RESUMO
BACKGROUND: Diabetic retinopathy (DR) is characterised by neurovascular degeneration as a result of chronic hyperglycaemia. Proliferative diabetic retinopathy (PDR) is the most serious complication of DR and can lead to total (central and peripheral) visual loss. PDR is characterised by the presence of abnormal new blood vessels, so-called "new vessels," at the optic disc (NVD) or elsewhere in the retina (NVE). PDR can progress to high-risk characteristics (HRC) PDR (HRC-PDR), which is defined by the presence of NVD more than one-fourth to one-third disc area in size plus vitreous haemorrhage or pre-retinal haemorrhage, or vitreous haemorrhage or pre-retinal haemorrhage obscuring more than one disc area. In severe cases, fibrovascular membranes grow over the retinal surface and tractional retinal detachment with sight loss can occur, despite treatment. Although most, if not all, individuals with diabetes will develop DR if they live long enough, only some progress to the sight-threatening PDR stage. OBJECTIVES: To determine risk factors for the development of PDR and HRC-PDR in people with diabetes and DR. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL; which contains the Cochrane Eyes and Vision Trials Register; 2022, Issue 5), Ovid MEDLINE, and Ovid Embase. The date of the search was 27 May 2022. Additionally, the search was supplemented by screening reference lists of eligible articles. There were no restrictions to language or year of publication. SELECTION CRITERIA: We included prospective or retrospective cohort studies and case-control longitudinal studies evaluating prognostic factors for the development and progression of PDR, in people who have not had previous treatment for DR. The target population consisted of adults (≥18 years of age) of any gender, sexual orientation, ethnicity, socioeconomic status, and geographical location, with non-proliferative diabetic retinopathy (NPDR) or PDR with less than HRC-PDR, diagnosed as per standard clinical practice. Two review authors independently screened titles and abstracts, and full-text articles, to determine eligibility; discrepancies were resolved through discussion. We considered prognostic factors measured at baseline and any other time points during the study and in any clinical setting. Outcomes were evaluated at three and eight years (± two years) or lifelong. DATA COLLECTION AND ANALYSIS: Two review authors independently extracted data from included studies using a data extraction form that we developed and piloted prior to the data collection stage. We resolved any discrepancies through discussion. We used the Quality in Prognosis Studies (QUIPS) tool to assess risk of bias. We conducted meta-analyses in clinically relevant groups using a random-effects approach. We reported hazard ratios (HR), odds ratios (OR), and risk ratios (RR) separately for each available prognostic factor and outcome, stratified by different time points. Where possible, we meta-analysed adjusted prognostic factors. We evaluated the certainty of the evidence with an adapted version of the GRADE framework. MAIN RESULTS: We screened 6391 records. From these, we identified 59 studies (87 articles) as eligible for inclusion. Thirty-five were prospective cohort studies, 22 were retrospective studies, 18 of which were cohort and six were based on data from electronic registers, and two were retrospective case-control studies. Twenty-three studies evaluated participants with type 1 diabetes (T1D), 19 with type 2 diabetes (T2D), and 17 included mixed populations (T1D and T2D). Studies on T1D included between 39 and 3250 participants at baseline, followed up for one to 45 years. Studies on T2D included between 100 and 71,817 participants at baseline, followed up for one to 20 years. The studies on mixed populations of T1D and T2D ranged from 76 to 32,553 participants at baseline, followed up for four to 25 years. We found evidence indicating that higher glycated haemoglobin (haemoglobin A1c (HbA1c)) levels (adjusted OR ranged from 1.11 (95% confidence interval (CI) 0.93 to 1.32) to 2.10 (95% CI 1.64 to 2.69) and more advanced stages of retinopathy (adjusted OR ranged from 1.38 (95% CI 1.29 to 1.48) to 12.40 (95% CI 5.31 to 28.98) are independent risk factors for the development of PDR in people with T1D and T2D. We rated the evidence for these factors as of moderate certainty because of moderate to high risk of bias in the studies. There was also some evidence suggesting several markers for renal disease (for example, nephropathy (adjusted OR ranged from 1.58 (95% CI not reported) to 2.68 (2.09 to 3.42), and creatinine (adjusted meta-analysis HR 1.61 (95% CI 0.77 to 3.36)), and, in people with T1D, age at diagnosis of diabetes (< 12 years of age) (standardised regression estimate 1.62, 95% CI 1.06 to 2.48), increased triglyceride levels (adjusted RR 1.55, 95% CI 1.06 to 1.95), and larger retinal venular diameters (RR 4.28, 95% CI 1.50 to 12.19) may increase the risk of progression to PDR. The certainty of evidence for these factors, however, was low to very low, due to risk of bias in the included studies, inconsistency (lack of studies preventing the grading of consistency or variable outcomes), and imprecision (wide CIs). There was no substantial and consistent evidence to support duration of diabetes, systolic or diastolic blood pressure, total cholesterol, low- (LDL) and high- (HDL) density lipoproteins, gender, ethnicity, body mass index (BMI), socioeconomic status, or tobacco and alcohol consumption as being associated with incidence of PDR. There was insufficient evidence to evaluate prognostic factors associated with progression of PDR to HRC-PDR. AUTHORS' CONCLUSIONS: Increased HbA1c is likely to be associated with progression to PDR; therefore, maintaining adequate glucose control throughout life, irrespective of stage of DR severity, may help to prevent progression to PDR and risk of its sight-threatening complications. Renal impairment in people with T1D or T2D, as well as younger age at diagnosis of diabetes mellitus (DM), increased triglyceride levels, and increased retinal venular diameters in people with T1D may also be associated with increased risk of progression to PDR. Given that more advanced DR severity is associated with higher risk of progression to PDR, the earlier the disease is identified, and the above systemic risk factors are controlled, the greater the chance of reducing the risk of PDR and saving sight.
ANTECEDENTES: La retinopatía diabética (RD) se caracteriza por la degeneración neurovascular como consecuencia de la hiperglucemia crónica. La retinopatía diabética proliferativa (RDP) es la complicación más grave de la RD y puede provocar una pérdida total (central y periférica) de la visión. La RDP se caracteriza por la presencia de vasos sanguíneos de neoformación anormales, neovascularización, en la papila óptica (NVP) o en cualquier otra parte de la retina (NVE). La RDP puede evolucionar a una RDP con características de alto riesgo (RDPCAR), que se define por la presencia de NVP de más de un cuarto a un tercio del área discal más hemorragia vítrea o prerretiniana, o hemorragia vítrea o prerretiniana que oscurece más de un área papilar. En los casos graves, crecen membranas fibrovasculares sobre la superficie retiniana y se puede producir un desprendimiento de retina por tracción con pérdida de la visión, a pesar del tratamiento. Aunque la mayoría de las personas con diabetes, si no todas, desarrollarán RD si viven lo suficiente, solo algunas llegan a la fase de RDP, que pone en peligro la vista. OBJETIVOS: Determinar los factores de riesgo de aparición de la RDP y RDPCAR en personas con diabetes y RD. MÉTODOS DE BÚSQUEDA: Se hicieron búsquedas en el Registro Cochrane central de ensayos controlados (Cochrane Central Register of Controlled Trials, CENTRAL; que contiene el Registro de ensayos del Grupo Cochrane de Salud ocular y de la visión [Cochrane Eyes and Vision]; 2022, número 5), Ovid MEDLINE y Ovid Embase. La fecha de búsqueda fue el 27 de mayo de 2022. Además, la búsqueda se complementó con el cribado de las listas de referencias de los artículos elegibles. No hubo restricciones en cuanto al idioma ni al año de publicación. CRITERIOS DE SELECCIÓN: Se incluyeron estudios de cohortes prospectivos o retrospectivos y estudios longitudinales de casos y controles que evaluaran los factores pronósticos para la aparición y la progresión de la RDP, en personas que no habían recibido tratamiento previo para la RD. La población de interés estaba formada por adultos (≥18 años de edad) de cualquier sexo, orientación sexual, etnia, nivel socioeconómico y ubicación geográfica, con retinopatía diabética no proliferativa (RDNP) o RDP sin llegar a RDPCAR, diagnosticada según la práctica clínica habitual. Dos autores de la revisión examinaron de forma independiente los títulos y resúmenes, así como los artículos completos, para determinar la elegibilidad; las discrepancias se resolvieron mediante debate. Se tuvieron en cuenta los factores pronósticos medidos al inicio del estudio y en cualquier otro punto temporal durante el estudio y en cualquier contexto clínico. Los desenlaces se evaluaron a los tres y ocho años (± dos años) o de por vida. OBTENCIÓN Y ANÁLISIS DE LOS DATOS: Dos autores de la revisión extrajeron de forma independiente los datos de los estudios incluidos mediante un formulario de extracción de datos que se desarrolló y evaluó antes de la etapa de obtención de datos. Las discrepancias se resolvieron mediante debate. Para evaluar el riesgo de sesgo se utilizó la herramienta Quality in Prognosis Studies (QUIPS). Se realizaron metanálisis en grupos clínicamente relevantes utilizando un enfoque de efectos aleatorios. Se proporcionaron los cociente de riesgos instantáneos (CRI), los odds ratios (OR) y las razones de riesgos (RR) por separado para cada factor pronóstico y desenlace disponibles, estratificados por diferentes puntos temporales. Cuando fue posible, se realizó un metanálisis de los factores pronósticos ajustados. La certeza de la evidencia se evaluó con una versión adaptada del método GRADE. RESULTADOS PRINCIPALES: Se han examinado 6391 registros. A partir de estos se identificaron 59 estudios (87 artículos) elegibles para inclusión. Treinta y cinco fueron estudios de cohortes prospectivos, 22 fueron estudios retrospectivos, 18 de los cuales fueron de cohortes y 6 se basaron en datos de registros electrónicos, y 2 fueron estudios retrospectivos de casos y controles. Veintitrés estudios evaluaron a participantes con diabetes tipo 1 (DT1), 19 con diabetes tipo 2 (DT2) y 17 incluyeron poblaciones mixtas (DT1 y DT2). Los estudios sobre la DT1 incluyeron entre 39 y 3250 participantes al inicio del estudio, con un seguimiento de 1 a 45 años. Los estudios sobre la DT2 incluyeron entre 100 y 71 817 participantes al inicio del estudio, con un seguimiento de 1 a 20 años. Los estudios sobre poblaciones mixtas de DT1 y DT2 variaron entre 76 y 32 553 participantes al inicio del estudio, con un seguimiento de 4 a 25 años. Se encontró evidencia que indicó que los niveles más altos de hemoglobina glucosilada (hemoglobina A1c [HbA1c]) (OR ajustado que varió de 1,11 [intervalo de confianza (IC) del 95%: 0,93 a 1,32] a 2,10 [IC del 95%: 1,64 a 2,69]) y los estadios más avanzados de retinopatía (OR ajustado que varió entre 1,38 [IC del 95%: 1,29 a 1,48] y 12,40 [IC del 95%: 5,31 a 28,98]) son factores de riesgo independientes para el desarrollo de RDP en personas con DT1 y DT2. La evidencia para estos factores se consideró de certeza moderada debido al riesgo moderado a alto de sesgo en los estudios. También hubo alguna evidencia que indicó varios marcadores de enfermedad renal (por ejemplo, nefropatía [OR ajustado que varió entre 1,58 (IC del 95% no proporcionado) y 2,68 (2,09 a 3,42)] y creatinina [metanálisis ajustado CRI 1,61 (IC del 95%: 0,77 a 3.36)]), y, en las personas con DT1, la edad en el momento del diagnóstico de la diabetes (< 12 años) (estimación de la regresión estandarizada 1,62; IC del 95%: 1,06 a 2,48), el aumento de los niveles de triglicéridos (RR ajustado 1,55; IC del 95%: 1,06 a 1,95) y los diámetros venulares retinianos mayores (RR 4,28; IC del 95%: 1,50 a 12,19) podrían aumentar el riesgo de progresión a RDP. Sin embargo, la certeza de la evidencia para estos factores fue de baja a muy baja, debido al riesgo de sesgo en los estudios incluidos, la inconsistencia (falta de estudios que impide la calificación de consistencia o desenlaces variables) y la imprecisión (IC amplios). No hubo evidencia importante ni consistente que apoyara que la duración de la diabetes, la presión arterial sistólica o diastólica, el colesterol total, las lipoproteínas de baja (LDL) y alta (HDL) densidad, el sexo, el origen étnico, el índice de masa corporal (IMC), el nivel socioeconómico o el consumo de tabaco y alcohol estuvieran asociados con la incidencia de RDP. No hubo evidencia suficiente para evaluar los factores pronósticos asociados con la progresión de la RDP a RDPCAR. CONCLUSIONES DE LOS AUTORES: Es probable que el aumento de la HbA1c se asocie con la progresión a la RDP; por lo tanto, mantener un control adecuado de la glucosa durante toda la vida, independientemente del estadio de gravedad de la RD, podría ayudar a prevenir la progresión a la RDP y el riesgo de sus complicaciones que ponen en peligro la vista. La insuficiencia renal en personas con DT1 o DT2, así como una menor edad en el momento del diagnóstico de la diabetes mellitus (DM), el aumento de los niveles de triglicéridos y el aumento de los diámetros venulares retinianos en personas con DT1 también se podrían asociar con un mayor riesgo de progresión a RDP. Dado que la gravedad más avanzada de la RD se asocia con un mayor riesgo de progresión a RDP, cuanto antes se identifique la enfermedad y se controlen los factores de riesgo sistémicos mencionados, mayores serán las posibilidades de reducir el riesgo de RDP y conservar la vista.
Assuntos
Diabetes Mellitus Tipo 1 , Diabetes Mellitus Tipo 2 , Retinopatia Diabética , Adulto , Feminino , Humanos , Masculino , Diabetes Mellitus Tipo 1/complicações , Diabetes Mellitus Tipo 2/complicações , Retinopatia Diabética/complicações , Hemoglobinas Glicadas , Prognóstico , Estudos Prospectivos , Hemorragia Retiniana , Estudos Retrospectivos , Triglicerídeos , Hemorragia Vítrea/complicaçõesRESUMO
We assessed efficacy and effectiveness of pharmacological and nonpharmacological interventions in improving symptom control, functional exercise capacity and quality of life (QoL) in people living with fibrotic interstitial lung disease (ILD). We summarised evidence from three previous reviews (to June 2014) and conducted an updated search of nine databases and grey literature (2011-2019) (registration: CRD42017065933) for prospective studies of interventions aimed to alleviate symptoms, improve QoL or functional exercise capacity in fibrotic ILD. Data were synthesised through narrative synthesis or meta-analysed as appropriate. Forty-seven studies with 2527 participants were included. From 22 pharmacological studies of 11 different interventions (n=1683), the most tested interventions were bosentan and sildenafil. From 25 nonpharmacological studies, the most tested intervention was for pulmonary rehabilitation/exercise training (PR) (22 studies, n=748). There was an improvement in 6-min walk distance immediately following PR (six studies; n=200, mean difference (MD) (95% CI) 39.9â m (18.2 to 61.5)), but not longer term (3 or 6â months, four studies; n=147, MD 5.3â m (-12.9 to 23.4). Multiple, varied outcome measures were used (e.g. 37 studies assessing dyspnoea used 10 different scales with a lack of reporting of rate of deterioration in outcomes). Evidence gap mapping highlighted the most and least researched symptoms, as dyspnoea and cough, respectively. This evidence synthesis highlights overwhelmingly that the most researched symptom is dyspnoea and the strongest evidence base is for short-term PR. The least researched symptom was cough. Research going forward must focus on prioritising and standardising meaningful outcomes and focussing interventions on neglected symptoms.
RESUMO
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.
Assuntos
Fenretinida/uso terapêutico , Atrofia Geográfica/tratamento farmacológico , Atrofia Geográfica/prevenção & controle , Degeneração Macular/complicações , Éteres Fenílicos/uso terapêutico , Propanolaminas/uso terapêutico , Conduta Expectante , Idoso , Idoso de 80 Anos ou mais , Neovascularização de Coroide/epidemiologia , Ensaios Clínicos Fase II como Assunto , Progressão da Doença , Fenretinida/efeitos adversos , Atrofia Geográfica/etiologia , Humanos , Incidência , Éteres Fenílicos/efeitos adversos , Placebos/uso terapêutico , Propanolaminas/efeitos adversos , Ensaios Clínicos Controlados Aleatórios como Assunto , Acuidade Visual/efeitos dos fármacosRESUMO
Ocrelizumab is indicated for relapsing remitting and primary progressive multiple sclerosis (RRMS and PPMS, respectively). In an appraisal undertaken by the National Institute for Health and Care Excellence (NICE), the company Roche presented the evidence for ocrelizumab used in patients with PPMS, which came from one single randomised controlled trial (RCT) comparing ocrelizumab versus placebo. Based on results from this trial, the licensed indication was restricted to patients with early PPMS in terms of disease duration and level of disability, and with imaging features characteristic of inflammatory activity. Overall, the Evidence Review Group (ERG) found that the RCT had a low risk of bias. In the post-hoc defined magnetic resonance imaging (MRI) active subgroup, matching the label indication, the risk of confirmed disability progression sustained for 12 weeks (CDP-12) was significantly delayed in the ocrelizumab group compared to placebo. However, considering the same risk with progression sustained for 24 weeks (CDP-24), which was deemed the most clinically relevant, the benefit from ocrelizumab did not reach statistical significance. In the same MRI active subgroup, benefits from ocrelizumab on functional outcomes and on health-related quality of life were not clearly demonstrated. A de novo Markov model was used to estimate the cost-effectiveness of ocrelizumab versus best supportive care (BSC) for treating patients with PPMS. Health states were defined by the Expanded Disability Status Scale (EDSS), ranging from 0 to 9. Disability progression was based on the MSBase natural history cohort that exhibited disease progression in the absence of disease-modifying therapy. Treatment with ocrelizumab delayed disability progression, with evidence of its clinical effectiveness obtained from the RCT. The economic analysis was undertaken from the National Health Service and Personal Social Services perspective, and the outcomes were reported in terms of life years gained and quality-adjusted life years (QALYs), with the overall results reported in terms of an incremental cost-effectiveness ratio (ICER), expressed as cost per QALY gained over a 50-year time horizon. Both costs and effects were discounted at 3.5% per annum. The company undertook deterministic one-way sensitivity analyses and scenario analyses, including probabilistic sensitivity analysis (PSA). The ERG raised several concerns, which were discussed at the appraisal committee meetings, resulting in the committee's preferences being applied and a revised economic analysis from the company. Under an approved patient access scheme with appraisal committee preferences applied, analyses yielded an ICER of approximately £78,300 per QALY. Sensitivity analysis results indicated that the treatment effect on CDP-12 had the greatest impact. Results for the PSA showed that at a willingness-to-pay threshold of £30,000 per QALY gained, ocrelizumab versus BSC had a zero probability of being cost-effective. Following new analyses submitted by the company, with a revised confidential patient access scheme, NICE recommended ocrelizumab in the treatment of early PPMS in adults with imaging features characteristic of inflammatory activity.
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Anticorpos Monoclonais Humanizados/uso terapêutico , Fatores Imunológicos/uso terapêutico , Esclerose Múltipla Crônica Progressiva/tratamento farmacológico , Adulto , Anticorpos Monoclonais Humanizados/economia , Análise Custo-Benefício , Progressão da Doença , Humanos , Fatores Imunológicos/economia , Esclerose Múltipla Crônica Progressiva/economia , Qualidade de Vida , Anos de Vida Ajustados por Qualidade de Vida , Ensaios Clínicos Controlados Aleatórios como Assunto , Medicina Estatal , Avaliação da Tecnologia BiomédicaRESUMO
Background and Objectives: Idiopathic pulmonary fibrosis (IPF) is a chronic condition leading to lung damage and deterioration in lung function. Following the availability of two new drugs, nintedanib and pirfenidone, a number of network meta-analyses (NMAs) of randomised controlled trials have been published which have conducted indirect comparisons on the two drugs. Differing recommendations from these studies are potentially confusing to clinicians and decision-makers. We aimed to systematically review published NMAs of IPF treatments, to compare their findings and summarise key recommendations. Materials and Methods: We systematically reviewed (PROSPERO: CRD42017072876) six eligible NMAs and investigated the differences in their findings with respect to key endpoints. We focused on differences in head-to-head comparisons between nintedanib and pirfenidone. Results: The NMAs were broadly consistent, with most differences being explained by model choice, endpoint definitions, inclusion of different studies, different follow-up durations, and access to unpublished data. A substantive difference remained, however, in the change from baseline forced vital capacity (FVC). One NMA favoured nintedanib, another found no statistical difference, whilst others did not conduct the analysis. These differences can be attributed to the choice of methodology, the use of the standardised mean difference (SMD) scale, and population heterogeneity. Conclusions: NMA methods facilitated the comparison of nintedanib and pirfenidone in the absence of a head-to-head trial. However, further work is needed to determine whether the trial populations are homogeneous and whether the SMD is appropriate in this population. Differences in patient characteristics may obscure the difference in treatment effects. To assist decision-makers, an exploration of efficacy in real-world populations may be prudent.
Assuntos
Fibrose Pulmonar Idiopática/tratamento farmacológico , Projetos de Pesquisa/normas , Resultado do Tratamento , Viés , Humanos , Indóis/normas , Indóis/uso terapêutico , Piridonas/normas , Piridonas/uso terapêutico , Projetos de Pesquisa/estatística & dados numéricosRESUMO
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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Meniscectomia/efeitos adversos , Meniscos Tibiais/transplante , Osteoartrite do Joelho/cirurgia , Transplante Homólogo/economia , Análise Custo-Benefício , Sobrevivência de Enxerto , Humanos , Osteoartrite do Joelho/etiologia , Complicações Pós-Operatórias , Qualidade de Vida , Reoperação/economia , Volta ao EsporteRESUMO
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.
Assuntos
Aloenxertos/economia , Reconstrução do Ligamento Cruzado Anterior/economia , Reconstrução do Ligamento Cruzado Anterior/métodos , Autoenxertos/economia , Análise Custo-Benefício , Sobrevivência de Enxerto , Humanos , Metanálise como Assunto , Complicações Pós-Operatórias , Anos de Vida Ajustados por Qualidade de Vida , ReoperaçãoRESUMO
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.
Assuntos
Aloenxertos/economia , Ligamento Cruzado Posterior/cirurgia , Autoenxertos/economia , Análise Custo-Benefício , Sobrevivência de Enxerto , Humanos , Escore de Lysholm para Joelho , Ligamento Cruzado Posterior/lesões , Qualidade de VidaRESUMO
Open Access This article is distributed under the terms of the Creative Commons Attribution-Non Commercial 4.0 International License ( http://creativecommons.org/licenses/by-nc/4.0/ ), which permits any noncommercial use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.
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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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Aloenxertos/economia , Transplante Ósseo/economia , Cartilagem/transplante , Sobrevivência de Enxerto , Articulação do Joelho/cirurgia , Análise Custo-Benefício , Humanos , Modelos Econômicos , Anos de Vida Ajustados por Qualidade de Vida , ReoperaçãoRESUMO
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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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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Degeneração Macular/congênito , Degeneração Macular/terapia , Condução de Veículo , Transplante de Células/métodos , Terapias Complementares/métodos , Suplementos Nutricionais , Progressão da Doença , Humanos , Terapia a Laser/métodos , Lentes Intraoculares , Degeneração Macular/tratamento farmacológico , Preferência do Paciente , Qualidade de Vida , Leitura , Doença de Stargardt , Acuidade VisualRESUMO
Venetoclax is licensed to treat relapsed or refractory (R/R) chronic lymphocytic leukaemia (CLL). As part of the Single Technology Appraisal (STA) ID944, the National Institute for Health and Care Excellence (NICE) invited AbbVie, the manufacturer, to submit evidence on the use of venetoclax, within its licensed indication. The Evidence Review Group (ERG), Warwick Evidence, was asked to provide an independent and critical review of the submitted evidence. Evidence came from three single-arm trials in CLL patients with or without 17p deletion [del(17p])/TP53 chromosomal abnormalities. The anticipated licensed indication specified that venetoclax-eligible del(17p)/TP53 patients should have not responded to, or be deemed unsuitable for, B-cell receptor inhibitor (BCRi) therapy, and that non-del(17p)/TP53 patients should have not responded to both chemoimmunotherapy and BCRi therapy. The three trials were heterogeneous in terms of both del(17p)/TP53 status and previous exposure to BCRi therapy. The M13-982 study investigated 158 R/R CLL patients with the 17p deletion, but only a small number had received previous BCRi therapy; the M12-175 study investigated 67 patients with CLL or small lymphocytic lymphoma, some with the 17p deletion, but very few previously treated with BCRi therapy; and the M14-032 study included 105 patients previously treated with BCRi therapy (either idelalisib or ibrutinib), some of whom had unknown mutation status. The ERG concluded that the study populations did not directly conform to those specified in the licensed indication or in the NICE scope. Outcomes reported included overall response rate (ORR), duration of response, progression-free survival (PFS) and overall survival (OS); adverse events were reported for the pooled population of all three studies, as well as separately for each study. The median PFS was 41.4 and 27.2 months among patients in the M12-175 and M13-982 trials, respectively, whereas the median PFS was not reached in the M14-032 trial. Some results were designated academic in confidence and cannot be reported here. The submission provided a de novo partitioned survival cost-effectiveness model with three health states: pre-progression, post-progression and dead. Transition probabilities between health states were estimated using Weibull models for PFS and OS. The ERG judged the model structure to be appropriate. Venetoclax was compared with best supportive care (BSC) in patients with or without del(17p)/TP53 mutation status, and with palliative care (PC). To populate the del(17p)/TP53 venetoclax arm, the submission pooled del(17p)/TP53 patients from all three studies and fitted Weibull models for PFS and OS. PFS and OS models for non-del(17p)/TP53 venetoclax patients were obtained by applying hazard ratios (HRs) to the del(17p)/TP53 OS and PFS models, derived using Cox's regression analysis comparing del(17p)/TP53 and non-del(17p)/TP53 patients pooled from the M14-032 and M12-175 studies. The ERG expressed reservations about the company's pooling procedure, but acknowledged its expedience given the small evidence base. For the BSC comparator arm, the submission used the rituximab + placebo arm from a randomised controlled trial comparing idelalisib + rituximab versus placebo + rituximab ('study 116'). Weibull regression data for OS and PFS were taken from the idelalisib STA (ID764) submitted by Gilead to NICE. The ERG considered the use of the study 116 rituximab arm to be inconsistent with the licensed indication for venetoclax because these patients had neither not responded to nor were inappropriate for BCRi therapy, being eligible to be randomised to idelalisib. Another difficulty was the requirement for a technical correction in survival analysis because of considerable switching from rituximab to idelalisib. The ERG considered that post-progression survival of patients from the idelalisib arm of study 116 provided a more appropriate representation of BSC since these patients had not responded to BCRi therapy, consistent with venetoclax's licensed indication. For PC, the company submission used data from the UK CLL Forum. The company's base-case analysis indicated that venetoclax was clinically effective, but the resulting incremental cost-effectiveness ratios (ICERs) for del(17p)/TP53 (£39,940/quality-adjusted life-year [QALY] gained) and non-del(17p)/TP53 (£47,370/QALY gained) patients were well above the NICE threshold of £20,000-30,000/QALY. The ERG identified two errors in the implementation of the company's parametric models-one related to the implementation of HRs, and the other to the derivation of the Weibull shape parameters obtained from the Gilead idelalisib submission. The ERG made plausible adjustments to the company's base-case and corrected errors, resulting in a reduced estimate of the cost effectiveness of venetoclax in non-del(17p)/TP53 and del(17p)/TP53 indications; in the ERG's preferred base case, using post-progression survival of patients in the idelalisib arm of study 116 as the BSC comparator, deterministic ICERs were higher than the company's base-case for both indications: £57,476/QALY gained for del(17p)/TP53 and £77,779/QALY gained for non-del(17p)/TP53. The NICE Appraisal Committee's preliminary recommendation was that venetoclax used within its licensed indication should not be recommended for use in the National Health Service (NHS). In response to the preliminary recommendation, the company submitted new analyses; however, at a subsequent appraisal committee meeting, the original recommendation was upheld and the committee concluded there were large uncertainties around the clinical effectiveness of venetoclax and BSC, and that under the committee's preferred assumptions, the ICERs were higher than those generally considered cost effective, even when end-of-life criteria were taken into account. The company submitted further evidence, and the final guidance recommended venetoclax for use with the Cancer Drugs Fund for the two populations in this technology appraisal.
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Compostos Bicíclicos Heterocíclicos com Pontes/economia , Análise Custo-Benefício/estatística & dados numéricos , Leucemia Linfocítica Crônica de Células B/economia , Sulfonamidas/economia , Avaliação da Tecnologia Biomédica/estatística & dados numéricos , Antineoplásicos/economia , Antineoplásicos/uso terapêutico , Compostos Bicíclicos Heterocíclicos com Pontes/uso terapêutico , Ensaios Clínicos como Assunto/estatística & dados numéricos , Humanos , Leucemia Linfocítica Crônica de Células B/tratamento farmacológico , Modelos Econômicos , Sulfonamidas/uso terapêuticoRESUMO
BACKGROUND: There is evidence from observational studies that whole grains can have a beneficial effect on risk for cardiovascular disease (CVD). Earlier versions of this review found mainly short-term intervention studies. There are now longer-term randomised controlled trials (RCTs) available. This is an update and expansion of the original review conducted in 2007. OBJECTIVES: The aim of this systematic review was to assess the effect of whole grain foods or diets on total mortality, cardiovascular events, and cardiovascular risk factors (blood lipids, blood pressure) in healthy people or people who have established cardiovascular disease or related risk factors, using all eligible RCTs. SEARCH METHODS: We searched CENTRAL (Issue 8, 2016) in the Cochrane Library, MEDLINE (1946 to 31 August 2016), Embase (1980 to week 35 2016), and CINAHL Plus (1937 to 31 August 2016) on 31 August 2016. We also searched ClinicalTrials.gov on 5 July 2017 and the World Health Organization International Clinical Trials Registry Platform (WHO ICTRP) on 6 July 2017. We checked reference lists of relevant articles and applied no language restrictions. SELECTION CRITERIA: We selected RCTs assessing the effects of whole grain foods or diets containing whole grains compared to foods or diets with a similar composition, over a minimum of 12 weeks, on cardiovascular disease and related risk factors. Eligible for inclusion were healthy adults, those at increased risk of CVD, or those previously diagnosed with CVD. DATA COLLECTION AND ANALYSIS: Two review authors independently selected studies. Data were extracted and quality-checked by one review author and checked by a second review author. A second review author checked the analyses. We assessed treatment effect using mean difference in a fixed-effect model and heterogeneity using the I2 statistic and the Chi2 test of heterogeneity. We assessed the overall quality of evidence using GRADE with GRADEpro software. MAIN RESULTS: We included nine RCTs randomising a total of 1414 participants (age range 24 to 70; mean age 45 to 59, where reported) to whole grain versus lower whole grain or refined grain control groups. We found no studies that reported the effect of whole grain diets on total cardiovascular mortality or cardiovascular events (total myocardial infarction, unstable angina, coronary artery bypass graft surgery, percutaneous transluminal coronary angioplasty, total stroke). All included studies reported the effect of whole grain diets on risk factors for cardiovascular disease including blood lipids and blood pressure. All studies were in primary prevention populations and had an unclear or high risk of bias, and no studies had an intervention duration greater than 16 weeks.Overall, we found no difference between whole grain and control groups for total cholesterol (mean difference 0.07, 95% confidence interval -0.07 to 0.21; 6 studies (7 comparisons); 722 participants; low-quality evidence).Using GRADE, we assessed the overall quality of the available evidence on cholesterol as low. Four studies were funded by independent national and government funding bodies, while the remaining studies reported funding or partial funding by organisations with commercial interests in cereals. AUTHORS' CONCLUSIONS: There is insufficient evidence from RCTs of an effect of whole grain diets on cardiovascular outcomes or on major CVD risk factors such as blood lipids and blood pressure. Trials were at unclear or high risk of bias with small sample sizes and relatively short-term interventions, and the overall quality of the evidence was low. There is a need for well-designed, adequately powered RCTs with longer durations assessing cardiovascular events as well as cardiovascular risk factors.
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Doenças Cardiovasculares/prevenção & controle , Grão Comestível , Adulto , Idoso , Doenças Cardiovasculares/sangue , Colesterol/sangue , HDL-Colesterol/sangue , LDL-Colesterol/sangue , Doença das Coronárias/sangue , Doença das Coronárias/dietoterapia , Humanos , Pessoa de Meia-Idade , Ensaios Clínicos Controlados Aleatórios como Assunto , Fatores de Risco , Triglicerídeos/sangueRESUMO
BACKGROUND: Adolescent overweight and obesity has increased globally, and can be associated with short- and long-term health consequences. Modifying known dietary and behavioural risk factors through behaviour changing interventions (BCI) may help to reduce childhood overweight and obesity. This is an update of a review published in 2009. OBJECTIVES: To assess the effects of diet, physical activity and behavioural interventions for the treatment of overweight or obese adolescents aged 12 to 17 years. SEARCH METHODS: We performed a systematic literature search in: CENTRAL, MEDLINE, Embase, PsycINFO, CINAHL, LILACS, and the trial registers ClinicalTrials.gov and ICTRP Search Portal. We checked references of identified studies and systematic reviews. There were no language restrictions. The date of the last search was July 2016 for all databases. SELECTION CRITERIA: We selected randomised controlled trials (RCTs) of diet, physical activity and behavioural interventions for treating overweight or obesity in adolescents aged 12 to 17 years. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed risk of bias, evaluated the overall quality of the evidence using the GRADE instrument and extracted data following the guidelines of the Cochrane Handbook for Systematic Reviews of Interventions. We contacted trial authors for additional information. MAIN RESULTS: We included 44 completed RCTs (4781 participants) and 50 ongoing studies. The number of participants in each trial varied (10 to 521) as did the length of follow-up (6 to 24 months). Participants ages ranged from 12 to 17.5 years in all trials that reported mean age at baseline. Most of the trials used a multidisciplinary intervention with a combination of diet, physical activity and behavioural components. The content and duration of the intervention, its delivery and the comparators varied across trials. The studies contributing most information to outcomes of weight and body mass index (BMI) were from studies at a low risk of bias, but studies with a high risk of bias provided data on adverse events and quality of life.The mean difference (MD) of the change in BMI at the longest follow-up period in favour of BCI was -1.18 kg/m2 (95% confidence interval (CI) -1.67 to -0.69); 2774 participants; 28 trials; low quality evidence. BCI lowered the change in BMI z score by -0.13 units (95% CI -0.21 to -0.05); 2399 participants; 20 trials; low quality evidence. BCI lowered body weight by -3.67 kg (95% CI -5.21 to -2.13); 1993 participants; 20 trials; moderate quality evidence. The effect on weight measures persisted in trials with 18 to 24 months' follow-up for both BMI (MD -1.49 kg/m2 (95% CI -2.56 to -0.41); 760 participants; 6 trials and BMI z score MD -0.34 (95% CI -0.66 to -0.02); 602 participants; 5 trials).There were subgroup differences showing larger effects for both BMI and BMI z score in studies comparing interventions with no intervention/wait list control or usual care, compared with those testing concomitant interventions delivered to both the intervention and control group. There were no subgroup differences between interventions with and without parental involvement or by intervention type or setting (health care, community, school) or mode of delivery (individual versus group).The rate of adverse events in intervention and control groups was unclear with only five trials reporting harms, and of these, details were provided in only one (low quality evidence). None of the included studies reported on all-cause mortality, morbidity or socioeconomic effects.BCIs at the longest follow-up moderately improved adolescent's health-related quality of life (standardised mean difference 0.44 ((95% CI 0.09 to 0.79); P = 0.01; 972 participants; 7 trials; 8 comparisons; low quality of evidence) but not self-esteem.Trials were inconsistent in how they measured dietary intake, dietary behaviours, physical activity and behaviour. AUTHORS' CONCLUSIONS: We found low quality evidence that multidisciplinary interventions involving a combination of diet, physical activity and behavioural components reduce measures of BMI and moderate quality evidence that they reduce weight in overweight or obese adolescents, mainly when compared with no treatment or waiting list controls. Inconsistent results, risk of bias or indirectness of outcome measures used mean that the evidence should be interpreted with caution. We have identified a large number of ongoing trials (50) which we will include in future updates of this review.
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Terapia Comportamental , Índice de Massa Corporal , Exercício Físico , Comportamento Alimentar , Sobrepeso/terapia , Obesidade Infantil/terapia , Adolescente , Terapia Combinada , Humanos , Qualidade de Vida , Ensaios Clínicos Controlados Aleatórios como AssuntoRESUMO
BACKGROUND: Most people with type 2 diabetes are overweight, so initial treatment is aimed at reducing weight and increasing physical activity. Even modest weight loss can improve control of blood glucose. If drug treatment is necessary, the drug of first choice is metformin. However, some people cannot tolerate metformin, which causes diarrhoea in about 10%, and it cannot be used in people with renal impairment. This review appraises three of the newest class of drugs for monotherapy when metformin cannot be used, the sodium-glucose co-transporter 2 (SGLT2) inhibitors. OBJECTIVE: To review the clinical effectiveness and cost-effectiveness of dapagliflozin (Farxiga, Bristol-Myers Squibb, Luton, UK), canagliflozin (Invokana, Janssen, High Wycombe, UK) and empagliflozin (Jardiance, Merck & Co., Darmstadt, Germany), in monotherapy in people who cannot take metformin. SOURCES: MEDLINE (1946 to February 2015) and EMBASE (1974 to February 2015) for randomised controlled trials lasting 24 weeks or more. For adverse events, a wider range of studies was used. Three manufacturers provided submissions. METHODS: Systematic review and economic evaluation. A network meta-analysis was carried out involving the three SGLT2 inhibitors and key comparators. Critical appraisal of submissions from three manufacturers. RESULTS: We included three trials of dapagliflozin and two each for canagliflozin and empagliflozin. The trials were of good quality. The canagliflozin and dapagliflozin trials compared them with placebo, but the two empagliflozin trials included active comparators. All three drugs were shown to be effective in improving glycaemic control, promoting weight loss and lowering blood pressure (BP). LIMITATIONS: There were no head-to-head trials of the different flozins, and no long-term data on cardiovascular outcomes in this group of patients. Most trials were against placebo. The trials were done in patient groups that were not always comparable, for example in baseline glycated haemoglobin or body mass index. Data on elderly patients were lacking. CONCLUSIONS: Dapagliflozin, canagliflozin and empagliflozin are effective in improving glycaemic control, with added benefits of some reductions in BP and weight. Adverse effects are urinary and genital tract infections in a small proportion of users. In monotherapy, the three drugs do not appear cost-effective compared with gliclazide or pioglitazone, but may be competitive against sitagliptin (Januvia, Boehringer Ingelheim, Bracknell, UK). FUNDING: The National Institute for Health Research Health Technology Assessment programme.
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Diabetes Mellitus Tipo 2/tratamento farmacológico , Hipoglicemiantes/economia , Hipoglicemiantes/uso terapêutico , Inibidores do Transportador 2 de Sódio-Glicose , Compostos Benzidrílicos/economia , Compostos Benzidrílicos/uso terapêutico , Glicemia , Pressão Sanguínea , Índice de Massa Corporal , Canagliflozina/economia , Canagliflozina/uso terapêutico , Análise Custo-Benefício , Relação Dose-Resposta a Droga , Glucosídeos/economia , Glucosídeos/uso terapêutico , Hemoglobinas Glicadas , Humanos , Hipoglicemiantes/administração & dosagem , Hipoglicemiantes/efeitos adversos , Modelos Econométricos , Qualidade de Vida , Anos de Vida Ajustados por Qualidade de Vida , Ensaios Clínicos Controlados Aleatórios como AssuntoAssuntos
Doenças Cardiovasculares/prevenção & controle , Dieta Saudável , Fibras na Dieta/administração & dosagem , Comportamento de Redução do Risco , Doenças Cardiovasculares/diagnóstico , Doenças Cardiovasculares/epidemiologia , Distribuição de Qui-Quadrado , Medicina Baseada em Evidências , Humanos , Razão de Chances , Fatores de Proteção , Ensaios Clínicos Controlados Aleatórios como Assunto , Recomendações Nutricionais , Fatores de RiscoRESUMO
BACKGROUND: Natural fluorescence in the eye may be increased or decreased by diseases that affect the retina. Imaging methods based on confocal scanning laser ophthalmoscopy (cSLO) can detect this 'fundus autofluorescence' (FAF) by illuminating the retina using a specific light 'excitation wavelength'. FAF imaging could assist the diagnosis or monitoring of retinal conditions. However, the accuracy of the method for diagnosis or monitoring is unclear. OBJECTIVE: To conduct a systematic review to determine the accuracy of FAF imaging using cSLO for the diagnosis or monitoring of retinal conditions, including monitoring of response to therapy. DATA SOURCES: Electronic bibliographic databases; scrutiny of reference lists of included studies and relevant systematic reviews; and searches of internet pages of relevant organisations, meetings and trial registries. Databases included MEDLINE, EMBASE, The Cochrane Library, Web of Science and the Medion database of diagnostic accuracy studies. Searches covered 1990 to November 2014 and were limited to the English language. REVIEW METHODS: References were screened for relevance using prespecified inclusion criteria to capture a broad range of retinal conditions. Two reviewers assessed titles and abstracts independently. Full-text versions of relevant records were retrieved and screened by one reviewer and checked by a second. Data were extracted and critically appraised using the Quality Assessment of Diagnostic Accuracy Studies criteria (QUADAS) for assessing risk of bias in test accuracy studies by one reviewer and checked by a second. At all stages any reviewer disagreement was resolved through discussion or arbitration by a third reviewer. RESULTS: Eight primary research studies have investigated the diagnostic accuracy of FAF imaging in retinal conditions: choroidal neovascularisation (one study), reticular pseudodrusen (three studies), cystoid macular oedema (two studies) and diabetic macular oedema (two studies). Sensitivity of FAF imaging using an excitation wavelength of 488 nm was generally high (range 81-100%), but was lower (55% and 32%) in two studies using longer excitation wavelengths (514 nm and 790 nm, respectively). Specificity ranged from 34% to 100%. However, owing to limitations of the data, none of the studies provide conclusive evidence of the diagnostic accuracy of FAF imaging. LIMITATIONS: No studies on the accuracy of FAF imaging for monitoring the progression of retinal conditions or response to therapy were identified. Owing to study heterogeneity, pooling of diagnostic outcomes in meta-analysis was not conducted. All included studies had high risk of bias. In most studies the patient spectrum was not reflective of those who would present in clinical practice and no studies adequately reported how FAF images were interpreted. CONCLUSIONS: Although already in use in clinical practice, it is unclear whether or not FAF imaging is accurate, and whether or not it is applied and interpreted consistently for the diagnosis and/or monitoring of retinal conditions. Well-designed prospective primary research studies, which conform to the paradigm of diagnostic test accuracy assessment, are required to investigate the accuracy of FAF imaging in diagnosis and monitoring of inherited retinal dystrophies, early age-related macular degeneration, geographic atrophy and central serous chorioretinopathy. STUDY REGISTRATION: This study is registered as PROSPERO CRD42014014997. FUNDING: The National Institute for Health Research Health Technology Assessment programme.
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Imagem Óptica/métodos , Doenças Retinianas/diagnóstico por imagem , Doenças Retinianas/diagnóstico , Avaliação da Tecnologia Biomédica , Neovascularização de Coroide/diagnóstico , Neovascularização de Coroide/diagnóstico por imagem , Retinopatia Diabética/diagnóstico , Retinopatia Diabética/diagnóstico por imagem , Humanos , Edema Macular/diagnóstico , Edema Macular/diagnóstico por imagem , Estudos ProspectivosRESUMO
BACKGROUND: Child overweight and obesity has increased globally, and can be associated with short- and long-term health consequences. OBJECTIVES: To assess the effects of diet, physical activity, and behavioural interventions for the treatment of overweight or obesity in preschool children up to the age of 6 years. SEARCH METHODS: We performed a systematic literature search in the databases Cochrane Library, MEDLINE, EMBASE, PsycINFO, CINAHL, and LILACS, as well as in the trial registers ClinicalTrials.gov and ICTRP Search Portal. We also checked references of identified trials and systematic reviews. We applied no language restrictions. The date of the last search was March 2015 for all databases. SELECTION CRITERIA: We selected randomised controlled trials (RCTs) of diet, physical activity, and behavioural interventions for treating overweight or obesity in preschool children aged 0 to 6 years. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed risk of bias, evaluated the overall quality of the evidence using the GRADE instrument, and extracted data following the Cochrane Handbook for Systematic Reviews of Interventions. We contacted trial authors for additional information. MAIN RESULTS: We included 7 RCTs with a total of 923 participants: 529 randomised to an intervention and 394 to a comparator. The number of participants per trial ranged from 18 to 475. Six trials were parallel RCTs, and one was a cluster RCT. Two trials were three-arm trials, each comparing two interventions with a control group. The interventions and comparators in the trials varied. We categorised the comparisons into two groups: multicomponent interventions and dietary interventions. The overall quality of the evidence was low or very low, and six trials had a high risk of bias on individual 'Risk of bias' criteria. The children in the included trials were followed up for between six months and three years.In trials comparing a multicomponent intervention with usual care, enhanced usual care, or information control, we found a greater reduction in body mass index (BMI) z score in the intervention groups at the end of the intervention (6 to 12 months): mean difference (MD) -0.3 units (95% confidence interval (CI) -0.4 to -0.2); P < 0.00001; 210 participants; 4 trials; low-quality evidence, at 12 to 18 months' follow-up: MD -0.4 units (95% CI -0.6 to -0.2); P = 0.0001; 202 participants; 4 trials; low-quality evidence, and at 2 years' follow-up: MD -0.3 units (95% CI -0.4 to -0.1); 96 participants; 1 trial; low-quality evidence.One trial stated that no adverse events were reported; the other trials did not report on adverse events. Three trials reported health-related quality of life and found improvements in some, but not all, aspects. Other outcomes, such as behaviour change and parent-child relationship, were inconsistently measured.One three-arm trial of very low-quality evidence comparing two types of diet with control found that both the dairy-rich diet (BMI z score change MD -0.1 units (95% CI -0.11 to -0.09); P < 0.0001; 59 participants) and energy-restricted diet (BMI z score change MD -0.1 units (95% CI -0.11 to -0.09); P < 0.0001; 57 participants) resulted in greater reduction in BMI than the comparator at the end of the intervention period, but only the dairy-rich diet maintained this at 36 months' follow-up (BMI z score change in MD -0.7 units (95% CI -0.71 to -0.69); P < 0.0001; 52 participants). The energy-restricted diet had a worse BMI outcome than control at this follow-up (BMI z score change MD 0.1 units (95% CI 0.09 to 0.11); P < 0.0001; 47 participants). There was no substantial difference in mean daily energy expenditure between groups. Health-related quality of life, adverse effects, participant views, and parenting were not measured.No trial reported on all-cause mortality, morbidity, or socioeconomic effects.All results should be interpreted cautiously due to their low quality and heterogeneous interventions and comparators. AUTHORS' CONCLUSIONS: Muticomponent interventions appear to be an effective treatment option for overweight or obese preschool children up to the age of 6 years. However, the current evidence is limited, and most trials had a high risk of bias. Most trials did not measure adverse events. We have identified four ongoing trials that we will include in future updates of this review.The role of dietary interventions is more equivocal, with one trial suggesting that dairy interventions may be effective in the longer term, but not energy-restricted diets. This trial also had a high risk of bias.