Off-label-dosing of non-vitamin K-dependent oral antagonists in AF patients before and after stroke: results of the prospective multicenter Berlin Atrial Fibrillation Registry

Aims

We aimed to analyze prevalence and predictors of NOAC off-label under-dosing in AF patients before and after the index stroke.

Methods

The post hoc analysis included 1080 patients of the investigator-initiated, multicenter prospective Berlin Atrial Fibrillation Registry, designed to analyze medical stroke prevention in AF patients after acute ischemic stroke.

Results

At stroke onset, an off-label daily dose was prescribed in 61 (25.5%) of 239 NOAC patients with known AF and CHA₂DS₂-VASc score ≥ 1, of which 52 (21.8%) patients were under-dosed. Under-dosing was associated with age ≥ 80 years in patients on rivaroxaban [OR 2.90, 95% CI 1.05–7.9, P = 0.04; n = 29] or apixaban [OR 3.24, 95% CI 1.04–10.1, P = 0.04; n = 22]. At hospital discharge after the index stroke, NOAC off-label dose on admission was continued in 30 (49.2%) of 61 patients. Overall, 79 (13.7%) of 708 patients prescribed a NOAC at hospital discharge received an off-label dose, of whom 75 (10.6%) patients were under-dosed. Rivaroxaban under-dosing at discharge was associated with age ≥ 80 years [OR 3.49, 95% CI 1.24–9.84, P = 0.02; n = 19]; apixaban under-dosing with body weight ≤ 60 kg [OR 0.06, 95% CI 0.01–0.47, P < 0.01; n = 56], CHA₂DS₂-VASc score [OR per point 1.47, 95% CI 1.08–2.00, P = 0.01], and HAS-BLED score [OR per point 1.91, 95% CI 1.28–2.84, P < 0.01].

Conclusion

At stroke onset, off-label dosing was present in one out of four, and under-dosing in one out of five NOAC patients. Under-dosing of rivaroxaban or apixaban was related to old age. In-hospital treatment after stroke reduced off-label NOAC dosing, but one out of ten NOAC patients was under-dosed at discharge.

Clinical trial registration

NCT02306824.

     

Serum cholesterol levels do not influence outcome or recovery in acute ischemic stroke

OBJECTIVE: To examine the influence of admission serum cholesterol levels (SCL) on severity of initial neurological deficit, neurological outcome at month 3 and neurological recovery in patients with acute first-ever ischemic stroke. METHODS: Prospectively collected data from 889 consecutive patients with first-ever acute ischemic stroke were retrospectively analysed. Patients who suffered a recurrent ischemic stroke (n=22) or died (n=30) during the follow-up period were excluded from this study. Age, gender, arterial hypertension, diabetes mellitus, smoking, stroke etiology, SCL and severity of neurological deficit, using the National Institute of Health Stroke Scale (NIHSS), at presentation (NIHSS0) and after 3 months (NIHSS1), were assessed. Neurological recovery was defined as difference in NIHSS score (Delta(NIHSS)), according to Delta(NIHSS)=NIHSS0 - NIHSS1. RESULTS: Data from 837 patients (66% men, age: 62 +/- 14 years) were analysed. NIHSS1 was 2.3 +/- 1.8 and Delta(NIHSS) was 3.4 +/- 3. Clinically insignificant correlations between SCL and NIHSS0 (r=-0.13, p=0.0002), NIHSS1 (r=-0.09, p=0.001) and Delta(NIHSS) (r=-0.1, p=0.03) were evident. Multivariate binary logistic regression analysis revealed smoking (p=0.008), stroke etiology (p=0.023) and NIHSS0 (p<0.001) but not age, gender, arterial hypertension, diabetes mellitus or SCL as predictors for Delta(NIHSS). CONCLUSION: Our data suggest that SCL in patients with acute ischemic stroke are not associated with neurological deficit on admission, outcome or neurological recovery.     

Long-term mortality and recurrence in patients treated for colonic diverticulitis with abscess formation: a nationwide register-based cohort study

Purpose

The study aimed to investigate long-term mortality, recurrence, and death related to recurrence for patients admitted with acute diverticulitis with abscess formation (Hinchey stage Ib-II).

Methods

The cohort was identified by linking administrative registers for all Danish citizens in years 2000–2012. Patients were identified from ICD-10 discharge codes and stratified according to treatment (antibiotics, percutaneous abscess drainage, or surgery).

Results

From 6,641,672 persons, 3148 patients were identified with acute diverticulitis with abscess formation. Survival was comparable between treatment groups with a 1-year survival of 81–83% and a 5-year survival of 66–67% (p?=?0.66). Glucocorticoid usage prior to admission increased risk of mortality with hazard ratio 1.64 (95%CI 1.39–1.93), 1.77 (1.20–2.63), and 1.92 (1.07–3.44) for the antibiotics, drainage, and operative treatment group, respectively. Drainage treatment increased risk of recurrence with sub-distribution hazard (SDH) of 1.52 (1.19–1.95) and operative treatment decreased risk with a SDH of 0.55 (0.32–0.93), both compared with antibiotic treatment (p?=?0.0001). Recurrence occurred in 23.6% (18.5–30.1%) of patients in the drainage group, 15.5% (13.9–17.3%) in the antibiotics group, and 9.1% (5.1–16.1%) in the operative group. Recurrence-related mortality was 2.0% (0.9–4.4%) for the drainage group, 1.1% (0.7–1.8%) for the antibiotics group, and 0.6% (0.1–4.3%) for the operative group (p?=?0.24). Most recurrences and recurrence-related mortality occurred within the first year after primary admission.

Conclusions

This study with complete national data revealed a high mortality and recurrence rate after diverticular abscesses. Survival was comparable between treatment groups, but patients treated with drainage had significantly higher risk of recurrence.

     

The concept of sustainable chemistry: Key drivers for the transition towards sustainable development

To achieve and safeguard the chemicals management “2020 goal” of least possible adverse effects, we need broad and global transformation to a sustainable chemistry, which can provide the most adequate solutions contributing to sustainable development as set out in the Agenda 2030. As a basis for effective progress, a common understanding is required of sustainable chemistry, of its scope, characteristic elements, and specific objectives, as well are guidelines requisite for influencing the speed and direction of this complex and encompassing transformation. This article aims at stimulating this transition process towards a sustainable chemical sector by proposing “100 words for sustainable chemistry”, objectives and guiding principles as well as actions steps towards the further implementation of sustainable chemistry.     

Preexisting musculoskeletal burden and its development under letrozole treatment in early breast cancer patients

One of the most common adverse events (AEs) occurring during treatment with aromatase inhibitors (AIs) is musculoskeletal pain. The aim of our study was to analyze the influence of preexisting muscle/limb pain and joint pain on the development of AI-induced musculoskeletal AEs. Women eligible for upfront adjuvant endocrine therapy with letrozole were included in the PreFace study, a multicenter phase IV trial. During the first treatment year, they were asked to record musculoskeletal AEs monthly by answering questions regarding pain symptoms and rating the pain intensity on a numeric rating scale from 0 (no pain) to 10 (very strong pain). Pain values were compared using nonparametric statistical tests. Overall, 1,416 patients were evaluable. The average pain value over all time points in women with preexisting muscle/limb pain was 4.3 (median 4.3); in those without preexisting pain, it was 2.0 (median 1.7). In patients without preexisting muscle/limb pain, pain levels increased relatively strongly within the first 6 months (mean increase +0.9, p < 0.00001) in comparison with those with preexisting pain (mean increase +0.3, p < 0.001), resulting in a statistically significant difference (p < 0.00001) between the two groups. The development of joint pain was similar in the two groups. Women without preexisting muscle/limb pain or joint pain have the greatest increase in pain after the start of adjuvant AI therapy. Women with preexisting pain have significantly higher pain values. The main increase in pain values takes place during the first 6 months of treatment.     

The sleep relay—the role of the thalamus in central and decentral sleep regulation

Surprisingly, the concept of sleep, its necessity and function, the mechanisms of action, and its elicitors are far from being completely understood. A key to sleep function is to determine how and when sleep is induced. The aim of this review is to merge the classical concepts of central sleep regulation by the brainstem and hypothalamus with the recent findings on decentral sleep regulation in local neuronal assemblies and sleep regulatory substances that create a scenario in which sleep is both local and use dependent. The interface between these concepts is provided by thalamic cellular and network mechanisms that support rhythmogenesis of sleep-related activity. The brainstem and the hypothalamus centrally set the pace for sleep-related activity throughout the brain. Decentral regulation of the sleep–wake cycle was shown in the cortex, and the homeostat of non-rapid-eye-movement sleep is made up by molecular networks of sleep regulatory substances, allowing individual neurons or small neuronal assemblies to enter sleep-like states. Thalamic neurons provide state-dependent gating of sensory information via their ability to produce different patterns of electrogenic activity during wakefulness and sleep. Many mechanisms of sleep homeostasis or sleep-like states of neuronal assemblies, e.g. by the action of adenosine, can also be found in thalamic neurons, and we summarize cellular and network mechanisms of the thalamus that may elicit non-REM sleep. It is argued that both central and decentral regulators ultimately target the thalamus to induce global sleep-related oscillatory activity. We propose that future studies should integrate ideas of central, decentral, and thalamic sleep generation.     

Neuropeptide S receptor gene is associated with cortisol responses to social stress in humans

The neuropeptide S (NPS) and its receptor NPSR represent a transmitter system critically involved in the modulation of anxiety and arousal in rodents. Initial human studies indicate that the T-allele of the functional NPSR gene (NPSR1) polymorphism (rs324981), which increases NPS potency at NPSR, is associated with anxiety-related phenotypes. Since stress is critically involved in the pathogenesis of anxiety disorders, we tested the association between rs324981 and stress reactivity in 196 healthy males. Participants were exposed to the Trier Social Stress Test for Groups (TSST-G), a standardized laboratory protocol for stress exposure in a group format. Salivary cortisol and subjective stress responses were assessed. A significant genotype by time interaction and a main effect of genotype were shown, with T-allele carriers displaying larger cortisol and subjective stress responses. This is the first report to show involvement of the NPS system in the regulation of the neuroendocrine stress response in humans.     

Antibody responses against galactocerebroside are potential stage-specific biomarkers in multiple sclerosis

BACKGROUND: Galactocerebroside, the major glycolipid of central nervous system myelin, is a known target for pathogenic demyelinating antibody responses in experimental allergic encephalomyelitis (EAE), the animal model of multiple sclerosis (MS). OBJECTIVE: To address the importance of anti-galactocerebroside (alpha-GalC) antibodies in MS and to evaluate them as biomarkers of disease. METHODS: alpha-GalC IgGs were quantified from sera of patients with MS and in marmoset EAE by a new immunosorbent assay. RESULTS: We report a significant difference in serum alpha-GalC IgG titers between patients with relapsing-remitting (RR)-MS and healthy controls (HCs; P < .001). The frequencies of alpha-GalC antibody-positive subjects (alpha-GalC titers > or = mean HC titers+3 SD) are also significantly elevated in RR-MS compared with HC (40% vs 0%; P = .0033). Immunoaffinity purified alpha-GalC IgGs from human serum bind to cultured human oligodendrocytes, indicating that the ELISA detects a biologically relevant epitope. Corroborating these findings, alpha-GalC antibody responses in marmoset EAE were similarly found to be specifically associated with the RR forms and not the peracute or progressive forms, in contrast with other anti-myelin antibodies (P = .0256). CONCLUSION: (1) alpha-GalC antibodies appear MS-specific and are not found in healthy subjects, unlike antibodies against myelin proteins; (2) when present, alpha-GalC antibodies identify mostly RR-MS and may be an indicator of ongoing disease activity. This novel assay is a suitable and valuable method to increase accuracy of diagnosis and disease staging in MS.     

Distinct functions of junD in cardiac hypertrophy and heart failure

Cardiac hypertrophic stimuli induce both adaptive and maladaptive growth response pathways in heart. Here we show that mice lacking junD develop less adaptive hypertrophy in heart after mechanical pressure overload, while cardiomyocyte-specific expression of junD in mice results in spontaneous ventricular dilation and decreased contractility. In contrast, fra-1 conditional knock-out mice have a normal hypertrophic response, whereas hearts from fra-1 transgenic mice decompensate prematurely. Moreover, fra-1 transgenic mice simultaneously lacking junD reveal a spontaneous dilated cardiomyopathy associated with increased cardiomyocyte apoptosis and a primary mitochondrial defect. These data suggest that junD promotes both adaptive-protective and maladaptive hypertrophy in heart, depending on its expression levels.