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The Cochrane Database of Systematic... Oct 2020Despite the availability of effective drug therapies that reduce low-density lipoprotein (LDL)-cholesterol (LDL-C), cardiovascular disease (CVD) remains an important... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Despite the availability of effective drug therapies that reduce low-density lipoprotein (LDL)-cholesterol (LDL-C), cardiovascular disease (CVD) remains an important cause of mortality and morbidity. Therefore, additional LDL-C reduction may be warranted, especially for people who are unresponsive to, or unable to take, existing LDL-C-reducing therapies. By inhibiting the proprotein convertase subtilisin/kexin type 9 (PCSK9) enzyme, monoclonal antibodies (PCSK9 inhibitors) reduce LDL-C and CVD risk.
OBJECTIVES
Primary To quantify the effects of PCSK9 inhibitors on CVD, all-cause mortality, myocardial infarction, and stroke, compared to placebo or active treatment(s) for primary and secondary prevention. Secondary To quantify the safety of PCSK9 inhibitors, with specific focus on the incidence of influenza, hypertension, type 2 diabetes, and cancer, compared to placebo or active treatment(s) for primary and secondary prevention.
SEARCH METHODS
We identified studies by systematically searching CENTRAL, MEDLINE, Embase, and Web of Science in December 2019. We also searched ClinicalTrials.gov and the International Clinical Trials Registry Platform in August 2020 and screened the reference lists of included studies. This is an update of the review first published in 2017.
SELECTION CRITERIA
All parallel-group and factorial randomised controlled trials (RCTs) with a follow-up of at least 24 weeks were eligible.
DATA COLLECTION AND ANALYSIS
Two review authors independently reviewed and extracted data. Where data were available, we calculated pooled effect estimates. We used GRADE to assess certainty of evidence and in 'Summary of findings' tables.
MAIN RESULTS
We included 24 studies with data on 60,997 participants. Eighteen trials randomised participants to alirocumab and six to evolocumab. All participants received background lipid-lowering treatment or lifestyle counselling. Six alirocumab studies used an active treatment comparison group (the remaining used placebo), compared to three evolocumab active comparison trials. Alirocumab compared with placebo decreased the risk of CVD events, with an absolute risk difference (RD) of -2% (odds ratio (OR) 0.87, 95% confidence interval (CI) 0.80 to 0.94; 10 studies, 23,868 participants; high-certainty evidence), decreased the risk of mortality (RD -1%; OR 0.83, 95% CI 0.72 to 0.96; 12 studies, 24,797 participants; high-certainty evidence), and MI (RD -2%; OR 0.86, 95% CI 0.79 to 0.94; 9 studies, 23,352 participants; high-certainty evidence) and for any stroke (RD 0%; OR 0.73, 95% CI 0.58 to 0.91; 8 studies, 22,835 participants; high-certainty evidence). Compared to active treatment the alirocumab effects, for CVD, the RD was 1% (OR 1.37, 95% CI 0.65 to 2.87; 3 studies, 1379 participants; low-certainty evidence); for mortality, RD was -1% (OR 0.51, 95% CI 0.18 to 1.40; 5 studies, 1333 participants; low-certainty evidence); for MI, RD was 1% (OR 1.45, 95% CI 0.64 to 3.28, 5 studies, 1734 participants; low-certainty evidence); and for any stroke, RD was less than 1% (OR 0.85, 95% CI 0.13 to 5.61; 5 studies, 1734 participants; low-certainty evidence). Compared to placebo the evolocumab, for CVD, the RD was -2% (OR 0.84, 95% CI 0.78 to 0.91; 3 studies, 29,432 participants; high-certainty evidence); for mortality, RD was less than 1% (OR 1.04, 95% CI 0.91 to 1.19; 3 studies, 29,432 participants; high-certainty evidence); for MI, RD was -1% (OR 0.72, 95% CI 0.64 to 0.82; 3 studies, 29,432 participants; high-certainty evidence); and for any stroke RD was less than -1% (OR 0.79, 95% CI 0.65 to 0.94; 2 studies, 28,531 participants; high-certainty evidence). Compared to active treatment, the evolocumab effects, for any CVD event RD was less than -1% (OR 0.66, 95% CI 0.14 to 3.04; 1 study, 218 participants; very low-certainty evidence); for all-cause mortality, the RD was less than 1% (OR 0.43, 95% CI 0.14 to 1.30; 3 studies, 5223 participants; very low-certainty evidence); and for MI, RD was less than 1% (OR 0.66, 95% CI 0.23 to 1.85; 3 studies, 5003 participants; very low-certainty evidence). There were insufficient data on any stroke. AUTHORS' CONCLUSIONS: The evidence for the clinical endpoint effects of evolocumab and alirocumab were graded as high. There is a strong evidence base to prescribe PCSK9 monoclonal antibodies to people who might not be eligible for other lipid-lowering drugs, or to people who cannot meet their lipid goals on more traditional therapies, which was the main patient population of the available trials. The evidence base of PCSK9 inhibitors compared with active treatment is much weaker (low very- to low-certainty evidence) and it is unclear whether evolocumab or alirocumab might be effectively used as replacement therapies. Related, most of the available studies preferentially enrolled people with either established CVD or at a high risk already, and evidence in low- to medium-risk settings is minimal. Finally, there is very limited evidence on any potential safety issues of both evolocumab and alirocumab. While the current evidence synthesis does not reveal any adverse signals, neither does it provide evidence against such signals. This suggests careful consideration of alternative lipid lowering treatments before prescribing PCSK9 inhibitors.
Topics: Antibodies, Monoclonal, Humanized; Anticholesteremic Agents; Cardiovascular Diseases; Cause of Death; Cholesterol, LDL; Cholinergic Antagonists; Ezetimibe; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Middle Aged; Myocardial Infarction; PCSK9 Inhibitors; Primary Prevention; Proprotein Convertase 9; Randomized Controlled Trials as Topic; Secondary Prevention; Stroke; Time Factors
PubMed: 33078867
DOI: 10.1002/14651858.CD011748.pub3 -
BMJ Clinical Evidence Oct 2014Raynaud's phenomenon is episodic vasospasm of the peripheral vessels. It presents as episodic colour changes of the digits (sometimes accompanied by pain and... (Review)
Review
INTRODUCTION
Raynaud's phenomenon is episodic vasospasm of the peripheral vessels. It presents as episodic colour changes of the digits (sometimes accompanied by pain and paraesthesia), usually in response to cold exposure or stress. The classic triphasic colour change is white (ischaemia), then blue (de-oxygenation), then red (reperfusion). Raynaud's phenomenon can be primary (idiopathic) or secondary to several different conditions and causes. When secondary (e.g., to systemic sclerosis), it can progress to ulceration of the fingers and toes. This review deals with secondary Raynaud's phenomenon.
METHODS AND OUTCOMES
We conducted a systematic review and aimed to answer the following clinical questions: What are the effects of surgical interventions in complicated secondary Raynaud's phenomenon? We searched: Medline, Embase, The Cochrane Library, and other important databases up to March 2014 (Clinical Evidence reviews are updated periodically; please check our website for the most up-to-date version of this review). We included harms alerts from relevant organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA).
RESULTS
We found two studies that met our inclusion criteria. We performed a GRADE evaluation of the quality of evidence for interventions.
CONCLUSIONS
In this systematic review, we present information relating to the effectiveness and safety of the following interventions: botulinum toxin, simple debridement/surgical toilet of ulcers, peripheral sympathectomy (digital, digital plus sympathectomy of the ulnar and/or radial artery, ligation of the ulnar artery), cervical/thoracic sympathectomy, arterial reconstruction (venous graft, arterial graft, balloon angioplasty), and amputation.
Topics: Amputation, Surgical; Botulinum Toxins; Debridement; Humans; Peripheral Nerves; Raynaud Disease; Sympathectomy; Ulcer
PubMed: 25322727
DOI: No ID Found -
The Cochrane Database of Systematic... Feb 2021Vascular cognitive impairment (VCI) describes a broad spectrum of cognitive impairments caused by cerebrovascular disease, ranging from mild cognitive impairment to... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Vascular cognitive impairment (VCI) describes a broad spectrum of cognitive impairments caused by cerebrovascular disease, ranging from mild cognitive impairment to dementia. There are currently no pharmacological treatments recommended for improving either cognition or function in people with VCI. Three cholinesterase inhibitors (donepezil, galantamine, and rivastigmine) are licenced for the treatment of dementia due to Alzheimer's disease. They are thought to work by compensating for reduced cholinergic neurotransmission, which is also a feature of VCI. Through pairwise comparisons with placebo and a network meta-analysis, we sought to determine whether these medications are effective in VCI and whether there are differences between them with regard to efficacy or adverse events.
OBJECTIVES
(1) To assess the efficacy and safety of cholinesterase inhibitors in the treatment of adults with vascular dementia and other VCI. (2) To compare the effects of different cholinesterase inhibitors on cognition and adverse events, using network meta-analysis.
SEARCH METHODS
We searched ALOIS, the Cochrane Dementia and Cognitive Improvement Group's register, MEDLINE (OvidSP), Embase (OvidSP), PsycINFO (OvidSP), CINAHL (EBSCOhost), Web of Science Core Collection (ISI Web of Science), LILACS (BIREME), ClinicalTrials.gov, and the World Health Organization International Clinical Trials Registry Platform on 19 August 2020.
SELECTION CRITERIA
We included randomised controlled trials in which donepezil, galantamine, or rivastigmine was compared with placebo or in which the drugs were compared with each other in adults with vascular dementia or other VCI (excluding cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL)). We included all drug doses and routes of administration.
DATA COLLECTION AND ANALYSIS
Two review authors independently identified eligible trials, extracted data, assessed risk of bias, and applied the GRADE approach to assess the certainty of the evidence. The primary outcomes were cognition, clinical global impression, function (performance of activities of daily living), and adverse events. Secondary outcomes were serious adverse events, incidence of development of new dementia, behavioural disturbance, carer burden, institutionalisation, quality of life and death. For the pairwise analyses, we pooled outcome data at similar time points using random-effects methods. We also performed a network meta-analysis using Bayesian methods.
MAIN RESULTS
We included eight trials (4373 participants) in the review. Three trials studied donepezil 5 mg or 10 mg daily (n= 2193); three trials studied rivastigmine at a maximum daily dose of 3 to 12 mg (n= 800); and two trials studied galantamine at a maximum daily dose of 16 to 24 mg (n= 1380). The trials included participants with possible or probable vascular dementia or cognitive impairment following stroke. Mean ages were between 72.2 and 73.9 years. All of the trials were at low or unclear risk of bias in all domains, and the evidence ranged from very low to high level of certainty. For cognition, the results showed that donepezil 5 mg improves cognition slightly, although the size of the effect is unlikely to be clinically important (mean difference (MD) -0.92 Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog) points (range 0 to 70), 95% confidence interval (CI) -1.44 to -0.40; high-certainty evidence). Donepezil 10 mg (MD -2.21 ADAS-Cog points, 95% CI -3.07 to -1.35; moderate-certainty evidence) and galantamine 16 to 24 mg (MD -2.01 ADAS-Cog point, 95%CI -3.18 to -0.85; moderate-certainty evidence) probably also improve cognition, although the larger effect estimates still may not be clinically important. With low certainty, there may be little to no effect of rivastigmine 3 to 12 mg daily on cognition (MD 0.03 ADAS-Cog points, 95% CI -3.04 to 3.10; low-certainty evidence). Adverse events reported in the studies included nausea and/or vomiting, diarrhoea, dizziness, headache, and hypertension. The results showed that there was probably little to no difference between donepezil 5 mg and placebo in the number of adverse events (odds ratio (OR) 1.22, 95% CI 0.94 to 1.58; moderate-certainty evidence), but there were slightly more adverse events with donepezil 10 mg than with placebo (OR 1.95, 95% CI 1.20 to 3.15; high-certainty evidence). The effect of rivastigmine 3 to 12 mg on adverse events was very uncertain (OR 3.21, 95% CI 0.36 to 28.88; very low-certainty evidence). Galantamine 16 to 24 mg is probably associated with a slight excess of adverse events over placebo (OR 1.57, 95% CI 1.02 to 2.43; moderate-certainty evidence). In the network meta-analysis (NMA), we included cognition to represent benefit, and adverse events to represent harm. All drugs ranked above placebo for cognition and below placebo for adverse events. We found donepezil 10 mg to rank first in terms of benefit, but third in terms of harms, when considering the network estimates and quality of evidence. Galantamine was ranked second in terms of both benefit and harm. Rivastigmine had the lowest ranking of the cholinesterase inhibitors in both benefit and harm NMA estimates, but this may reflect possibly inadequate doses received by some trial participants and small trial sample sizes.
AUTHORS' CONCLUSIONS
We found moderate- to high-certainty evidence that donepezil 5 mg, donepezil 10 mg, and galantamine have a slight beneficial effect on cognition in people with VCI, although the size of the change is unlikely to be clinically important. Donepezil 10 mg and galantamine 16 to 24 mg are probably associated with more adverse events than placebo. The evidence for rivastigmine was less certain. The data suggest that donepezil 10 mg has the greatest effect on cognition, but at the cost of adverse effects. The effect is modest, but in the absence of any other treatments, people living with VCI may still wish to consider the use of these agents. Further research into rivastigmine is needed, including the use of transdermal patches.
Topics: Activities of Daily Living; Bias; Cholinesterase Inhibitors; Cognition; Dementia, Vascular; Donepezil; Galantamine; Humans; Network Meta-Analysis; Nootropic Agents; Physical Functional Performance; Placebos; Randomized Controlled Trials as Topic; Rivastigmine
PubMed: 33704781
DOI: 10.1002/14651858.CD013306.pub2 -
The Cochrane Database of Systematic... Aug 2020Asthma is an illness that commonly affects adults and children, and it serves as a common reason for children to attend emergency departments. An asthma exacerbation is...
BACKGROUND
Asthma is an illness that commonly affects adults and children, and it serves as a common reason for children to attend emergency departments. An asthma exacerbation is characterised by acute or subacute worsening of shortness of breath, cough, wheezing, and chest tightness and may be triggered by viral respiratory infection, poor compliance with usual medication, a change in the weather, or exposure to allergens or irritants. Most children with asthma have mild or moderate exacerbations and respond well to first-line therapy (inhaled short-acting beta-agonists and systemic corticosteroids). However, the best treatment for the small proportion of seriously ill children who do not respond to first-line therapy is not well understood. Currently, a large number of treatment options are available and there is wide variation in management.
OBJECTIVES
Main objective - To summarise Cochrane Reviews with or without meta-analyses of randomised controlled trials on the efficacy and safety of second-line treatment for children with acute exacerbations of asthma (i.e. after first-line treatments, titrated oxygen delivery, and administration of intermittent inhaled short-acting beta-agonists and oral corticosteroids have been tried and have failed) Secondary objectives - To identify gaps in the current evidence base that will inform recommendations for future research and subsequent Cochrane Reviews - To categorise information on reported outcome measures used in trials of escalation of treatment for acute exacerbations of asthma in children, and to make recommendations for development and reporting of standard outcomes in future trials and reviews - To identify relevant randomised controlled trials that have been published since the date of publication of each included review METHODS: We included Cochrane Reviews assessing interventions for children with acute exacerbations of asthma. We searched the Cochrane Database of Systematic Reviews. The search is current to 28 December 2019. We also identified trials that were potentially eligible for, but were not currently included in, published reviews. We assessed the quality of included reviews using the ROBIS criteria (tool used to assess risk of bias in systematic reviews). We presented an evidence synthesis of data from reviews alongside an evidence map of clinical trials. Primary outcomes were length of stay, hospital admission, intensive care unit admission, and adverse effects. We summarised all findings in the text and reported data for each outcome in 'Additional tables'.
MAIN RESULTS
We identified 17 potentially eligible Cochrane Reviews but extracted data from, and rated the quality of, 13 reviews that reported results for children alone. We excluded four reviews as one did not include any randomised controlled trials (RCTs), one did not provide subgroup data for children, and the last two had been updated and replaced by subsequent reviews. The 13 reviews included 67 trials; the number of trials in each review ranged from a single trial up to 27 trials. The vast majority of comparisons included between one and three trials, involving fewer than 100 participants. The total number of participants included in reviews ranged from 40 to 2630. All studies included children; 16 (24%) included children younger than two years of age. Most of the reviews reported search dates older than four years. We have summarised the published evidence as outlined in Cochrane Reviews. Key findings, in terms of our primary outcomes, are that (1) intravenous magnesium sulfate was the only intervention shown to reduce hospital length of stay (high-certainty evidence); (2) no evidence suggested that any intervention reduced the risk of intensive care admission (low- to very low-certainty evidence); (3) the risk of hospital admission was reduced by the addition of inhaled anticholinergic agents to inhaled beta-agonists (moderate-certainty evidence), the use of intravenous magnesium sulfate (high-certainty evidence), and the use of inhaled heliox (low-certainty evidence); (4) the addition of inhaled magnesium sulfate to usual bronchodilator therapy appears to reduce serious adverse events during hospital admission (moderate-certainty evidence); (5) aminophylline increased vomiting compared to placebo (moderate-certainty evidence) and increased nausea and nausea/vomiting compared to intravenous beta-agonists (low-certainty evidence); and (6) the addition of anticholinergic therapy to short-acting beta-agonists appeared to reduce the risk of nausea (high-certainty evidence) and tremor (moderate-certainty evidence) but not vomiting (low-certainty evidence). We considered 4 of the 13 reviews to be at high risk of bias based on the ROBIS framework. In all cases, this was due to concerns regarding identification and selection of studies. The certainty of evidence varied widely (by review and also by outcome) and ranged from very low to high.
AUTHORS' CONCLUSIONS
This overview provides the most up-to-date evidence on interventions for escalation of therapy for acute exacerbations of asthma in children from Cochrane Reviews of randomised controlled trials. A vast majority of comparisons involved between one and three trials and fewer than 100 participants, making it difficult to assess the balance between benefits and potential harms. Due to the lack of comparative studies between various treatment options, we are unable to make firm practice recommendations. Intravenous magnesium sulfate appears to reduce both hospital length of stay and the risk of hospital admission. Hospital admission is also reduced with the addition of inhaled anticholinergic agents to inhaled beta-agonists. However, further research is required to determine which patients are most likely to benefit from these therapies. Due to the relatively rare incidence of acute severe paediatric asthma, multi-centre research will be required to generate high-quality evidence. A number of existing Cochrane Reviews should be updated, and we recommend that a new review be conducted on the use of high-flow nasal oxygen therapy. Important priorities include development of an internationally agreed core outcome set for future trials in acute severe asthma exacerbations and determination of clinically important differences in these outcomes, which can then inform adequately powered future trials.
Topics: Acute Disease; Administration, Inhalation; Adrenergic beta-2 Receptor Agonists; Aminophylline; Anti-Asthmatic Agents; Anti-Bacterial Agents; Asthma; Bias; Bronchodilator Agents; Child; Child, Preschool; Cholinergic Antagonists; Disease Progression; Helium; Humans; Infant; Length of Stay; Leukotriene Antagonists; Magnesium Sulfate; Nausea; Oxygen; Positive-Pressure Respiration; Randomized Controlled Trials as Topic; Systematic Reviews as Topic; Vomiting; Work of Breathing
PubMed: 32767571
DOI: 10.1002/14651858.CD012977.pub2 -
The Cochrane Database of Systematic... Dec 2018Long-acting bronchodilators such as long-acting β-agonist (LABA), long-acting muscarinic antagonist (LAMA), and LABA/inhaled corticosteroid (ICS) combinations have been... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Long-acting bronchodilators such as long-acting β-agonist (LABA), long-acting muscarinic antagonist (LAMA), and LABA/inhaled corticosteroid (ICS) combinations have been used in people with moderate to severe chronic obstructive pulmonary disease (COPD) to control symptoms such as dyspnoea and cough, and prevent exacerbations. A number of LABA/LAMA combinations are now available for clinical use in COPD. However, it is not clear which group of above mentioned inhalers is most effective or if any specific formulation works better than the others within the same group or class.
OBJECTIVES
To compare the efficacy and safety of available formulations from four different groups of inhalers (i.e. LABA/LAMA combination, LABA/ICS combination, LAMA and LABA) in people with moderate to severe COPD. The review will update previous systematic reviews on dual combination inhalers and long-acting bronchodilators to answer the questions described above using the strength of a network meta-analysis (NMA).
SEARCH METHODS
We identified studies from the Cochrane Airways Specialised Register, which contains several databases. We also conducted a search of ClinicalTrials.gov and manufacturers' websites. The most recent searches were conducted on 6 April 2018.
SELECTION CRITERIA
We included randomised controlled trials (RCTs) that recruited people aged 35 years or older with a diagnosis of COPD and a baseline forced expiratory volume in one second (FEV1) of less than 80% of predicted. We included studies of at least 12 weeks' duration including at least two active comparators from one of the four inhaler groups.
DATA COLLECTION AND ANALYSIS
We conducted NMAs using a Bayesian Markov chain Monte Carlo method. We considered a study as high risk if recruited participants had at least one COPD exacerbation within the 12 months before study entry and as low risk otherwise. Primary outcomes were COPD exacerbations (moderate to severe and severe), and secondary outcomes included symptom and quality-of-life scores, safety outcomes, and lung function. We collected data only for active comparators and did not consider placebo was not considered. We assumed a class/group effect when a fixed-class model fitted well. Otherwise we used a random-class model to assess intraclass/group differences. We supplemented the NMAs with pairwise meta-analyses.
MAIN RESULTS
We included a total of 101,311 participants from 99 studies (26 studies with 32,265 participants in the high-risk population and 73 studies with 69,046 participants in the low-risk population) in our systematic review. The median duration of studies was 52 weeks in the high-risk population and 26 weeks in the low-risk population (range 12 to 156 for both populations). We considered the quality of included studies generally to be good.The NMAs suggested that the LABA/LAMA combination was the highest ranked treatment group to reduce COPD exacerbations followed by LAMA in the both populations.There is evidence that the LABA/LAMA combination decreases moderate to severe exacerbations compared to LABA/ICS combination, LAMA, and LABA in the high-risk population (network hazard ratios (HRs) 0.86 (95% credible interval (CrI) 0.76 to 0.99), 0.87 (95% CrI 0.78 to 0.99), and 0.70 (95% CrI 0.61 to 0.8) respectively), and that LAMA decreases moderate to severe exacerbations compared to LABA in the high- and low-risk populations (network HR 0.80 (95% CrI 0.71 to 0.88) and 0.87 (95% CrI 0.78 to 0.97), respectively). There is evidence that the LABA/LAMA combination reduces severe exacerbations compared to LABA/ICS combination and LABA in the high-risk population (network HR 0.78 (95% CrI 0.64 to 0.93) and 0.64 (95% CrI 0.51 to 0.81), respectively).There was a general trend towards a greater improvement in symptom and quality-of-life scores with the combination therapies compared to monotherapies, and the combination therapies were generally ranked higher than monotherapies.The LABA/ICS combination was the lowest ranked in pneumonia serious adverse events (SAEs) in both populations. There is evidence that the LABA/ICS combination increases the odds of pneumonia compared to LAMA/LABA combination, LAMA and LABA (network ORs: 1.69 (95% CrI 1.20 to 2.44), 1.78 (95% CrI 1.33 to 2.39), and 1.50 (95% CrI 1.17 to 1.92) in the high-risk population and network or pairwise OR: 2.33 (95% CI 1.03 to 5.26), 2.02 (95% CrI 1.16 to 3.72), and 1.93 (95% CrI 1.29 to 3.22) in the low-risk population respectively). There were significant overlaps in the rank statistics in the other safety outcomes including mortality, total, COPD, and cardiac SAEs, and dropouts due to adverse events.None of the differences in lung function met a minimal clinically important difference criterion except for LABA/LAMA combination versus LABA in the high-risk population (network mean difference 0.13 L (95% CrI 0.10 to 0.15). The results of pairwise meta-analyses generally agreed with those of the NMAs. There is no evidence to suggest intraclass/group differences except for lung function at 12 months in the high-risk population.
AUTHORS' CONCLUSIONS
The LABA/LAMA combination was the highest ranked treatment group to reduce COPD exacerbations although there was some uncertainty in the results. LAMA containing inhalers may have an advantage over those without a LAMA for preventing COPD exacerbations based on the rank statistics. Combination therapies appear more effective than monotherapies for improving symptom and quality-of-life scores. ICS-containing inhalers are associated with an increased risk of pneumonia.Our most comprehensive review including intraclass/group comparisons, free combination therapies, 99 studies, and 20 outcomes for each high- and low-risk population summarises the current literature and could help with updating existing COPD guidelines.
Topics: Administration, Inhalation; Adrenal Cortex Hormones; Adrenergic beta-2 Receptor Agonists; Adult; Bayes Theorem; Bronchodilator Agents; Disease Progression; Drug Therapy, Combination; Humans; Middle Aged; Monte Carlo Method; Muscarinic Antagonists; Network Meta-Analysis; Pneumonia; Pulmonary Disease, Chronic Obstructive; Randomized Controlled Trials as Topic; Secondary Prevention
PubMed: 30521694
DOI: 10.1002/14651858.CD012620.pub2 -
The Cochrane Database of Systematic... Jun 2023Autism spectrum disorder (autism) is a neurodevelopmental condition characterised by impairments in social communication and interaction, plus restricted, repetitive... (Review)
Review
BACKGROUND
Autism spectrum disorder (autism) is a neurodevelopmental condition characterised by impairments in social communication and interaction, plus restricted, repetitive patterns of behaviour and interests. Whilst some people embrace autism as part of their identity, others struggle with their difficulties, and some seek treatment. There are no current interventions that result in complete reduction of autism features. Acetylcholine is a neurotransmitter for the cholinergic system and has a role in attention, novelty seeking, and memory. Low levels of acetylcholine have been investigated as a potential contributor to autism symptomatology. Donepezil, galantamine, and rivastigmine (commonly referred to as acetylcholinesterase inhibitors) all inhibit acetylcholinesterase, and have slightly different modes of action and biological availability, so their effectiveness and side-effect profiles may vary. The effect of various acetylcholinesterase inhibitor on core autism features across the lifespan, and possible adverse effects, have not been thoroughly investigated.
OBJECTIVES
To evaluate the efficacy and harms of acetylcholinesterase inhibitors for people with the core features (social interaction, communication, and restrictive and repetitive behaviours) of autism. To assess the effects of acetylcholinesterase inhibitors on non-core features of autism.
SEARCH METHODS
In November 2022, we searched CENTRAL, MEDLINE, Embase, eight other databases, and two trials registers. We also searched the reference lists of included studies and relevant reviews, and contacted authors of relevant studies.
SELECTION CRITERIA
Randomised controlled trials (RCTs), comparing acetylcholinesterase inhibitors (e.g. galantamine, donepezil, or rivastigmine) of varying doses, delivered orally or via transdermal patch, either as monotherapy or adjunct therapy, with placebo. People of any age, with a clinical diagnosis of autism were eligible for inclusion.
DATA COLLECTION AND ANALYSIS
We used standard methodological procedures expected by Cochrane. Our primary outcomes were core features of autism and adverse effects. Secondary outcomes were language, irritability, hyperactivity, and general health and function. We used GRADE to assess certainty of evidence.
MAIN RESULTS
We included two RCTs (74 participants). One study was conducted in Iran, the second in the USA, although exact location in the USA is unclear. Galantamine plus risperidone versus placebo plus risperidone One study compared the effects of galantamine plus risperidone to placebo plus risperidone (40 participants, aged 4 years to 12 years). Primary and secondary outcomes of interest were measured postintervention, using subscales of the Aberrant Behavior Checklist (score 0 to 3; higher scores = greater impairment). Very low-certainty evidence showed there was little to no difference between the two groups postintervention for social communication (mean difference (MD) -2.75, 95% confidence interval (CI) -5.88 to 0.38), and restricted and repetitive behaviour (MD -0.55, 95% CI -3.47 to 2.37). Overall autism features were not assessed. Adverse events may be higher in the galantamine plus risperidone group (75%) compared with the placebo plus risperidone group (35%): odds ratio 5.57, 95% CI 1.42 to 21.86, low-certainty evidence. No serious adverse events were reported. Low-certainty evidence showed a small difference in irritability (MD -3.50, 95% CI -6.39 to -0.61), with the galantamine plus risperidone group showing a greater decline on the irritability subscale than the placebo group postintervention. There was no evidence of a difference between the groups in hyperactivity postintervention (MD -5.20, 95% CI -10.51 to 0.11). General health and function were not assessed. Donepezil versus placebo One study compared donepezil to placebo (34 participants aged 8 years to 17 years). Primary outcomes of interest were measured postintervention, using subscales of the Modified Version of The Real Life Rating Scale (scored 0 to 3; higher scores = greater impairment). Very low-certainty evidence showed no evidence of group differences immediately postintervention in overall autism features (MD 0.07, 95% CI -0.19 to 0.33), or in the autism symptom domains of social communication (MD -0.02, 95% CI -0.34 to 0.30), and restricted and repetitive behaviours (MD 0.04, 95% CI -0.27 to 0.35). Significant adverse events leading to study withdrawal in at least one participant was implied in the data analysis section, but not explicitly reported. The evidence is very uncertain about the effect of donepezil, compared to placebo, on the secondary outcomes of interest, including irritability (MD 1.08, 95% CI -0.41 to 2.57), hyperactivity (MD 2.60, 95% CI 0.50 to 4.70), and general health and function (MD 0.03, 95% CI -0.48 to 0.54) postintervention. Across all analyses within this comparison, we judged the evidence to be very low-certainty due to high risk of bias, and very serious imprecision (results based on one small study with wide confidence intervals). The study narratively reported adverse events for the study as a whole, rather than by treatment group.
AUTHORS' CONCLUSIONS
Evidence about the effectiveness of acetylcholinesterase inhibitors as a medication to improve outcomes for autistic adults is lacking, and for autistic children is very uncertain. There is a need for more evidence of improvement in outcomes of relevance to clinical care, autistic people, and their families. There are a number of ongoing studies involving acetylcholinesterase inhibitors, and future updates of this review may add to the current evidence.
Topics: Child; Humans; Acetylcholine; Autism Spectrum Disorder; Cholinesterase Inhibitors; Donepezil; Galantamine; Risperidone; Rivastigmine; Child, Preschool; Adolescent
PubMed: 37267443
DOI: 10.1002/14651858.CD013851.pub2 -
Toxins Oct 2022Disabling limb spasticity can result from stroke, traumatic brain injury or other disorders causing upper motor neuron lesions such as multiple sclerosis. Clinical... (Review)
Review
Disabling limb spasticity can result from stroke, traumatic brain injury or other disorders causing upper motor neuron lesions such as multiple sclerosis. Clinical studies have shown that abobotulinumtoxinA (AboBoNT-A) therapy reduces upper and lower limb spasticity in adults. However, physicians may administer potentially inadequate doses, given the lack of consensus on adjusting dose according to muscle volume, the wide dose ranges in the summary of product characteristics or cited in the published literature, and/or the high quantity of toxin available for injection. Against this background, a systematic literature review based on searches of MEDLINE and Embase (via Ovid SP) and three relevant conferences (2018 to 2020) was conducted in November 2020 to examine AboBoNT-A doses given to adults for upper or lower limb muscles affected by spasticity of any etiology in clinical and real-world evidence studies. From the 1781 unique records identified from the electronic databases and conference proceedings screened, 49 unique studies represented across 56 publications (53 full-text articles, 3 conference abstracts) were eligible for inclusion. Evidence from these studies suggested that AboBoNT-A dose given per muscle in clinical practice varies considerably, with only a slight trend toward a relationship between dose and muscle volume. Expert-based consensus is needed to inform recommendations for standardizing AboBoNT-A treatment initiation doses based on muscle volume.
Topics: Adult; Humans; Injections, Intramuscular; Treatment Outcome; Botulinum Toxins, Type A; Muscle Spasticity; Stroke; Lower Extremity; Neuromuscular Agents; Upper Extremity
PubMed: 36355984
DOI: 10.3390/toxins14110734 -
Respiratory Research Nov 2017Long-acting bronchodilators are the cornerstone of pharmacologic treatment of COPD. The new combination of long-acting muscarinic antagonist (LAMA) tiotropium (TIO) and... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Long-acting bronchodilators are the cornerstone of pharmacologic treatment of COPD. The new combination of long-acting muscarinic antagonist (LAMA) tiotropium (TIO) and long acting beta-agonists (LABA) olodaterol (OLO) has been introduced as fist line therapy for COPD. This article analyses the evidence of efficacy and safety of the TIO/OLO combination.
METHODS
A systematic review and metaanalysis of randomized controlled trials (RCT) with a period of treatment of at least 6 weeks, in patients with COPD confirmed by spirometry, comparing combined treatment with TIO/OLO (approved doses only), with any of the mono-components or any other active comparator administered as an inhalator.
RESULTS
A total of 10 Randomized controlled trials (RCT) were identified (N = 10,918). TIO/OLO significantly improved trough FEV from baseline to week 12 versus TIO, OLO and LABA/ICS (0.06 L, 0.09 L and between 0.04 and 0.05 L, respectively). TIO/OLO improved transitional dyspnea index (TDI) and St. George's Respiratory Questionnaire (SGRQ) compared with mono-components, with patients more likely to achieve clinically important improvements in TDI (risk ratio [RR]: 1.17, 95% confidence interval [CI]: [1.07, 1.28] versus TIO and RR: 1.14, 95%CI: [1.01, 1.28] versus OLO) and in SGRQ (RR: 1.21, 95%CI: [1.12, 1.30] versus TIO and RR: 1.28, 95%CI: [1.18, 1.40] versus OLO). Patients treated with TIO/OLO showed a significant reduction in the use of rescue medication and no significant differences in frequency of general and serious adverse events were observed between TIO/OLO and mono-components.
CONCLUSIONS
Treatment with TIO/OLO provided significant improvements in lung function versus mono-components and LABA/ICS with more patients achieving significant improvements in dyspnea and health status. No differences in adverse events were observed compared with other active treatments.
CLINICAL TRIAL REGISTRATION
PROSPERO register of systematic reviews ( CRD42016040162 ).
Topics: Administration, Inhalation; Adrenergic beta-2 Receptor Agonists; Benzoxazines; Bronchodilator Agents; Drug Combinations; Forced Expiratory Volume; Humans; Muscarinic Antagonists; Pulmonary Disease, Chronic Obstructive; Randomized Controlled Trials as Topic; Spirometry; Tiotropium Bromide; Treatment Outcome
PubMed: 29178871
DOI: 10.1186/s12931-017-0683-x -
Urologia Internationalis 2023The aim of the study was to assess the effectiveness of the main classes of drugs used at reducing morbidity related to ureteric stents.
BACKGROUND
The aim of the study was to assess the effectiveness of the main classes of drugs used at reducing morbidity related to ureteric stents.
SUMMARY
After establishing a priori protocol, a systematic electronic literature search was conducted in July 2019. The randomized clinical trials (RCTs) selection proceeded in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines and was registered (PROSPERO ID 178130). The risk of bias and the quality assessment of the included RCTs were performed. Ureteral Stent Symptom Questionnaire (USSQ), International Prostate Symptom Score (IPSS), and quality of life (QoL) were pooled for meta-analysis. Mean difference and risk difference were calculated as appropriate for each outcome to determine the cumulative effect size. Fourteen RCTs were included in the analysis accounting for 2,842 patients. Alpha antagonist, antimuscarinic, and phosphodiesterase (PDE) inhibitors significatively reduced all indexes of the USSQ, the IPSS and QoL scores relative to placebo. Conversely, combination therapy (alpha antagonist plus antimuscarinic) showed in all indexes of the USSQ, IPSS, and QoL over alpha antagonist or antimuscarinic alone. On comparison with alpha blockers, PDE inhibitors were found to be equally effective for urinary symptoms, general health, and body pain parameters, but sexual health parameters improved significantly with PDE inhibitors. Finally, antimuscarinic resulted in higher decrease in all indexes of the USSQ, the IPSS, and QoL relative to alpha antagonist.
KEY MESSAGE
Relative to placebo, alpha antagonist alone, antimuscarinics alone, and PDE inhibitors alone have beneficial effect in reducing stent-related symptoms. Furthermore, there are significant advantages of combination therapy compared with monotherapy. Finally, PDE inhibitors are comparable to alpha antagonist, and antimuscarinic seems to be more effective than alpha antagonist alone.
Topics: Humans; Male; Adrenergic alpha-Antagonists; Muscarinic Antagonists; Pain; Quality of Life; Stents; Ureter
PubMed: 34818261
DOI: 10.1159/000518387 -
Drugs & Aging Nov 2023The acetylcholinesterase inhibitors (AChEIs) donepezil, galantamine, and rivastigmine are commonly used in the management of various forms of dementia. (Meta-Analysis)
Meta-Analysis
BACKGROUND
The acetylcholinesterase inhibitors (AChEIs) donepezil, galantamine, and rivastigmine are commonly used in the management of various forms of dementia.
OBJECTIVES
While these drugs are known to induce classic cholinergic adverse events such as diarrhea, their potential to cause psychiatric adverse events has yet to be thoroughly examined.
METHODS
We sought to determine the risk of psychiatric adverse events associated with the use of AChEIs through a systematic review and meta-analysis of double-blind randomized controlled trials involving patients with Alzheimer's dementia and Parkinson's dementia.
RESULTS
A total of 48 trials encompassing 22,845 patients were included in our analysis. Anorexia was the most commonly reported psychiatric adverse event, followed by agitation, insomnia, and depression. Individuals exposed to AChEIs had a greater risk of experiencing appetite disorders, insomnia, or depression compared with those who received placebo (anorexia: odds ratio [OR] 2.93, 95% confidence interval [CI] 2.29-3.75; p < 0.00001; decreased appetite: OR 1.93, 95% CI 1.33-2.82; p = 0.0006; insomnia: OR 1.55, 95% CI 1.25-1.93; p < 0.0001; and depression: OR 1.59, 95% CI 1.23-2.06, p = 0.0004). Appetite disorders were also more frequent with high-dose versus low-dose therapy. A subgroup analysis revealed that the risk of insomnia was higher for donepezil than for galantamine.
CONCLUSIONS
Our findings suggest that AChEI therapy may negatively impact psychological health, and careful monitoring of new psychiatric symptoms is warranted. Lowering the dose may resolve some psychiatric adverse events, as may switching to galantamine in the case of insomnia.
CLINICAL TRIAL REGISTRATION
The study was pre-registered on PROSPERO (CRD42021258376).
Topics: Humans; Acetylcholinesterase; Alzheimer Disease; Anorexia; Cholinesterase Inhibitors; Donepezil; Galantamine; Parkinson Disease; Phenylcarbamates; Randomized Controlled Trials as Topic; Rivastigmine; Sleep Initiation and Maintenance Disorders
PubMed: 37682445
DOI: 10.1007/s40266-023-01065-x