Daisy Abreu

Non-vitamin K antagonist oral anticoagulants and major bleeding-related fatality in patients with atrial fibrillation and venous thromboembolism: a systematic review and meta-analysis

Objective Non-vitamin K antagonist oral anticoagulants (NOACs) are efficacious and safe antithrombotic drugs but the non-availability of an antidote for potential fatal haemorrhagic events is clinically perceived as a strong limitation. We aimed at evaluating the risk of haemorrhage-related fatalities associated with NOACs in patients requiring long-term anticoagulation. Methods MEDLINE, Cochrane Library and Web of Science databases were searched in November 2014 for atrial fibrillation (AF) or venous thromboembolism (VTE) phase III randomised controlled trials (RCT) comparing NOACs with vitamin K antagonists (VKAs) or low molecular weight heparin (LMWH) followed by VKAs. Pooled OR and 95% CIs were estimated through meta-analysis. Heterogeneity was assessed with the I2 test. Results Eleven studies were included: 5 on AF and 6 on VTE. A total of 100 324 patients were evaluated in 4 rivaroxaban, 3 dabigatran, 2 apixaban and 2 edoxaban studies. NOAC-treated patients had a 47% odds reduction compared with VKA (OR 0.53; 95% CI 0.42 to 0.68; I2=0%; 3 events avoided per 1000 patients) and 64% odds reduction compared with LMWH–VKA (OR 0.36; 95% CI 0.15 to 0.84; I2=0%; 1 event avoided per 1000 patients) regarding fatal bleeding risk. Case fatality due to major bleeding was lower in NOAC-treated patients both in AF (OR 0.68; 95% CI 0.48 to 0.96; I2=37%; 1 death avoided per 39 major bleedings) and VTE (OR 0.54; 95% CI 0.22 to 1.32; I2=0%) patients. AF survivors of major bleeding events treated with NOACs had lower mortality compared with patients treated with VKAs (OR 0.57; 95% CI 0.45 to 0.73; I2=0%; 78 events avoided per 1000 survivors to major bleeding). Conclusions These data suggest that NOACs decrease the risk of fatality cases related to major bleeding events, particularly in AF patients. These results support the safety profile of NOACs even without having a widely available drug-specific antidote.

Risk of drug-induced liver injury with the new oral anticoagulants: systematic review and meta-analysis

Objective In recent years, safety alerts have been made warning of the risk of serious drug-induced liver injury (DILI) caused by cardiovascular drugs. The new oral anticoagulants (NOACs) have now reached the market. However, safety concerns have been raised about their hepatic safety. Therefore we aimed to evaluate NOAC liver-related safety. Methods Systematic review and meta-analysis of phase III randomised controlled trials (RCTs). Medline and CENTRAL were searched to September 2013. Reviews and reference lists were also searched. Two reviewers independently searched for studies and retrieved data estimates. Primary outcome was DILI (transaminases elevations >3× upper limit of normal (ULN) with total bilirubin >2× ULN). NOACs were compared against any control group. Random-effects meta-analysis was performed, and pooled estimates were expressed as relative risk (RR) and 95% CI heterogeneity was evaluated with I2 test. Results Twenty-nine RCTs evaluating 152 116 patients (mean follow-up of 16 months) were included. All RCTs were rated as having low risk of bias. NOAC were not associated with an increased risk of DILI (RR 0.90, 95% CI 0.72 to 1.13, I2=0%). Similar results were obtained for individual NOAC (rivaroxaban, apixaban, dabigatran, darexaban, edoxaban) and considering the different control groups (vitamin K antagonists, low molecular weight heparin (LMWH) and placebo). The risk of transaminases elevations (>3×ULN) was lower among NOAC-treated patients, in particular in comparison with LMWH-treated patients (RR 0.71, 95% CI 0.59 to 0.85; I2=27%) Conclusions NOACs are not associated with an increased risk of DILI. The unexpected ‘protective’ effect of NOAC is probably due to LMWH-associated hepatotoxicity.

A systematic review of the characteristics and validity of monitoring technologies to assess Parkinson’s disease

BackgroundThere is growing interest in having objective assessment of health-related outcomes using technology-based devices that provide unbiased measurements which can be used in clinical practice and scientific research. Many studies have investigated the clinical manifestations of Parkinson’s disease using such devices. However, clinimetric properties and clinical validation vary among the different devices.MethodsGiven such heterogeneity, we sought to perform a systematic review in order to (i) list, (ii) compare and (iii) classify technological-based devices used to measure motor function in individuals with Parkinsons disease into three groups, namely wearable, non-wearable and hybrid devices. A systematic literature search of the PubMed database resulted in the inclusion of 168 studies. These studies were grouped based on the type of device used. For each device we reviewed availability, use, reliability, validity, and sensitivity to change. The devices were then classified as (i) ‘recommended’, (ii) ‘suggested’ or (iii) ‘listed’ based on the following criteria: (1) used in the assessment of Parkinson’s disease (yes/no), (2) used in published studies by people other than the developers (yes/no), and (3) successful clinimetric testing (yes/no).ResultsSeventy-three devices were identified, 22 were wearable, 38 were non-wearable, and 13 were hybrid devices. In accordance with our classification method, 9 devices were ‘recommended’, 34 devices were ‘suggested’, and 30 devices were classified as ‘listed’. Within the wearable devices group, the Mobility Lab sensors from Ambulatory Parkinson’s Disease Monitoring (APDM), Physilog®, StepWatch 3, TriTrac RT3 Triaxial accelerometer, McRoberts DynaPort, and Axivity (AX3) were classified as ‘recommended’. Within the non-wearable devices group, the Nintendo Wii Balance Board and GAITRite® gait analysis system were classified as ‘recommended’. Within the hybrid devices group only the Kinesia® system was classified as ‘recommended’.

Substantia nigra neuromelanin magnetic resonance imaging in de novo Parkinson's disease patients

Depigmentation of the substantia nigra (SN) and locus coeruleus (LC) is a conspicuous pathological feature of Parkinsons disease (PD) and is related to the loss of neuromelanin, whose paramagnetic properties result in high signal on specific T1‐weighted magnetic resonance imaging (MRI). Recent studies have suggested that neuromelanin decrease in the SN and LC of PD patients may emerge as a possible diagnostic biomarker. The SN neuromelanin signal in de novo and early stage PD patients was studied to assess its diagnostic accuracy. This is the first study based on a semi‐automated MRI analysis of the neuromelanin signal in de novo PD patients.

Substantia nigra neuromelanin-MR imaging differentiates essential tremor from Parkinson's disease.

Essential tremor (ET) is a very common movement disorder that has no diagnostic markers. Differentiation with Parkinsons disease (PD) can be clinically challenging in some cases, with a high rate of misdiagnosis. Magnetic resonance imaging (MRI) studies have been able to identify neuromelanin changes in the substantia nigra (SN) of PD patients, but they have thus far not been investigated in ET. In this study, we aimed to characterize neuromelanin‐MR signal changes in ET and evaluate its diagnostic accuracy in the differential diagnosis with PD.

Delayed diagnosis in ALS: the problem continues.

We studied the limitations to early diagnosis in amyotrophic lateral sclerosis (ALS). The diagnostic process was assessed in 120 consecutive patients, including onset, interval to diagnosis, investigations, specialist assessment and pre-diagnostic management. Times from onset to first consultation (T1), second consultation (T2) and diagnosis (TD) were considered. Predictors of diagnostic delay were determined by multivariate logistic regression, adjusted for gender, age, clinical manifestations, and specialism of the first and second consultants. There were 101 consecutive ALS patients with complete datasets (69% men; median age at diagnosis 61.5 years). The mean TD and median TD were respectively 10.1 and 9.5 months. In 55%, the first consultant was a general practitioner (GP), in 16% a neurologist and in 14% an orthopedist. The diagnosis of ALS was made by non-neurologists in 9 patients. The odds of delayed diagnosis (≥ 12 months) were higher (1.56; 0.19-12.56) in younger patients (≤ 45 years) (p<0.05). Female gender (0.56; 0.29-1.70) and bulbar-onset (0.56; 0.29-1.70) were independently associated with earlier diagnosis (p<0.05). Assessment by a neurologist at the first (0.32; 0.19-2.46) or second consultation (0.87; 0.21-1.21) was associated with a shorter diagnosis time (< 12 months) (p<0.05). We conclude that diagnostic delay mainly resulted from delayed referral from non-neurologist physicians to a neurologist. Moreover, incomplete neurophysiological investigation had a relevant impact.

Magnetic resonance correlation of iron content with neuromelanin in the substantia nigra of early‐stage Parkinson's disease

Magnetic resonance (MR) studies have demonstrated a significant reduction of neuromelanin in the substantia nigra (SN) of Parkinsons disease (PD) patients with high accuracy for differential diagnosis compared to non‐PD controls and essential tremor. However, studies state that not knowing how paramagnetic effects of iron influence neuromelanin signal is a limitation. In this study a neuromelanin‐sensitive MR sequence was combined with T2* relaxometry iron quantification analysis to study the SN of early‐stage PD patients to investigate the correlation between these parameters.

Clinical trials in palliative care: a systematic review of their methodological characteristics and of the quality of their reporting

BackgroundOver the past decades there has been a significant increase in the number of published clinical trials in palliative care. However, empirical evidence suggests that there are methodological problems in the design and conduct of studies, which raises questions about the validity and generalisability of the results and of the strength of the available evidence. We sought to evaluate the methodological characteristics and assess the quality of reporting of clinical trials in palliative care.MethodsWe performed a systematic review of published clinical trials assessing therapeutic interventions in palliative care. Trials were identified using MEDLINE (from its inception to February 2015). We assessed methodological characteristics and describe the quality of reporting using the Cochrane Risk of Bias tool.ResultsWe retrieved 107 studies. The most common medical field studied was oncology, and 43.9% of trials evaluated pharmacological interventions. Symptom control and physical dimensions (e.g. intervention on pain, breathlessness, nausea) were the palliative care-specific issues most studied. We found under-reporting of key information in particular on random sequence generation, allocation concealment, and blinding.ConclusionsWhile the number of clinical trials in palliative care has increased over time, methodological quality remains suboptimal. This compromises the quality of studies. Therefore, a greater effort is needed to enable the appropriate performance of future studies and increase the robustness of evidence-based medicine in this important field.

Subthalamic deep brain stimulation effects on odor identification in Parkinson's disease

Olfactory dysfunction is common in Parkinsons disease (PD) and it is one of the earliest non‐motor symptoms. A few studies have suggested that deep brain stimulation of the subthalamic nucleus (STN‐DBS) could improve olfactory function. Our aim was to evaluate the acute effect of bilateral STN‐DBS on a commonly used smell test in PD patients.

Placebo and nocebo responses in restless legs syndrome: A systematic review and meta-analysis

Objective: To estimate the placebo and nocebo responses in restless legs syndrome (RLS) and explore their determinants. Methods: Databases were searched up to October 2015. Randomized, double-blind, placebo-controlled trials of patients with RLS were included if quantitative data were extractable in the placebo arm. Placebo response was defined as the within-group change from baseline, using any scale measuring RLS severity or disability. Nocebo response was defined as the proportion of patients experiencing adverse events in the placebo arm. Random-effects meta-analysis was used to pool data. Statistical heterogeneity was assessed with I2 statistic. Several predetermined subgroup and sensitivity analysis were performed. PROSPERO registration number is CRD42015027992. Results: We included 85 randomized controlled trials (5,046 participants). Pooled placebo response effect size was −1.41 (95% confidence interval [CI] −1.56 to −1.25, 64 trials, I2 = 88.1%), corresponding to −6.58 points in the International RLS Study Group Scale (IRLS). Pooled nocebo response was 45.36% (95% CI 40.47%–50.29%, 72 trials; I2 = 89.8%). The placebo and nocebo responses were greater in trials with longer duration, evaluating pharmacologic interventions and idiopathic RLS, and in industry-funded and unpublished studies. The placebo response was considerably smaller in objective as compared to subjective outcomes. In addition, the nocebo response increases proportionally with the placebo response, and has the same predictors. Conclusions: The magnitude of the placebo response in RLS is above the threshold of minimal clinical important difference, and the frequency of adverse events is also considerable. These results are relevant to inform the design and interpretation of future clinical trials.