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BACKGROUND: Age-related macular degeneration (AMD) is a highly prevalent condition in an ever-increasing elderly population. Although insidious in the early stages, advanced AMD (neovascular and atrophic forms) can cause significant visual disability and economic burden on health systems worldwide. The most common form, geographic atrophy, has no effective treatment to date, whereas neovascular AMD can be treated with intravitreal anti-vascular endothelial growth factor (anti-VEGF) injections. Geographic atrophy has a slow disease progression and patients tend to have preserved central vision until the final stages. This tendency, coupled with the use of modern imaging modalities, provides a large window of opportunity to intervene with validated methods to assess treatment efficacy. As geographic atrophy is an increasingly common condition with no effective intervention, many treatments are under investigation, one of which is visual cycle modulators. These medications have been shown to reduce lipofuscin accumulation in pre-clinical studies that have led to several clinical trials, reviewed herein. OBJECTIVES: To assess the efficacy and safety of visual cycle modulators for the prevention and treatment of geographic atrophy secondary to AMD. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (which contains the Cochrane Eyes and Vision Trials Register) (2020, Issue 1); MEDLINE Ovid; Embase Ovid; Web of Science Core Collection; Scopus; Association for Research in Vision and Ophthalmology (ARVO) website; ClinicalTrials.gov and the WHO ICTRP to 11 January 2020 with no language restrictions. We also searched using the reference lists of reviews and existing studies and the Cited Reference Search function in Web of Science to identify further relevant studies. SELECTION CRITERIA: We included randomised controlled trials (RCTs) and quasi-randomised clinical studies (if available) that compared visual cycle modulators to placebo or no treatment (observation) in people diagnosed with AMD (early, intermediate or geographic atrophy). DATA COLLECTION AND ANALYSIS: Two authors independently assessed risk of bias in the included studies and extracted data. Both authors entered data into RevMan 5. We resolved discrepancies through discussion. We graded the certainty of the evidence using the GRADE approach. MAIN RESULTS: We included three RCTs from the USA; one of these had clinical sites in Germany. Two studies compared emixustat to placebo while the other compared fenretinide to placebo. All assigned one study eye per participant and, combined, have a total of 821 participants with a majority white ethnicity (97.6%). All participants were diagnosed with geographic atrophy due to AMD based on validated imaging modalities. All three studies have high risk of attrition bias mainly due to ocular adverse effects of emixustat and fenretinide. We considered only one study to be adequately conducted and reported with high risk of bias in only one domain (attrition bias). We considered the other two studies to be poorly reported and to have high risk of attrition bias and reporting bias. People with geographic atrophy treated with emixustat may not experience a clinically important change in best-corrected visual acuity (BCVA) between baseline and 24 months compared to people treated with placebo (mean difference (MD) 1.9 Early Treatment Diabetic Retinopathy Study (ETDRS) letters, 95% confidence interval (CI) -2.34 to 6.14, low-certainty evidence). Emixustat may also result in little or no difference in loss of 15 ETDRS letters or more of BCVA compared with placebo at 24 months (16.4% versus 18%) (risk ratio (RR) 0.91, 95% CI 0.59 to 1.4, low-certainty evidence). In terms of disease progression, emixustat may result in little or no difference in the annual growth rate of geographic atrophy compared with placebo (mean difference MD 0.09 mm2/year (95% CI -0.26 to 0.44, low-certainty evidence). All three studies reported adverse events of both drugs (emixustat: moderate-certainty evidence; fenretinide: low-certainty evidence). The main adverse events were ocular in nature and associated with the mechanism of action of the drugs. Delayed dark adaptation (emixustat: 54.5%; fenretinide: 39.3%) and chromatopsia (emixustat: 22.6%; fenretinide: 25.2%) were the most common adverse events reported, and were the most prevalent reasons for study dropout in emixustat trials. These effects were dose-dependent and resolved after drug cessation. No specific systemic adverse events were considered related to emixustat; only pruritus and rash were considered to be due to fenretinide. One emixustat study reported six deaths, none deemed related to the drug. None of the included RCTs reported the other pre-specified outcomes, including proportion of participants losing 10 letters or more, and mean change in macular sensitivity. We planned to investigate progression to advanced AMD (geographic atrophy or neovascular AMD) in prevention studies, including participants with early or intermediate AMD, but we identified no such studies. Two of the included studies reported an additional outcome - incidence of choroidal neovascularisation (CNV) - that was not in our published protocol. CNV onset may be reduced in those treated with emixustat but the evidence was uncertain (risk ratio (RR) 0.67, 95% CI 0.27 to 1.65, low-certainty evidence), or fenretinide (RR 0.5, 95% CI 0.26 to 0.98, low-certainty evidence) compared to placebo. A dose-dependent relationship was observed with emixustat. AUTHORS' CONCLUSIONS: There is limited evidence to support the use of visual cycle modulators (emixustat and fenretinide) for the treatment of established geographic atrophy due to AMD. The possible reduction in the incidence of CNV observed with fenretinide, and to a lesser extent, emixustat, requires formal assessment in focused studies.
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Fenretinida/uso terapéutico , Atrofia Geográfica/tratamiento farmacológico , Atrofia Geográfica/prevención & control , Degeneración Macular/complicaciones , Éteres Fenílicos/uso terapéutico , Propanolaminas/uso terapéutico , Espera Vigilante , Anciano , Anciano de 80 o más Años , Neovascularización Coroidal/epidemiología , Ensayos Clínicos Fase II como Asunto , Progresión de la Enfermedad , Fenretinida/efectos adversos , Atrofia Geográfica/etiología , Humanos , Incidencia , Éteres Fenílicos/efectos adversos , Placebos/uso terapéutico , Propanolaminas/efectos adversos , Ensayos Clínicos Controlados Aleatorios como Asunto , Agudeza Visual/efectos de los fármacosRESUMEN
BACKGROUND: A review of therapies for advanced cancers licenced by the EMA between 2009 and 2013 concluded that for more than half of these drugs there was little evidence of overall survival or quality of life benefit. Recent years have witnessed a growing number of licensed second-line pharmacotherapies for advanced/metastatic non-small cell lung cancer (NSCLC). With the aim of gauging patient survival benefit, we conducted a systematic review of randomised controlled trials (RCT) and compared survival outcomes from available licensed treatments for patients with advanced/metastatic NSCLC. METHODS: RCTs of second/third line treatments in participants with advanced/metastatic NSCLC and negative/low expression of Anaplastic Lymphoma Kinase (ALK) and of Epidermal Growth Factor Receptor (EGFR) were included. We searched electronic databases (MEDLINE; EMBASE; Web of Science) from January, 2000 up to July, 2017. Two or more independent reviewers screened bibliographic records, extracted data, and assessed risk of bias of studies. Published Kaplan Meier plots for OS and PFS along with restricted-mean-survival methods and parametric modelling were used to estimate the survival outcomes as mean number of months of survival. Network meta-analysis was undertaken to rank interventions and to make indirect comparisons. RESULTS: We included 11 RCTs with data for 7581 participants that compared nine different drugs. In studies of patients regardless of histology groups, targeted drugs (ramucirumab and nintedanib) yielded small overall survival gains of < 2.5 months over docetaxel, erlotinib provided no benefit, while immunotherapies (atezolizumab and pembrolizumab) delivered 5 to 6 months gain. Studies with patients stratified by histology confirmed the apparent superiority of immunotherapy (nivolumab and atezolizumab) over targeted treatments (ramucirumab, nintedanib, afatinib) providing between about 4 to 8 months OS gain over docetaxel. In network analysis immunotherapies consistently ranked higher than alternatives irrespective of population histology and outcome measure. CONCLUSION: Our review indicates that nivolumab, pembrolizumab and atezolizumab provide superior survival benefits compared to other licensed drugs for late stage NSCLC. Patient gains from these immunotherapies are substantial compared to the expected average survival with chemotherapy (docetaxel) of < 1 year for people with squamous histology and about 1.25 year for those with non-squamous histology.
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Quinasa de Linfoma Anaplásico/genética , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Anticuerpos Monoclonales/uso terapéutico , Anticuerpos Monoclonales Humanizados , Carcinoma de Pulmón de Células no Pequeñas/genética , Carcinoma de Pulmón de Células no Pequeñas/patología , Receptores ErbB/genética , Clorhidrato de Erlotinib/uso terapéutico , Humanos , Inmunoterapia , Metástasis de la Neoplasia , Neoplasias Primarias Secundarias/tratamiento farmacológico , Neoplasias Primarias Secundarias/genética , Neoplasias Primarias Secundarias/patología , Supervivencia sin Progresión , Inhibidores de Proteínas Quinasas/uso terapéutico , Calidad de Vida , Ensayos Clínicos Controlados Aleatorios como Asunto , RamucirumabRESUMEN
PURPOSE: To assess the clinical and cost-effectiveness of allografts versus autografts in the reconstruction of anterior cruciate ligaments. METHODS: Systematic review of comparative clinical effectiveness and cost-effectiveness analysis. RESULTS: Both autograft and allograft reconstruction are highly effective. Recent studies show little difference in failure rates between autografts and allografts (about 6% and 7%, respectively). In cost-effectiveness analysis, the price differential is the main factor, making autografts the first choice. However, there will be situations, particularly in revision ACL reconstruction, where an allograft may be preferred, or may be the only reasonable option available. CONCLUSION: In ACL reconstruction, clinical results with autografts are as good as or slightly better than with allografts. Allografts cost more, indicating that autografts are more cost-effective and should usually be first choice. LEVEL OF EVIDENCE: II.
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Aloinjertos/economía , Reconstrucción del Ligamento Cruzado Anterior/economía , Reconstrucción del Ligamento Cruzado Anterior/métodos , Autoinjertos/economía , Análisis Costo-Beneficio , Supervivencia de Injerto , Humanos , Metaanálisis como Asunto , Complicaciones Posoperatorias , Años de Vida Ajustados por Calidad de Vida , ReoperaciónRESUMEN
PURPOSE: To review the relative cost-effectiveness of allografts and autografts in reconstruction of the posterior cruciate ligament. METHODS: Systematic review and cost-effectiveness analysis. RESULTS: The available evidence does not show any significant difference in clinical effectiveness between autografts and allografts. Given that, only a cost analysis is provided, which shows that allografts are more costly. CONCLUSION: Given the lack of any benefit of allografts over autografts, autografts should be preferred on cost grounds, if available. However, there may be situations where an allograft is indicated, for example, in multiple ligament reconstructions. LEVEL OF EVIDENCE: IV.
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Aloinjertos/economía , Ligamento Cruzado Posterior/cirugía , Autoinjertos/economía , Análisis Costo-Beneficio , Supervivencia de Injerto , Humanos , Escala de Puntuación de Rodilla de Lysholm , Ligamento Cruzado Posterior/lesiones , Calidad de VidaRESUMEN
PURPOSE: Osteochondral allografts (OCA) consist of a layer of hyaline cartilage and a layer of underlying bone. They are used to repair combined defects of articular cartilage and bone. Such defects often occur in people far too young to have knee arthroplasty, for whom the main alternative to OCA is conservative symptomatic care, which will not prevent development of osteoarthritis. The aim of this report was to assess the cost-effectiveness of osteochondral allograft transplantation in the knee. METHODS: Systematic review of evidence on clinical effectiveness and economic modelling. RESULTS: The evidence on osteochondral allograft transplantation comes from observational studies, but often based on good quality prospective registries of all patients having such surgery. Without controlled trials, it was necessary to use historical cohorts to assess the effect of osteochondral grafts. There is good evidence that OCA are clinically effective with a high graft survival rate over 20 years. If an OCA graft fails, there is some evidence that revision with a second OCA is also effective, though less so than primary OCA. Economic modelling showed that osteochondral allograft transplantation was highly cost-effective, with costs per quality adjusted life year much lower than many other treatments considered cost effective. CONCLUSIONS: Osteochondral allograft transplantation appears highly cost-effective though the cost per quality adjusted life year varies according to the widely varying costs of allografts. Based on one small study, revision OCA also appears very cost-effective, but more evidence is needed. LEVEL OF EVIDENCE: II.
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Aloinjertos/economía , Trasplante Óseo/economía , Cartílago/trasplante , Supervivencia de Injerto , Articulación de la Rodilla/cirugía , Análisis Costo-Beneficio , Humanos , Modelos Económicos , Años de Vida Ajustados por Calidad de Vida , ReoperaciónRESUMEN
PURPOSE: To assess the clinical effectiveness and cost-effectiveness of meniscal allograft transplantation (MAT) after meniscal injury and subsequent meniscectomy. METHODS: Systematic review of clinical effectiveness and cost-effectiveness analysis. RESULTS: There is considerable evidence from observational studies, of improvement in symptoms after meniscal allograft transplantation, but we found only one small pilot trial with a randomised comparison with a control group that received non-surgical care. MAT has not yet been proven to be chondroprotective. Cost-effectiveness analysis is not possible due to a lack of data on the effectiveness of MAT compared to non-surgical care. CONCLUSION: The benefits of MAT include symptomatic relief and restoration of at least some previous activities, which will be reflected in utility values and hence in quality-adjusted life years, and in the longer term, prevention or delay of osteoarthritis, and avoidance or postponement of some knee replacements, with resulting savings. It is likely to be cost-effective, but this cannot be proven on the basis of present evidence. LEVEL OF EVIDENCE: IV.
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Meniscectomía/efectos adversos , Meniscos Tibiales/trasplante , Osteoartritis de la Rodilla/cirugía , Trasplante Homólogo/economía , Análisis Costo-Beneficio , Supervivencia de Injerto , Humanos , Osteoartritis de la Rodilla/etiología , Complicaciones Posoperatorias , Calidad de Vida , Reoperación/economía , Volver al DeporteRESUMEN
BACKGROUND: Using surrogate biomarkers for disease progression as endpoints in neuroprotective clinical trials may help differentiate symptomatic effects of potential neuroprotective agents from true disease-modifying effects. A systematic review was undertaken to determine what biomarkers for disease progression in Parkinson's disease (PD) exist. METHODS: MEDLINE and EMBASE (1950-2010) were searched using five search strategies. Abstracts were assessed to identify papers meriting review in full. Studies of participants with idiopathic PD diagnosed by formal criteria or clearly described clinical means were included. We made no restriction on age, disease duration, drug treatment, or study design. We included studies which attempted to draw associations between any tests used to investigate disease progression and any clinical measures of disease progression. The electronic search was validated by hand-searching the two journals from which most included articles came. RESULTS: 183 studies were included: 163 (89%) cross-sectional, 20 (11%) longitudinal. The electronic search strategy had a sensitivity of 71.4% (95% CI 51.1-86.0) and a specificity of 97.1% (95% CI 96.5-97.7). In longitudinal studies median follow-up was 2.0 years (IQR 1.1-3.5). Included studies were generally poor quality--cross-sectional with small numbers of participants, applying excessive inclusion/exclusion criteria, with flawed methodologies and simplistic statistical analyses. CONCLUSION: We found insufficient evidence to recommend the use of any biomarker for disease progression in PD clinical trials, which may simply reflect the poor quality of research in this area. We therefore present a provisional 'roadmap' for conducting future disease progression biomarker studies, and recommend new quality criteria by which future studies may be judged.
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Biomarcadores/metabolismo , Enfermedad de Parkinson/diagnóstico , Progresión de la Enfermedad , Humanos , Enfermedad de Parkinson/metabolismoRESUMEN
BACKGROUND: Making healthcare treatment decisions is a complex process involving a broad stakeholder base including patients, their families, health professionals, clinical practice guideline developers and funders of healthcare. METHODS: This paper presents a review of a methodology for the development of urological cancer care pathways (UCAN care pathways), which reflects an appreciation of this broad stakeholder base. The methods section includes an overview of the steps in the development of the UCAN care pathways and engagement with clinical content experts and patient groups. RESULTS: The development process is outlined, the uses of the urological cancer care pathways discussed and the implications for clinical practice highlighted. The full set of UCAN care pathways is published in this paper. These include care pathways on localised prostate cancer, locally advanced prostate cancer, metastatic prostate cancer, hormone-resistant prostate cancer, localised renal cell cancer, advanced renal cell cancer, testicular cancer, penile cancer, muscle invasive and metastatic bladder cancer and non-muscle invasive bladder cancer. CONCLUSION: The process provides a useful framework for improving urological cancer care through evidence synthesis, research prioritisation, stakeholder involvement and international collaboration. Although the focus of this work is urological cancers, the methodology can be applied to all aspects of urology and is transferable to other clinical specialties.
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Medicina Basada en la Evidencia/tendencias , Guías de Práctica Clínica como Asunto , Literatura de Revisión como Asunto , Neoplasias Urológicas/terapia , Toma de Decisiones , Humanos , Terminología como AsuntoRESUMEN
BACKGROUND: Glucagon-like peptide analogues are a new class of drugs used in the treatment of type 2 diabetes that mimic the endogenous hormone glucagon-like peptide 1 (GLP-1). GLP-1 is an incretin, a gastrointestinal hormone that is released into the circulation in response to ingested nutrients. GLP-1 regulates glucose levels by stimulating glucose-dependent insulin secretion and biosynthesis, and by suppressing glucagon secretion, delayed gastric emptying and promoting satiety. OBJECTIVES: To assess the effects of glucagon-like peptide analogues in patients with type 2 diabetes mellitus. SEARCH STRATEGY: Studies were obtained from electronic searches of The Cochrane Library (last search issue 1, 2011), MEDLINE (last search March 2011), EMBASE (last search March 2011), Web of Science (last search March 2011) and databases of ongoing trials. SELECTION CRITERIA: Studies were included if they were randomised controlled trials of a minimum duration of eight weeks comparing a GLP-1 analogue with placebo, insulin, an oral anti-diabetic agent, or another GLP-1 analogue in people with type 2 diabetes. DATA COLLECTION AND ANALYSIS: Data extraction and quality assessment of studies were done by one reviewer and checked by a second. Data were analysed by type of GLP-1 agonist and comparison treatment. Where appropriate, data were summarised in a meta-analysis (mean differences and risk ratios summarised using a random-effects model). MAIN RESULTS: Seventeen randomised controlled trials including relevant analyses for 6899 participants were included in the analysis. Studies were mostly of short duration, usually 26 weeks.In comparison with placebo, all GLP-1 agonists reduced glycosylated haemoglobin A1c (HbA1c) levels by about 1%. Exenatide 2 mg once weekly and liraglutide 1.8 mg reduced it by 0.20% and 0.24% respectively more than insulin glargine. Exenatide 2 mg once weekly reduced HbA1c more than exenatide 10 µg twice daily, sitagliptin and pioglitazone. Liraglutide 1.8 mg reduced HbA1c by 0.33% more than exenatide 10 µg twice daily. Liraglutide led to similar improvements in HbA1c compared to sulphonylureas but reduced it more than sitagliptin and rosiglitazone.Both exenatide and liraglutide led to greater weight loss than most active comparators, including in participants not experiencing nausea. Hypoglycaemia occurred more frequently in participants taking concomitant sulphonylurea. GLP-1 agonists caused gastrointestinal adverse effects, mainly nausea. These adverse events were strongest at the beginning and then subsided. Beta-cell function was improved with GLP-1 agonists but the effect did not persist after cessation of treatment.None of the studies was long enough to assess long-term positive or negative effects. AUTHORS' CONCLUSIONS: GLP-1 agonists are effective in improving glycaemic control.
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Diabetes Mellitus Tipo 2/tratamiento farmacológico , Péptido 1 Similar al Glucagón/análogos & derivados , Hipoglucemiantes/uso terapéutico , Diabetes Mellitus Tipo 2/sangre , Hemoglobina Glucada/metabolismo , Humanos , Ensayos Clínicos Controlados Aleatorios como AsuntoRESUMEN
BACKGROUND: Glucagon-like peptide (GLP-1) analogues are a new class of drugs used in the treatment of type 2 diabetes. They are given by injection, and regulate glucose levels by stimulating glucose-dependent insulin secretion and biosynthesis, suppressing glucagon secretion, and delaying gastric emptying and promoting satiety. This systematic review aims to provide evidence on the clinical effectiveness of the GLP-1 agonists in patients not achieving satisfactory glycaemic control with one or more oral glucose lowering drugs. METHODS: MEDLINE, EMBASE, the Cochrane Library and Web of Science were searched to find the relevant papers. We identified 28 randomised controlled trials comparing GLP-1 analogues with placebo, other glucose-lowering agents, or another GLP-1 analogue, in patients with type 2 diabetes with inadequate control on a single oral agent, or on dual therapy. Primary outcomes included HbA1c, weight change and adverse events. RESULTS: Studies were mostly of short duration, usually 26 weeks. All GLP-1 agonists reduced HbA1c by about 1% compared to placebo. Exenatide twice daily and insulin gave similar reductions in HbA1c, but exenatide 2 mg once weekly and liraglutide 1.8 mg daily reduced it by 0.20% and 0.30% respectively more than glargine. Liraglutide 1.2 mg daily reduced HbA1c by 0.34% more than sitagliptin 100 mg daily. Exenatide and liraglutide gave similar improvements in HbA1c to sulphonylureas. Exenatide 2 mg weekly and liraglutide 1.8 mg daily reduced HbA1c by more than exenatide 10 µg twice daily and sitagliptin 100 mg daily. Exenatide 2 mg weekly reduced HbA1c by 0.3% more than pioglitazone 45 mg daily.Exenatide and liraglutide resulted in greater weight loss (from 2.3 to 5.5 kg) than active comparators. This was not due simply to nausea. Hypoglycaemia was uncommon, except when combined with a sulphonylurea. The commonest adverse events with all GLP-1 agonists were initial nausea and vomiting. The GLP-1 agonists have some effect on beta-cell function, but this is not sustained after the drug is stopped. CONCLUSIONS: GLP-1 agonists are effective in improving glycaemic control and promoting weight loss.
RESUMEN
BACKGROUND: Many children with type 1 diabetes have poor glycaemic control. Since the Diabetes Control and Complications Trial (DCCT) showed that tighter control reduces complication rates, there has been more emphasis on intensified insulin therapy. We know that patients and families are afraid of hypoglycaemia. We hypothesised that fear of hypoglycaemia might take precedence over concern about long-term complications, and that behaviour to avoid hypoglycaemia might be at the cost of poorer control, and aimed to evaluate the effectiveness of any interventions designed to prevent that. The objective of this review was to systematically review studies concerning the extent and consequences of fear of hypoglycaemia in parents of children under 12 years of age with type 1 diabetes, and interventions to reduce it. DATA SOURCES: MEDLINE, EMBASE, PsycINFO, The Cochrane Library, Web of Science, meeting abstracts of EASD, ADA and Diabetes UK, Current Controlled Trials, ClinicalTrials.gov, UK CRN, scrutiny of bibliographies of retrieved papers and contact with experts in the field.Inclusions: Relevant studies of any design of parents of children under 12 years of age with Type 1 diabetes were included. The key outcomes were the extent and impact of fear, hypoglycaemia avoidance behaviour in parents due to parental fear of hypoglycaemia in their children, the effect on diabetes control, and the impact of interventions to reduce this fear and hypoglycaemia avoidance behaviour. RESULTS: Eight articles from six studies met the inclusion criteria. All were cross sectional studies and most were of good quality. Parental fear of hypoglycaemia, anxiety and depression were reported to be common. There was a paucity of evidence on behaviour to avoid hypoglycaemia, but there were some suggestions that higher than desirable blood glucose levels might be permitted in order to avoid hypoglycaemia. No studies reporting interventions to reduce parental fear of hypoglycaemia were found. CONCLUSIONS: The evidence base was limited. Parents of children with Type 1 diabetes reported considerable parental fear of hypoglycaemia, affecting both parental health and quality of life. There is some suggestion that hypoglycaemia avoidance behaviours by parents might adversely affect glycaemic control. Trials of interventions to reduce parental anxiety and hypoglycaemia avoidance behaviour are needed. We suggest that there should be a trial of structured education for parents of young children with Type 1 diabetes.
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Ansiedad , Diabetes Mellitus Tipo 1/sangre , Miedo , Hipoglucemia/prevención & control , Padres/psicología , Glucemia/análisis , Niño , Preescolar , Diabetes Mellitus Tipo 1/tratamiento farmacológico , Humanos , Hipoglucemia/complicaciones , Hipoglucemia/terapia , Hipoglucemiantes/uso terapéutico , Insulina/uso terapéutico , Factores SocioeconómicosRESUMEN
OBJECTIVE: To summarise studies describing incidence of sudden cardiac death in a general population of young individuals to inform screening policy. DESIGN: Systematic review. DATA SOURCES: Database searches of MEDLINE, EMBASE and the Cochrane library (all inception to current) on 29 April 2019 (updated 16 November 2019), and forward/backward citation tracking of eligible studies. STUDY ELIGIBILITY CRITERIA: All studies that reported incidence of sudden cardiac death in young individuals (12-39 years) in a general population, with no restriction on language or date. Planned subgroups were incidence by age, sex, race and athletic status (including military personnel). DATA EXTRACTION: Two reviewers independently assessed study eligibility, extracted study data and assessed risk of bias using the Joanna Briggs Institute critical appraisal checklist for prevalence studies. ANALYSIS: Reported incidence of sudden cardiac death in the young per 100 000 person-years. RESULTS: 38 studies that reported incidence across five continents. We identified substantial heterogeneity in population, sudden cardiac death definition, and case ascertainment methods, precluding meta-analysis. Median reported follow-up years was 6.97 million (IQR 2.34 million-23.70 million) and number of sudden cardiac death cases was 64 (IQR 40-251). In the general population, the median of reported incidence was 1.7 sudden cardiac death per 100 000 person-years (IQR 1.3-2.6, range 0.75-11.9). Most studies (n=14, 54%) reported an incidence between one and two cases per 100 000 person-years. Incidence was higher in males and older individuals. CONCLUSIONS: This systematic review identified variability in the reported incidence of sudden cardiac death in the young across studies. Most studies reported an incidence between one and two cases per 100 000 person-years. PROSPERO REGISTRATION NUMBER: CRD42019120563.
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Lista de Verificación , Muerte Súbita Cardíaca , Adolescente , Adulto , Factores de Edad , Niño , Estudios Transversales , Bases de Datos Factuales , Muerte Súbita Cardíaca/epidemiología , Femenino , Humanos , Incidencia , Masculino , Adulto JovenRESUMEN
BACKGROUND: Insulin therapy often relies on multiple daily injections of insulin. However this is a considerable burden to many people with diabetes and adherence to such an insulin regimen can be difficult to maintain, hence compromising optimal glycaemic control. Also, short acting injected insulin is absorbed more slowly than insulin released by the normal pancreas in response to a meal. Inhaled insulin has the potential to reduce the number of injections to perhaps one long-acting insulin per day, and provide a closer match to the natural state, by more rapid absorption from the lung. OBJECTIVES: To compare the efficacy, adverse effects and patient acceptability of inhaled versus injected insulin. SEARCH STRATEGY: A sensitive search strategy for randomised controlled or cross-over trials was combined with key terms for inhaled insulins. Databases searched were: The Cochrane Library, MEDLINE, PubMed, EMBASE, Science Citation Index, BIOSIS, Web of Science Proceedings, National Research Register UK, Current Controlled Trials, ClinicalTrials.gov, Conference Papers Index, LexisNexis, and web sites of the ADA and EASD were searched for recent meeting abstracts. Reference lists and journals were handsearched. There were no language restrictions on searching. Manufacturers of inhaled insulin were also contacted. Date of last search October 2002. SELECTION CRITERIA: Only randomised controlled trials with parallel groups or controlled cross-over trials, including type 1 or type 2 diabetic patients of any age treated with insulin, were considered eligible. The minimum trial duration considered was 10 weeks, as this is the time taken for glycated haemoglobin to reliably reflect changes in glycaemic control. DATA COLLECTION AND ANALYSIS: Trial selection and evaluation of study quality was performed independently by two reviewers. The quality of reporting of each trial was assessed according to a modification of the criteria outlined in Centre for Reviews and Dissemination (CRD) Report 4, Spitzer; and Jadad. MAIN RESULTS: Six randomised controlled trials were found and the overall number of participants was 1191. Three trials included patients with type 1 diabetes and three with type 2 diabetes. Three trials had a duration of 24 weeks, and three of 12 weeks. All were open label. There was insufficient information to determine the study quality. Results for HbA1c were similar for all trials, in that all showed comparable glycaemic control for inhaled insulin compared to an entirely subcutaneous regimen. All trials that reported patient satisfaction and quality of life showed that these were significantly greater in the inhaled insulin group. Overall there was no difference in total hypoglycaemic episodes between the groups, but one trial showed a statistically significant increase in severe hypoglycaemic episodes for the inhaled insulin group. No adverse pulmonary effects were observed in any of the studies, but longer follow-up will be required to be sure that there are no adverse side-effects. Cavets include: few studies published in full (so quality could not be assessed), and only two studies used the same basal regimen in both the inhaled and injected groups. AUTHORS' CONCLUSIONS: Inhaled insulin taken before meals, in conjunction with an injected basal insulin, has been shown to maintain glycaemic control comparable to that of patients taking multiple daily injections. The key benefit appears to be that patient satisfaction and quality of life are significantly improved, presumably due to the reduced number of daily injections required. However, the patient satisfaction data is based on five trials, of which only two have been published in full; also the three trials containing quality of life data are all only published in abstract form at present. In addition, longer term pulmonary safety data are still needed. Also, the lower bioavailability, and hence higher doses of inhaled insulin required, may make it less cost-effective than injected insulin.
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Diabetes Mellitus Tipo 1/tratamiento farmacológico , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Hipoglucemiantes/administración & dosificación , Insulina/administración & dosificación , Administración por Inhalación , Humanos , Ensayos Clínicos Controlados Aleatorios como AsuntoRESUMEN
BACKGROUND: Non-small cell lung cancer (NSCLC) is one of the most commonly diagnosed cancers. There are many published studies of cost-effectiveness analyses of licensed treatments, but no study has compared these studies or their approaches simultaneously. OBJECTIVE: To investigate the methodology used in published economic analyses of licensed interventions for previously treated advanced/metastatic NSCLC in patients without anaplastic lymphoma kinase or epidermal growth factor receptor expression. METHODS: A systematic review was performed, including a systematic search of key databases (e.g. MEDLINE, EMBASE, Web of Knowledge, Cost-effectiveness Registry) limited to the period from 01 January 2001 to 26 July 2019. Two reviewers independently screened, extracted data and quality appraised identified studies. The reporting quality of the studies was assessed by using the Consolidated Health Economic Evaluation Reporting Standards and the Philips' checklists. RESULTS: Thirty-one published records met the inclusion criteria, which corresponded to 30 individual cost-effectiveness analyses. Analytical approaches included partitioned survival models (n = 14), state-transition models (n = 7) and retrospective analyses of new or published data (n = 8). Model structure was generally consistent, with pre-progression, post-progression and death health states used most commonly. Other characteristics varied more widely, including the perspective of analysis, discounting, time horizon, usually to align with the country that the analysis was set in. CONCLUSIONS: There are a wide range of approaches in the modelling of treatments for advanced NSCLC; however, the model structures are consistent. There is variation in the exploration of sensitivity analyses, with considerable uncertainty remaining in most evaluations. Improved reporting is necessary to ensure transparency in future analyses.
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Quinasa de Linfoma Anaplásico/análisis , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Neoplasias Pulmonares/tratamiento farmacológico , Carcinoma de Pulmón de Células no Pequeñas/química , Carcinoma de Pulmón de Células no Pequeñas/secundario , Receptores ErbB/análisis , Humanos , Neoplasias Pulmonares/química , Neoplasias Pulmonares/patología , Estudios RetrospectivosRESUMEN
Chondrosphere (Spherox) is a form of autologous chondrocyte implantation (ACI). It is licensed for repair of symptomatic articular cartilage defects of the femoral condyle and the patella of the knee with defect sizes up to 10 cm2 in adults. In a single technology appraisal (STA) [TA508] undertaken by the National Institute of Health and Care Excellence (NICE), Warwick Evidence was the Evidence Review Group (ERG) invited to independently review the evidence submitted by the manufacturer, Co.Don. The clinical effectiveness data came from their COWISI randomised controlled trial (RCT), which compared Chondrosphere with microfracture (MF). The timing of this appraisal was unfortunate given that MF was no longer the most relevant comparator because NICE had contemporaneously published guidance approving ACI in place of MF. Moreover, the COWISI RCT enrolled mostly patients with small defect sizes. Evidence of clinical effectiveness for Chondrosphere used in people with larger defect size came from another RCT, which compared three doses of Chondrosphere and that by design could not provide evidence comparing Chondrosphere to any other forms of ACI. To estimate the relative clinical performance of Chondrosphere versus other ACI, Co.Don conducted an indirect treatment comparison by network meta-analyses (NMA). The NMA was flawed in that the distribution of population characteristics that are effect modifiers greatly differed across the treatment comparisons of the network. The ERG questioned both the appropriateness of the NMA and the validity of the resulting estimates. Co.Don estimated the cost-effectiveness of Chondrosphere using a lifetime Markov model with all patients receiving the first repair during the first cycle of the model then moving into one of three health states: success, no further repair (NFR), or a second repair, if necessary. Subsequent to the first cycle, those who were a success either remained a success or moved to second repair. All those in NFR remained in NFR. The cost-effectiveness of Chondrosphere compared to other ACI forms relied on the clinical effectiveness estimates of success and failure rates obtained from the company's indirect comparisons, the validity of which the ERG questioned. The company revised cost-effectiveness estimates for Chondrosphere versus MF and for Chondrosphere versus matrix-applied characterised autologous cultured chondrocyte implant (MACI) were £4360 and around £18,000 per quality-adjusted life year gained, respectively. NICE recommended ACI using Chondrosphere for treating symptomatic articular cartilage defects of the femoral condyle and patella of the knee in adults only if certain requirements were met.
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Cartílago Articular/cirugía , Condrocitos/trasplante , Articulación de la Rodilla/cirugía , Adulto , Cartílago Articular/patología , Análisis Costo-Beneficio , Humanos , Años de Vida Ajustados por Calidad de Vida , Ensayos Clínicos Controlados Aleatorios como Asunto , Evaluación de la Tecnología Biomédica , Trasplante Autólogo/economíaRESUMEN
The aim of this systematic review is to look at the barriers to uptake and interventions to improve uptake of postnatal screening in women who have had gestational diabetes mellitus (GDM). Increasing postnatal screening rates could lead to timely interventions that could reduce the incidence of type 2 diabetes mellitus (T2DM), the associated long-term health complications, and the financial burden of T2DM. A systematic review of the literature was undertaken. PubMed, Embase, Medline, CINAHL and the Cochrane library databases were searched using well-defined search terms. Predefined inclusion and exclusion criteria were used to identify relevant manuscripts. Data extractions and quality assessments were performed by one reviewer and checked by a second reviewer. Eleven primary studies of various research design and three systematic reviews were included. We identified seven themes within these studies and these were described in two categories, barriers and interventions. There appeared to be no single intervention that would overcome all the identified barriers, however, reminders to women and healthcare professionals appear to be most effective. Uptake rates of testing for T2DM are low in women with GDM. Interventions developed with consideration of the identified barriers to uptake could promote greater numbers of women attending for follow-up.
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PURPOSE: This systematic review with network meta-analysis compared the efficacy and safety of currently licensed second-line treatments in patients with late stage non-small cell lung cancer (NSCLC). METHODS: Randomised controlled trials (RCTs) of participants with advanced/metastatic NSCLC receiving second/third line treatments were screened. We searched electronic databases (MEDLINE; EMBASE; Web of Science) from January, 2000 to July, 2017. Two reviewers screened bibliographic records, extracted data, and assessed risk of bias of included studies. The outcomes were overall survival (OS), progression-free survival (PFS), and drug-related grade 3-5 adverse-events (AEs). We pooled study-specific hazard ratios (HR; for OS and PFS) and risk ratios (RR; for AEs) using conventional and network-meta-analyses, and ranked interventions by the surface under the cumulative ranking curve. FINDINGS: We included 11 RCTs (7,581 participants) comparing nine drugs. All drugs except for erlotinib significantly improved OS compared to docetaxel. Nivolumab was the highest ranking drug followed by atezolizumab and pembrolizumab. There was no significant difference in OS across these three drugs (HR = 0.98, 95% CI 0.79, 1.21 for nivolumab vs atezolizumab; HR = 0.98, 95% CI 0.77, 1.25 for nivolumab vs pembrolizumab). For PFS, ramucirumab + docetaxel and nivolumab were the drugs with the highest ranking. All interventions except ramucirumab + docetaxel had a reduced risk for severe drug-related AEs vs. docetaxel. Of the drugs with the highest ranking on AEs, nivolumab was significantly safer compared to atezolizumab (RR = 0.55, 95% CI 0.38, 0.79) or pembrolizumab (RR = 0.52, 95% CI 0.34, 0.81). IMPLICATIONS: Nivolumab, pembrolizumab and atezolizumab exhibited superior benefit/risk balance compared to other licensed drugs used late stage NSCLC. Our results indicate that the use of immunotherapies in people diagnosed with non-specific late stage NSCLC should be promoted. The use of docetaxel may now be judged irrelevant as a comparator intervention for approval of new drugs for second line treatment of NSCLC. STUDY REGISTRATION NUMBER: PROSPERO CRD42017065928.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Carcinoma de Pulmón de Células no Pequeñas/patología , Carcinoma de Pulmón de Células no Pequeñas/terapia , Neoplasias Pulmonares/patología , Neoplasias Pulmonares/terapia , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Carcinoma de Pulmón de Células no Pequeñas/mortalidad , Progresión de la Enfermedad , Humanos , Neoplasias Pulmonares/mortalidad , Metaanálisis en Red , Modelos de Riesgos Proporcionales , Retratamiento , Resultado del TratamientoRESUMEN
BACKGROUND: Age-related macular degeneration (AMD) is the leading cause of visual loss in older people. Advanced AMD takes two forms, neovascular (wet) and atrophic (dry). Stargardt disease (STGD) is the commonest form of inherited macular dystrophy. OBJECTIVE: To carry out a systematic review of treatments for dry AMD and STGD, and to identify emerging treatments where future NIHR research might be commissioned. DESIGN: Systematic review. METHODS: We searched MEDLINE, EMBASE, Web of Science and The Cochrane Library from 2005 to 13 July 2017 for reviews, journal articles and meeting abstracts. We looked for studies of interventions that aim to preserve or restore vision in people with dry AMD or STGD. The most important outcomes are those that matter to patients: visual acuity (VA), contrast sensitivity, reading speed, ability to drive, adverse effects of treatment, quality of life, progression of disease and patient preference. However, visual loss is a late event and intermediate predictors of future decline were accepted if there was good evidence that they are strong predictors of subsequent visual outcomes. These include changes detectable by investigation, but not necessarily noticed by people with AMD or STGD. ClinicalTrials.gov, the World Health Organization search portal and the UK Clinical Trials gateway were searched for ongoing and recently completed clinical trials. RESULTS: The titles and abstracts of 7948 articles were screened for inclusion. The full text of 398 articles were obtained for further screening and checking of references and 112 articles were included in the final report. Overall, there were disappointingly few good-quality studies (including of sufficient size and duration) reporting useful outcomes, particularly in STGD. However we did identify a number of promising research topics, including drug treatments, stem cells, new forms of laser treatment, and implantable intraocular lens telescopes. In many cases, research is already under way, funded by industry or governments. LIMITATIONS: In AMD, the main limitation came from the poor quality of much of the evidence. Many studies used VA as their main outcome despite not having sufficient duration to observe changes. The evidence on treatments for STGD is sparse. Most studies tested interventions with no comparison group, were far too short term, and the quality of some studies was poor. FUTURE WORK: We think that the topics on which the Health Technology Assessment (HTA) and Efficacy Mechanism and Evaluation (EME) programmes might consider commissioning primary research are in STGD, a HTA trial of fenretinide (ReVision Therapeutics, San Diego, CA, USA), a visual cycle inhibitor, and EME research into the value of lutein and zeaxanthin supplements, using short-term measures of retinal function. In AMD, we suggest trials of fenretinide and of a potent statin. There is epidemiological evidence from the USA that the drug, levodopa, used for treating Parkinson's disease, may reduce the incidence of AMD. We suggest that similar research should be carried out using the large general practice databases in the UK. Ideally, future research should be at earlier stages in both diseases, before vision is impaired, using sensitive measures of macular function. This may require early detection of AMD by screening. STUDY REGISTRATION: This study is registered as PROSPERO CRD42016038708. FUNDING: The National Institute for Health Research HTA programme.
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Degeneración Macular/congénito , Degeneración Macular/terapia , Conducción de Automóvil , Trasplante de Células/métodos , Terapias Complementarias/métodos , Suplementos Dietéticos , Progresión de la Enfermedad , Humanos , Terapia por Láser/métodos , Lentes Intraoculares , Degeneración Macular/tratamiento farmacológico , Prioridad del Paciente , Calidad de Vida , Lectura , Enfermedad de Stargardt , Agudeza VisualRESUMEN
BACKGROUND: The full extent to which childhood pneumococcal conjugate vaccines (PCV) can indirectly reduce illness in unvaccinated populations is not known. We aimed to estimate the magnitude and timing of indirect effects of PCVs on invasive pneumococcal disease. METHODS: In this systematic review and meta-analysis, we searched bibliographic databases for non-randomised quasi-experimental or observational studies reporting invasive pneumococcal disease changes following PCV introduction in unvaccinated populations (studies published Sept 1, 2010, to Jan 6, 2016), updating the previous systematic review of the same topic (studies published Jan 1, 1994, to Sept 30, 2010). Two reviewers extracted summary data by consensus. We used a Bayesian mixed-effects model to account for between-study heterogeneity to estimate temporal indirect effects by pooling of invasive pneumococcal disease changes by serotype and serogroup. FINDINGS: Data were extracted from 70 studies included in the previous review and 172 additional studies, covering 27 high-income and seven middle-income countries. The predicted mean times to attaining a 90% reduction in invasive pneumococcal disease were 8·9 years (95% credible interval [CrI] 7·8-10·3) for grouped serotypes contained in the seven-valent PCV (PCV7), and 9·5 years (6·1-16·6) for the grouped six additional serotypes contained in the 13-valent PCV (PCV13) but not in PCV7. Disease due to grouped serotypes contained in the 23-valent pneumococcal polysaccharide vaccine (PPV23) decreased at similar rates per year in adults aged 19-64 years (relative risk [RR] 0·85, 95% CrI 0·75-0·95) and 65 years and older (0·87, 0·84-0·90). However, we noted no changes in either group in invasive pneumococcal disease caused by the additional 11 serotypes covered by PPV23 but not PCV13. INTERPRETATION: Population childhood PCV programmes will lead, on average, to substantial protection across the whole population within a decade. This large indirect protection should be considered when assessing vaccination of older age groups. FUNDING: Policy Research Programme of the Department of Health, England.