Effectiveness and safety of opicapone in Parkinson’s disease patients with motor fluctuations: the OPTIPARK open-label study

Background The efficacy and safety of opicapone, a once-daily catechol-O-methyltransferase inhibitor, have been established in two large randomized, placebo-controlled, multinational pivotal trials. Still, clinical evidence from routine practice is needed to complement the data from the pivotal trials. Methods OPTIPARK (NCT02847442) was a prospective, open-label, single-arm trial conducted in Germany and the UK under clinical practice conditions. Patients with Parkinson’s disease and motor fluctuations were treated with opicapone 50 mg for 3 (Germany) or 6 (UK) months in addition to their current levodopa and other antiparkinsonian treatments. The primary endpoint was the Clinician’s Global Impression of Change (CGI-C) after 3 months. Secondary assessments included Patient Global Impressions of Change (PGI-C), the Unified Parkinson’s Disease Rating Scale (UPDRS), Parkinson’s Disease Questionnaire (PDQ-8), and the Non-Motor Symptoms Scale (NMSS). Safety assessments included evaluation of treatment-emergent adverse events (TEAEs) and serious adverse events (SAEs). Results Of the 506 patients enrolled, 495 (97.8%) took at least one dose of opicapone. Of these, 393 (79.4%) patients completed 3 months of treatment. Overall, 71.3 and 76.9% of patients experienced any improvement on CGI-C and PGI-C after 3 months, respectively (full analysis set). At 6 months, for UK subgroup only (n = 95), 85.3% of patients were judged by investigators as improved since commencing treatment. UPDRS scores at 3 months showed statistically significant improvements in activities of daily living during OFF (mean ± SD change from baseline: − 3.0 ± 4.6, p < 0.0001) and motor scores during ON (− 4.6 ± 8.1, p < 0.0001). The mean ± SD improvements of − 3.4 ± 12.8 points for PDQ-8 and -6.8 ± 19.7 points for NMSS were statistically significant versus baseline (both p < 0.0001). Most of TEAEs (94.8% of events) were of mild or moderate intensity. TEAEs considered to be at least possibly related to opicapone were reported for 45.1% of patients, with dyskinesia (11.5%) and dry mouth (6.5%) being the most frequently reported. Serious TEAEs considered at least possibly related to opicapone were reported for 1.4% of patients. Conclusions Opicapone 50 mg was effective and generally well-tolerated in PD patients with motor fluctuations treated in clinical practice. Trial registration Registered in July 2016 at clinicaltrials.gov (NCT02847442)

Multicenter prospective analysis of hypertrophic olivary degeneration following infratentorial stroke (HOD-IS): evaluation of disease epidemiology, clinical presentation, and MR-imaging aspects

Introduction: Ischemic and hemorrhagic strokes in the brainstem and cerebellum with injury to the functional loop of the Guillain-Mollaret triangle (GMT) can trigger a series of events that result in secondary trans-synaptic neurodegeneration of the inferior olivary nucleus. In an unknown percentage of patients, this leads to a condition called hypertrophic olivary degeneration (HOD). Characteristic clinical symptoms of HOD progress slowly over months and consist of a rhythmic palatal tremor, vertical pendular nystagmus, and Holmes tremor of the upper limbs. Diffusion Tensor Imaging (DTI) with tractography is a promising method to identify functional pathway lesions along the cerebello-thalamo-cortical connectivity and to generate a deeper understanding of the HOD pathophysiology. The incidence of HOD development following stroke and the timeline of clinical symptoms have not yet been determined in prospective studies—a prerequisite for the surveillance of patients at risk. Methods and Analysis: Patients with ischemic and hemorrhagic strokes in the brainstem and cerebellum with a topo-anatomical relation to the GMT are recruited within certified stroke units of the Interdisciplinary Neurovascular Network of the Rhine-Main. Matching lesions are identified using a predefined MRI template. Eligible patients are prospectively followed up and present at 4 and 8 months after the index event. During study visits, a clinical neurological examination and brain MRI, including high-resolution T2-, proton-density-weighted imaging, and DTI tractography, are performed. Fiberoptic endoscopic evaluation of swallowing is optional if palatal tremor is encountered. Study Outcomes: The primary endpoint of this prospective clinical multicenter study is to determine the frequency of radiological HOD development in patients with a posterior fossa stroke affecting the GMT at 8 months after the index event. Secondary endpoints are identification of (1) the timeline and relevance of clinical symptoms, (2) lesion localizations more prone to HOD occurrence, and (3) the best MR-imaging regimen for HOD identification. Additionally, (4) DTI tractography data are used to analyze individual pathway lesions. The aim is to contribute to the epidemiological and pathophysiological understanding of HOD and hereby facilitate future research on therapeutic and prophylactic measures

The impact of platelet indices on clinical outcome in heart failure:results from the MyoVasc study

Abstract Aims Platelet indices have been associated with traditional cardiovascular risk factors, cardiovascular diseases and all‐cause mortality. This study aimed to investigate the role of platelet count, mean platelet volume (MPV) and platelet‐to‐leukocyte ratio, including platelet‐to‐monocyte and platelet‐to‐lymphocyte ratio with cardiac function, heart failure (HF) phenotypes and clinical outcome, worsening of HF. Methods and results Univariate and multivariable linear and Cox regression analyses were used to investigate the associations between platelet indices, cardiac function and worsening of HF in 3250 subjects enrolled in the MyoVasc study. Higher MPV, lower platelet count, lower platelet‐to‐leukocyte and platelet‐to‐monocyte ratios have been associated with reduced left ventricular ejection fraction (beta estimate [β]MPV [fL] = −0.05 [−0.09; −0.02], βplatelet count (× 10/L)9 = 3.4 [1.2; 5.6], βplatelet‐to‐leukocyte ratio = 1.4 [1.1; 1.8], βplatelet‐to‐monocyte ratio = 28 [20; 36]) and increased E/E' ratio (β MPV [fL] = 0.04 [0.003; 0.07], βplatelet count (× 10/L)9 = −3.1 [−5.3; −0.92], βplatelet‐to‐leukocyte ratio = −0.83 [−1.2; −0.46], βplatelet‐to‐monocyte ratio = −20 [−28; −12]), independent of age and sex. Cox regression demonstrated an increased risk for worsening of HF in subjects with MPV > 75th percentile (hazard ratio [HR] = 1.47 [1.16; 1.87]), platelet count  75th percentile (HR = 1.50 [1.17; 1.93]) ratios, independent of potential confounders. MPV > 75th percentile and platelet count < 25th percentile were strongly related to outcome in HFpEF vs. HFrEF (P for difference = 0.040). Platelet‐to‐leukocyte ratios were associated with worse outcome in both HF phenotypes, without a significant difference between HFpEF and HFrEF. Conclusions Platelet indices are linked with worse cardiac function and adverse clinical outcome, independent of subjects' underlying cardiovascular profile. This study emphasizes their important value to provide additional information on pathophysiology and risk stratification in HF syndrome

Sex-Specific Relationship Between Parathyroid Hormone and Platelet Indices in Phenotypes of Heart Failure - Results From the MyoVasc Study

Background: Heart failure (HF) is a multifactorial syndrome with pathophysiological complexities still not fully understood. Higher mean platelet volume (MPV), a potential marker of platelet activation, and high concentrations of parathyroid hormone (PTH) have been implicated in the pathogenesis of HF. Aim: This study aims to investigate sex-specifically the association between PTH concentrations and platelet indices in phenotypes of HF. Methods and Results: PTH and platelet indices (MPV and platelet count) were available in 1,896 participants from the MyoVasc study in Mainz, Germany. Multivariable linear regression models, adjusted for age, sex, season, vitamin D status, cardiovascular risk factors, comorbidities, estimated glomerular filtration rate, and medication, were used to assess the associations between platelet indices and PTH. The results showed distinct sex-specific associations between PTH and platelet indices. A positive association between PTH and MPV was found in females with symptomatic HF with reduced ejection fraction (HFrEF) only [β = 0.60 (0.19; 1.00)]. Platelet count was inversely associated with PTH in male HFrEF individuals [β = −7.6 (−15; −0.30)] and in both males and females with HF with preserved ejection fraction (HFpEF). Conclusion: This study reports differential, sex-specific relationships between PTH and platelet indices in HF individuals independent of vitamin D status and clinical profile. Particularly in phenotypes of symptomatic HF, distinct associations were observed, suggesting a sex-specific mechanism involved in the interaction between PTH and platelets

Implementation of stroke teams and simulation training shortened process times in a regional stroke network-A network-wide prospective trial.

To meet the requirements imposed by the time-dependency of acute stroke therapies, it is necessary 1) to initiate structural and cultural changes in the breadth of stroke-ready hospitals and 2) to find new ways to train the personnel treating patients with acute stroke. We aimed to implement and validate a composite intervention of a stroke team algorithm and simulation-based stroke team training as an effective quality initiative in our regional interdisciplinary neurovascular network consisting of 7 stroke units.We recorded door-to-needle times of all consecutive stroke patients receiving thrombolysis at seven stroke units for 3 months before and after a 2 month intervention which included setting up a team-based stroke workflow at each stroke unit, a train-the-trainer seminar for stroke team simulation training and a stroke team simulation training session at each hospital as well as a recommendation to take up regular stroke team trainings.The intervention reduced the network-wide median door-to-needle time by 12 minutes from 43,0 (IQR 29,8-60,0, n = 122) to 31,0 (IQR 24,0-42,0, n = 112) minutes (p < 0.001) and substantially increased the share of patients receiving thrombolysis within 30 minutes of hospital arrival from 41.5% to 59.6% (p < 0.001). Stroke team training participants stated a significant increase in knowledge on the topic of acute stroke care and in the perception of patient safety. The overall course concept was regarded as highly useful by most participants from different professional backgrounds.The composite intervention of a binding team-based algorithm and stroke team simulation training showed to be well-transferable in our regional stroke network. We provide suggestions and materials for similar campaigns in other stroke networks

Implementation of stroke teams and simulation training shortened process times in a regional stroke network-A network-wide prospective trial.

To meet the requirements imposed by the time-dependency of acute stroke therapies, it is necessary 1) to initiate structural and cultural changes in the breadth of stroke-ready hospitals and 2) to find new ways to train the personnel treating patients with acute stroke. We aimed to implement and validate a composite intervention of a stroke team algorithm and simulation-based stroke team training as an effective quality initiative in our regional interdisciplinary neurovascular network consisting of 7 stroke units.We recorded door-to-needle times of all consecutive stroke patients receiving thrombolysis at seven stroke units for 3 months before and after a 2 month intervention which included setting up a team-based stroke workflow at each stroke unit, a train-the-trainer seminar for stroke team simulation training and a stroke team simulation training session at each hospital as well as a recommendation to take up regular stroke team trainings.The intervention reduced the network-wide median door-to-needle time by 12 minutes from 43,0 (IQR 29,8-60,0, n = 122) to 31,0 (IQR 24,0-42,0, n = 112) minutes (p < 0.001) and substantially increased the share of patients receiving thrombolysis within 30 minutes of hospital arrival from 41.5% to 59.6% (p < 0.001). Stroke team training participants stated a significant increase in knowledge on the topic of acute stroke care and in the perception of patient safety. The overall course concept was regarded as highly useful by most participants from different professional backgrounds.The composite intervention of a binding team-based algorithm and stroke team simulation training showed to be well-transferable in our regional stroke network. We provide suggestions and materials for similar campaigns in other stroke networks

Exemplary team-based acute stroke care algorithm.

<p>The algorithm needs to be adapted to the infrastructure and staff availiability of each individual hospital. The algorithm relies on a seamless cooperation with preclinical emergency medical services and encourages working in parallel with defined tasks for each stroke team member. The stroke alert is a speed dial collective call that summons all team members simultaneously to their respective workplaces.</p