phase IIa study of the safety, tolerability, and symptomatic efficacy of the ROCK-inhibitor Fasudil in patients with Parkinson's disease (ROCK-PD).

Background: The Rho-kinase (ROCK) inhibitor Fasudil has shown symptomatic and disease-modifying effects in Parkinson's disease (PD) models in vitro and in vivo. In Japan, Fasudil has been approved for the treatment of subarachnoid haemorrhage since 1995 and shows a favourable safety profile. Objectives/design: To investigate the safety, tolerability, and symptomatic efficacy of ROCK-inhibitor Fasudil in comparison to placebo in a randomized, national, multicenter, double-blind phase IIa study in patients with PD. Methods/analysis: We plan to include 75 patients with at least 'probable' PD (MDS criteria), Hoehn and Yahr stages 1-3, and age 30-80 years in 13 German study sites. Patients must be non-fluctuating and their response to PD medication must have been stable for 6 weeks. Patients will be randomly allocated to treatment with the oral investigational medicinal product (IMP) containing either Fasudil in two dosages, or placebo, for a total of 22 days. As primary analysis, non-inferiority of low/high dose of Fasudil on the combined endpoint consisting of occurrence of intolerance and/or treatment-related serious adverse events (SAEs) over 22 days will be assessed in a sequential order, starting with the lower dose. Secondary endpoints will include tolerability alone over 22 days and occurrence of treatment-related SAEs (SARs) over 22 and 50 days and will be compared on group level. Additional secondary endpoints include efficacy on motor and non-motor symptoms, measured on established scales, and will be assessed at several timepoints. Biomaterial will be collected to determine pharmacokinetics of Fasudil and its active metabolite, and to evaluate biomarkers of neurodegeneration. Ethics/registration/discussion: After positive evaluation by the competent authority and the ethics committee, patient recruitment started in the 3rd quarter of 2023. ROCK-PD is registered with Eudra-CT (2021-003879-34) and clinicaltrials.gov (NCT05931575). Results of this trial can pave way for conducting extended-duration studies assessing both symptomatic efficacy and disease-modifying properties of Fasudil.

Nationwide Retrospective Analysis of Combinations of Advanced Therapies in Patients With Parkinson Disease.

BACKGROUND AND OBJECTIVES: Advanced therapies (ATs; deep brain stimulation [DBS] or pump therapies: continuous subcutaneous apomorphine infusion [CSAI], levodopa/carbidopa intestinal gel [LCIG]) are used in later stages of Parkinson disease (PD). However, decreasing efficacy over time and/or side effects may require an AT change or combination in individual patients. Current knowledge about changing or combining ATs is limited to mostly retrospective and small-scale studies. The nationwide case collection Combinations of Advanced Therapies in PD assessed simultaneous or sequential AT combinations in Germany since 2005 to analyze their clinical outcome, their side effects, and the reasons for AT modifications. METHODS: Data were acquired retrospectively by modular questionnaires in 22 PD centers throughout Germany based on clinical records and comprised general information about the centers/patients, clinical (Mini-Mental Status Test/Montréal Cognitive Assessment, Movement Disorder Society-Sponsored Revision of the Unified Parkinson's Disease Rating Scale [MDS-UPDRS], side effects, reasons for AT modification), and therapeutical (ATs with specifications, oral medication) data. Data assessment started with initiation of the second AT. RESULTS: A total of 148 AT modifications in 116 patients were associated with significantly improved objective (median decrease of MDS-UPDRS Part III 4.0 points [p < 0.001], of MDS-UPDRS Part IV 6.0 points [p < 0.001], of MDS-UPDRS Part IV-off-time item 1.0 points [p < 0.001]) and subjective clinical outcome and decreasing side effect rates. Main reasons for an AT modification were insufficient symptom control and side effects of the previous therapy. Subgroup analyses suggest addition of DBS in AT patients with leading dyskinesia, addition of LCIG for leading other cardinal motor symptoms, and addition of LCIG or CSAI for dominant off-time. The most long-lasting therapy-until requiring a modification-was DBS. DISCUSSION: Changing or combining ATs may be beneficial when 1 AT is insufficient in efficacy or side effects. The outcome of an AT combination is comparable with the clinical benefit by introducing the first AT. The added AT should be chosen dependent on dominant clinical symptoms and adverse effects. Furthermore, prospective trials are needed to confirm the results of this exploratory case collection. CLASSIFICATION OF EVIDENCE: This study provides Class IV evidence that, in patients with PD, changing or combining ATs is associated with an improvement in the MDS-UPDRS or subjective symptom reporting.

Parkinson's disease therapy: what lies ahead?

The worldwide prevalence of Parkinson's disease (PD) has been constantly increasing in the last decades. With rising life expectancy, a longer disease duration in PD patients is observed, further increasing the need and socioeconomic importance of adequate PD treatment. Today, PD is exclusively treated symptomatically, mainly by dopaminergic stimulation, while efforts to modify disease progression could not yet be translated to the clinics. New formulations of approved drugs and treatment options of motor fluctuations in advanced stages accompanied by telehealth monitoring have improved PD patients care. In addition, continuous improvement in the understanding of PD disease mechanisms resulted in the identification of new pharmacological targets. Applying novel trial designs, targeting of pre-symptomatic disease stages, and the acknowledgment of PD heterogeneity raise hopes to overcome past failures in the development of drugs for disease modification. In this review, we address these recent developments and venture a glimpse into the future of PD therapy in the years to come.

Long-Lasting Impact of the COVID-19 Pandemic on Patients with Parkinson's Disease and Their Relatives.

Background: The coronavirus disease 2019 (COVID-19) pandemic has heavily impacted medical care of patients with Parkinson's disease (PwP). Objective: To assess the longitudinal impact of the COVID-19 pandemic on PwP and their relatives in Germany. Methods: Two online, nationwide, cross-sectional surveys were conducted from December 2020 to March 2021 and from July to September 2021. Results: A total of 342 PwP and 113 relatives participated. Despite partial resumption of social and group activities, healthcare was continuously disrupted during times of loosened restrictions. Respondents' willingness to use telehealth infrastructure increased, yet the availability remained low. PwP reported worsened symptoms and further deterioration during the pandemic, resulting in an increase in new symptoms and relatives' burden. We identified patients at particular risk: young patients and those with long disease duration. Conclusions: The COVID-19 pandemic persistently disrupts the care and quality of life of PwP. Although willingness to use telemedicine services has increased, its availability needs to be improved.

Multidisciplinary management of chronic refractory pain in autosomal dominant polycystic kidney disease.

BACKGROUND: Chronic pain is often difficult to manage in autosomal dominant polycystic kidney disease (ADPKD) patients and sometimes even leads to nephrectomy. We analyzed the long-term efficacy of our innovative multidisciplinary protocol to treat chronic refractory pain that aims to preserve kidney function by applying among other sequential nerve blocks. METHODS: Patients were eligible if pain was present ≥3 months with a score of ≥50 on a visual analog scale (VAS) of 100, was negatively affecting quality of life and if there had been insufficient response to previous therapies, including opioid treatment. Treatment options were, in order, analgesics, cyst aspiration and fenestration, nerve blocks and nephrectomy. RESULTS: A total of 101 patients were assessed in our clinic (mean age 50 ± 11 years, 65.3% females). Eight patients were treated with medication, 6 by cyst aspiration or fenestration, 63 by nerve blocks and 6 received surgery as the first treatment option. Overall, 76.9% experienced a positive effect on pain complaints shortly after treatment. The VAS score was reduced from 60/100 to 20/100 (P < 0.001) and patients decreased their number of nonopioid and opioid analgesics significantly (P < 0.001, P = 0.01, respectively). A substantial number of the patients (n = 51) needed additional treatment. At the end of follow-up in only 13 patients (12.9%) was surgical intervention necessary: 11 nephrectomies (of which 10 were in patients already on kidney function replacement treatment), 1 liver transplantation and 1 partial hepatectomy. After a median follow-up of 4.5 years (interquartile range 2.5-5.3), 69.0% of the patients still had fewer pain complaints. CONCLUSIONS: These data indicate that our multidisciplinary treatment protocol appears effective in reducing pain in the majority of patients with chronic refractory pain, while postponing or even avoiding in most patients surgical interventions such as nephrectomy in most patients.

SARS-CoV-2 and neurodegenerative diseases: what we know and what we don't.

Infection of the CNS with the SARS-CoV-2 can occur via different routes and results in para- or post-infectious manifestations with a variety of neurological symptoms. In patients with neurodegenerative diseases, SARS-CoV-2 is often associated with a higher fatality rate, which is a relevant problem in increasingly older populations. Apart from the direct consequences of an infection in patients with neurodegenerative diseases, indirect consequences of the pandemic such as limited access to care facilities and treatment have negative effects on the course of these chronic disorders. The occurrence of long-lasting neurological symptoms after infection with SARS-CoV-2 indicates a prolonged impact on the CNS. However, while it is known that SARS-CoV-2 affects neuronal populations that are relevant in the pathogenesis of neurodegenerative diseases, it is yet unclear whether an infection with SARS-CoV-2 is sufficient to trigger neurodegeneration. Reflecting on the impact of SARS-CoV-2 on neurodegeneration, we provide a concise overview on the current knowledge of SARS-CoV-2-induced pathology in the CNS and discuss yet open questions in the field.

Binding Stability of Antibody-α-Synuclein Complexes Predicts the Protective Efficacy of Anti-α-synuclein Antibodies.

Spreading of alpha-synuclein (αSyn) may play an important role in Parkinson's disease and related synucleinopathies. Passive immunization with anti-αSyn antibodies is a promising method to slow down the spreading process and thereby the progression of synucleinopathies. Currently, it remains elusive which specific characteristics are essential to render therapeutic antibodies efficacious. Here, we established a neuronal co-culture model, in which αSyn species are being released from αSyn-overexpressing cells and induce toxicity in a priori healthy GFP-expressing cells. In this model, we investigated the protective efficacy of three anti-αSyn antibodies. Only two of these antibodies, one C-terminal and one N-terminal, protected from αSyn-induced toxicity by inhibiting the uptake of spreading-competent αSyn from the cell culture medium. Neither the binding epitope nor the affinity of the antibodies towards recombinant αSyn could explain differences in biological efficacy. However, both protective antibodies formed more stable antibody-αSyn complexes than the non-protective antibody. These findings indicate that the stability of antibody-αSyn complexes may be more important to confer protection than the binding epitope or affinity to recombinant αSyn.

Impact of the COVID-19 Pandemic on Patients with Parkinson's Disease from the Perspective of Treating Physicians-A Nationwide Cross-Sectional Study.

The COVID-19 pandemic has posed challenges to maintaining medical care for patients with Parkinson's disease (PD). The Parkinson's Disease during the COVID-19 Pandemic (ParCoPa) survey was conducted as an online, nationwide, cross-sectional survey from December 2020 to March 2021 and aimed to assess the impact of the pandemic on the medical care of PD patients from the physicians' perspective. Invitations containing a randomly generated registration code were mailed to healthcare professionals from sixty-seven specialty centers in Germany. Confounders for the worsening of subjective treatment quality, perceived health risk due to the profession, and adequate protective measures against SARS-CoV-2 were assessed using logistic regression analysis. Of all forty physicians who responded, 87.5% reported a worsening of motor and nonmotor symptoms in their patients, 97.5% experienced cancellation of appointments, and difficulties in organizing advanced and supplementary therapies were reported by over 95%. Participants offered alternative consultation options, mostly in the form of telephone (77.5%) or online (64.1%) consultations, but telephone consultations were the most accepted by patients ("broadly accepted", 40.0%). We identified pandemic-related deficits in providing care for patients with PD and areas of improvement to ensure continued care for this vulnerable patient population.

Best practice approaches to outpatient management of people living with Parkinson's disease during the COVID-19 pandemic.

The prevalence of Parkinson's disease (PD) is rising, rendering it one of the most common neurodegenerative diseases. Treatment and monitoring of patients require regular specialized in- and outpatient care. Patients with PD are more likely to have a complicated disease course if they become infected with severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2). Regular in-hospital appointments place these patients at risk of exposure to SARS-CoV-2 due to travel and contact with other patients and staff. However, guidelines for the management of outpatients with PD during times of increased risk of infection are currently lacking. These are urgently needed to conduct risk-benefit evaluations to recommend the best medical treatment. This article discusses best practice approaches based on the current literature, as suggested by the multidisciplinary Network of University Medicine (NUM) in Germany. These include measures such as mask-wearing, hand hygiene, social distancing measures, and appropriate testing strategies in outpatient settings, which can minimize the risk of exposure. Furthermore, the urgency of appointments should be considered. Visits of low urgency may be conducted by general practitioners or via telemedicine consultations, whereas in-person presentation is required in case of moderate and high urgency visits. Classification of urgency should be carried out by skilled medical staff, and telemedicine (telephone or video consultations) may be a useful tool in this situation. The currently approved vaccines against SARS-CoV-2 are safe and effective for patients with PD and play a key role in minimizing infection risk for patients with PD.

Alcohol-induced right bundle branch block is associated with a benign outcome in HOCM after alcohol septum ablation (ASA).

INTRODUCTION: Alcohol septum ablation (ASA) is a treatment option for hypertrophic obstructive cardiomyopathy (HOCM). We examined the impact of ASA-induced bundle branch block (BBB) on clinical and hemodynamic features. METHODS AND RESULTS: We retrospectively analysed 98 HOCM patients with regard to ASA-induced BBB. Clinical examination was performed at baseline, early after ASA and at chronic follow-up (FU). ASA reduced left ventricular outflow tract gradient (LVOTG) during chronic FU (69.2 ± 41.6 pre vs. 31.8 ± 30.3 mmHg post ASA; p < 0.05) and interventricular septal diameter (21.7 ± 3.4 pre vs. 18.7 ± 5.0 mm post ASA; p < 0.05). ASA-induced early right BBB (RBBB) until discharge was observed in 44.9% and chronic RBBB at FU in 32.7%. Left BBB (LBBB) occurred in 13.3% early after ASA and in only 4.1% at chronic FU. Chronic RBBB was associated with more pronounced exercise-induced LVOTG reduction (102.1 ± 55.2 with vs. 73.6 ± 60.0 mmHg without; p < 0.05). 6-min-walk-test (6-MWT) and NYHA class were not affected by RBBB. LBBB had no influence on LVOTG, 6-MWT and symptoms. More ethanol was injected in patients with early RBBB (1.1 ± 0.4 vs. 0.8 ± 0.3 ml without; p < 0.05), who also showed higher mean CK release (827 ± 341 vs. 583 ± 279 U/l without; p < 0.05). Pacemaker implantation during FU was necessary in 11.5% of patients with early RBBB, 3.1% with chronic RBBB, 7.7% with early LBBB and 0% with chronic LBBB (p = n.s. for BBB vs. no BBB). CONCLUSION: ASA-induced RBBB is associated with a higher volume of infused ethanol and higher maximum CK release. RBBB does not adversely affect the clinical outcome or need for pacemaker implantation but was associated with higher exercise-induced LVOTG reduction during chronic FU.

Guideline-Adherent Treatment for Stroke and Death in Atrial Fibrillation Patients From UK and Japanese AF Registries.

BACKGROUND: Guideline-adherent antithrombotic treatment (ATT) reduces the risk of stroke and death in patients with atrial fibrillation (AF). However, the effect of ATT adherence among different ethnicities remains uncertain. We compared the prognosis of AF patients in Japan and the UK according to guideline adherence status.Methods and Results:We compared the clinical characteristics and outcomes of AF patients from the Fushimi AF registry (Japan; n=4,239) and the Darlington AF registry (UK; n=2,259). ATT adherence was assessed against the Japanese Circulation Society Guidelines and UK National Institute for Health and Care Excellence guidelines. The rates of guideline-adherent ATT were 58.6% and 50.8% in the Fushimi and Darlington registries, respectively. There was no significant difference in 1-year stroke rates between Fushimi and Darlington (2.6% vs. 3.0%, P=0.342). On multivariate logistic regression analysis, non-guideline adherent-ATT was significantly associated with an increased risk of stroke (odds ratio [OR]: 1.69, 95% confidence interval [CI]: 1.21-2.34, P=0.002 for undertreatment, OR: 2.13, 95% CI: 1.19-3.80, P=0.010 for overtreatment). No significant interaction for ATT and the 2 populations was found in the incidence of stroke, all-cause death, and the composite outcome. CONCLUSIONS: Approximately half of the AF patients received optimal ATT according to guideline recommendations, which was associated with a lower risk of stroke. Furthermore, there was no interaction for the 2 populations and the influence of ATT adherence.

One-year risks of stroke and mortality in patients with atrial fibrillation from different clinical settings: The Gulf SAFE registry and Darlington AF registry.

BACKGROUND: Differences exist in oral anticoagulation (OAC) use between different populations with atrial fibrillation (AF), which may be associated with varying outcomes. PURPOSE: We aimed to provide patient level comparisons of two cohorts of patients with AF, from the United Kingdom (UK) and Middle East (ME). METHODS: The clinical characteristics, prescription of OAC, one-year risk of stroke and mortality were compared between individual patients with AF included into the Darlington AF registry (UK, n = 2258) and the Gulf SAFE (Survey of atrial fibrillation events) registry (ME, n = 1740). RESULTS: A high percentage of patients from the Darlington registry were candidates for OAC (i.e., CHA2DS2-VASc score ≥2 in males or ≥3 in females; 82.0% in Darlington and 57.1% in Gulf SAFE). OAC use was suboptimal (52.0% in Darlington vs 58.4% in Gulf SAFE). One-year rates of stroke and mortality were high in both populations, especially in those with CHA2DS2-VASc score ≥2 in males and ≥3 in females (Darlington vs. Gulf SAFE: 3.51% vs. 5.63 for stroke; 11.4% vs. 16.8% for mortality). On multivariate analyses, female sex and previous stroke were independently associated with stroke events; while elderly age, female sex, vascular disease and heart failure were independent risk factors for mortality (all p < 0.05). Patients from Gulf SAFE registry had higher risk of stroke (odds ratio, 2.18 [1.47-3.23]) and mortality (odds ratio, 1.67 [1.31-2.14]) compared with those from Darlington registry. The CHA2DS2-VASc score showed good discrimination in predicting one-year risk of stroke (area under curve, 0.71 [0.65-0.76] in non-anticoagulated patients) and mortality (area under curve, 0.70 [0.68-0.72]) in the whole study population, as well as in Darlington or Gulf SAFE registry separately. CONCLUSIONS: Stroke prevention was generally suboptimal in patient cohorts from the two registries, which was associated with high one-year risks of stroke and mortality, particularly so among patients from the Gulf SAFE registry. The higher risks for stroke and mortality in AF patients from the Gulf SAFE registry (compared to a UK cohort) merit further implementation of cardiovascular prevention strategies.

Guideline-Adherent Antithrombotic Treatment Improves Outcomes in Patients With Atrial Fibrillation: Insights From the Community-Based Darlington Atrial Fibrillation Registry.

OBJECTIVE: To assess the influence of guideline-adherent vs nonadherent antithrombotic treatment (ATT) on stroke and mortality rates in an atrial fibrillation (AF) primary care population. PATIENTS AND METHODS: We used the Darlington Registry cohort, which included 105,000 patients from March 31, 2012, through March 31, 2013. Guideline adherence in ATT was assessed against 2014 National Institute for Health and Care Excellence guidelines, which recommend oral anticoagulation for stroke prevention as a default management unless a truly low risk of stroke (CHA2DS2-VASc=0 in men and 1 in women) is evident. RESULTS: Of 2259 patients with AF (2.15%), 36.1% were undertreated, 50.8% were guideline adherent, and 13.1% were overtreated. Oral anticoagulation was declined by 5.0% and contraindicated in 8.3%. Of 67 incident strokes (3.0%), 66 (98.5%) occurred in high-risk patients (CHA2DS2-VASc ≥2). For the high-risk cohort, 1-year stroke rates were 4.5% (95% CI, 3.2%-6.3%) for undertreatment, 1.9% (95% CI, 1.2%-2.9%) for guideline adherence, and 7.2% (95% CI, 4.4%-11.6%) for overtreatment; corresponding mortality rates were 16.1% (95% CI, 13.6%-19.0%), 8.0% (95% CI, 6.5%-9.8%), and 8.2% (95% CI, 5.2%-12.7%), respectively. On multivariable analysis, both undertreatment and overtreatment of high-risk patients were associated with significant increases in stroke rates (odds ratio [OR]=2.32; 95% CI, 1.30-3.14; P=.005 and OR=2.28; 95% CI, 1.12-4.63; P=.02, respectively). Undertreatment was also associated with a significant increase in all-cause mortality (OR=1.59; 95% CI, 1.14-2.21; P=.006). CONCLUSION: Only half of all eligible patients with AF are prescribed oral anticoagulation in accordance with guideline recommendations. Guideline-adherent ATT significantly reduces the risk of stroke and improves survival.

Secondary Versus Primary Stroke Prevention in Atrial Fibrillation: Insights From the Darlington Atrial Fibrillation Registry.

BACKGROUND AND PURPOSE: Although patients with atrial fibrillation (AF) who experienced an acute stroke are at high risk for recurrence, many patients are untreated or treated suboptimally for stroke prevention. The objective of this study is to compare clinical outcomes of AF patients with versus without previous stroke in relation to guideline-adherent antithrombotic treatment in a contemporary primary care population. METHODS: Community cohort of 105 000 patients from 11 general practices in Darlington, England, was used to assess AF stroke prevention strategies against 2014 National Institute for Health and Care Excellence guidelines. RESULTS: Overall, 2259 (2.15%) patients with AF were identified, of which 18.9% constituted a secondary prevention cohort. For secondary prevention, antithrombotic treatment was guideline adherent in 56.3%, 18.9% were overtreated, and 24.8% undertreated; corresponding proportions for primary prevention were 49.5%, 11.7%, and 38.8%, respectively. One-year stroke rates were 8.6% and 1.6% for secondary and primary prevention, respectively (P<0.001); corresponding all-cause mortality rates were 9.8% and 9.4%, respectively (P=0.79). On multivariable analysis, lack of antithrombotic treatment guideline adherence was associated with increased stroke risk for primary prevention (odds ratio, 2.95; 95% confidence interval, 1.26-6.90; P=0.013 for undertreatment); for secondary prevention, lack of guideline adherence was associated with increased risk of recurrent stroke (odds ratio, 2.80; 95% confidence interval, 1.25-6.27; P=0.012 for overtreatment) and all-cause death (odds ratio, 2.75; 95% confidence interval, 1.33-5.69; P=0.006 for undertreatment). CONCLUSIONS: Only approximately half of eligible patients with AF are prescribed oral anticoagulation in line with guidelines. Guideline-adherent antithrombotic treatment significantly reduces the risk of stroke among primary prevention patients and both risk of recurrent stroke and death in patients with previous stroke.

Clinical Features and Prognosis in Patients with Atrial Fibrillation and Prior Stroke: Comparing the Fushimi and Darlington AF Registries.

BACKGROUND: Ethnic differences in clinical characteristics, stroke risk profiles and outcomes among atrial fibrillation (AF) patients may exist. We therefore compared AF patients with previous stroke from Japan and the United Kingdom (UK). METHODS: We compared clinical characteristics, stroke risk and outcomes among AF patients from the Fushimi AF registry who had experienced a previous stroke (Japan; n=688; 19.7%) and the Darlington AF registry (UK; n=428; 19.0%). RESULTS: AF patients with previous stroke in Fushimi were significantly younger (76.8 and 79.6years of age in Fushimi and Darlington; p<0.01) with a lower proportion of females (37.4% vs. 45.1%; p=0.01) than those from Darlington. Although the CHA2DS2-VASc score was lower in AF patients in Fushimi than those in Darlington (5.18 vs. 5.57; p<0.01), oral anticoagulation (OAC) was prescribed significantly more frequently in Fushimi (68.3%) than Darlington (61.7%) (p=0.02). Multivariate logistic regression analysis showed that Japanese ethnicity was associated with a significantly decreased risk of recurrent stroke (OR 0.59. 95% CI 0.36-0.97; p=0.04) but a significantly increased risk of all-cause mortality (OR 1.76, 95% CI 1.18-2.66; p<0.01) in AF patients with previous stroke. CONCLUSIONS: AF patients with previous stroke in the UK were at higher risk of recurrent stroke compared to Japanese patients, but OAC was utilised less frequently. There was a lower risk of recurrent stroke in the secondary prevention cohort from the Fushimi registry, but an increased risk of all-cause mortality.

Novel treatment protocol for ameliorating refractory, chronic pain in patients with autosomal dominant polycystic kidney disease.

Autosomal dominant polycystic kidney disease (ADPKD) patients can suffer from chronic pain that can be refractory to conventional treatment, resulting in a wish for nephrectomy. This study aimed to evaluate the effect of a multidisciplinary treatment protocol with sequential nerve blocks on pain relief in ADPKD patients with refractory chronic pain. As a first step a diagnostic, temporary celiac plexus block with local anesthetics was performed. If substantial pain relief was obtained, the assumption was that pain was relayed via the celiac plexus and major splanchnic nerves. When pain recurred, patients were then scheduled for a major splanchnic nerve block with radiofrequency ablation. In cases with no pain relief, it was assumed that pain was relayed via the aortico-renal plexus, and catheter-based renal denervation was performed. Sixty patients were referred, of which 44 were eligible. In 36 patients the diagnostic celiac plexus block resulted in substantial pain relief with a change in the median visual analogue scale (VAS) score pre-post intervention of 50/100. Of these patients, 23 received a major splanchnic nerve block because pain recurred, with a change in median VAS pre-post block of 53/100. In 8 patients without pain relief after the diagnostic block, renal denervation was performed in 5, with a borderline significant change in the median VAS pre-post intervention of 20/100. After a median follow-up of 12 months, 81.8% of the patients experienced a sustained improvement in pain intensity, indicating that our treatment protocol is effective in obtaining pain relief in ADPKD patients with refractory chronic pain.

Stroke and death in elderly patients with atrial fibrillation in Japan compared with the United Kingdom.

BACKGROUND: Data on stroke, mortality and associated comorbidities in elderly patients with atrial fibrillation (AF) in Japan may differ from Western countries. There have been few systematic comparisons between stroke risk profiles and outcomes among community-based elderly (aged ≥75 years) patients with AF in Japan and the UK. OBJECTIVE AND METHODS: We compared clinical characteristics, stroke risk and outcomes among elderly patients with AF from the Fushimi AF Registry (Japan; N=1791) and the Darlington AF Registry (UK; N=1338). RESULTS: The Fushimi cohort had a mean age 81.8 (standard deviation (SD) 5.3) years and CHA2DS2-VASc (congestive heart failure, hypertension, age ≥75 years (double), diabetes mellitus, previous thromboembolism (double), vascular disease, age 65-74 years and female gender) score 4.3 (1.4), whereas the Darlington cohort had a mean age 83.6 (5.7) years and CHA2DS2-VASc score 4.4 (1.4). Over a 12-month follow-up period, observed stroke and mortality rates in Fushimi were 3.4% (n=61) and 11.5% (n=206), while corresponding event rates in the Darlington cohort were 4.4% (n=59) and 14.1% (n=188), respectively. Appropriate use of oral anticoagulation (OAC, essentially a vitamin K antagonist) was <60% in both registries.On multivariable analysis, ethnicity (Japan vs UK) was neither associated with the risk of stroke (OR 0.92, 95% CI 0.63 to 1.36; p=0.69) nor death (OR 0.92, 95% CI 0.80 to 1.27; p=0.92). In a subgroup analysis of elderly patients not receiving OAC (n=1489), a history of stroke was associated with the risk of stroke (OR 2.42, 95% CI 1.39 to 4.12; p=0.002), but not ethnicity (OR 0.86, 95% CI 0.50 to 1.47; p=0.58). CONCLUSIONS: Elderly (age ≥75 years) patients with AF in both Japan and the UK are at similarly high risk of stroke and death, with OAC still underused in both populations. Ethnicity was not independently associated with the risk of stroke, regardless of OAC use or non-use.

Impact of advanced age on management and prognosis in atrial fibrillation: insights from a population-based study in general practice.

OBJECTIVES: to examine the use of antithrombotic therapy and predictors of stroke and death in very elderly (≥85 years) atrial fibrillation (AF) patients in a general practice cohort from the UK. DESIGN: retrospective, observational cohort study; 12-month follow-up period. SETTING: eleven general practices serving the town of Darlington, England representing a population of 105,000 patients. PATIENTS: two thousand two hundred and fifty-nine patients with a history of AF, 561 (24.8%) aged ≥85 years. MAIN OUTCOME MEASURES: use of antithrombotic therapy by age group and predictors of stroke and death. RESULTS: five hundred and sixty-one (24.8%) AF patients aged ≥85 years (mean (SD) age 89 (4) years; 66% female) identified with a mean CHA2DS2-VASc score of 4.6 (SD 1.4). Thirty-six per cent received oral anticoagulation (OAC) compared with 57% in the 75-84 years age group. Forty-nine per cent of the very elderly received antiplatelet (AP) monotherapy; recorded OAC contraindications and declines were greatest among those aged ≥85 years. Stroke risk was highest among the very elderly (5.2% per annum), despite anticoagulation (3.9%). Multivariate analyses demonstrated an increased risk of stroke with AP monotherapy (odds ratio (OR) 2.45, 95% confidence intervals (CIs) 1.05-5.70) and a significant reduction in all-cause mortality with OAC therapy (OR 0.59, 95% CI 0.36-0.99). CONCLUSION: the majority of very elderly AF patients in general practice do not receive OAC despite their higher stroke risk; almost half received AP monotherapy. AP use independently increased the risk of stroke, signifying that effective stroke prevention requires OAC regardless of age, except where true contraindications exist.