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1.
Health Technol Assess ; 25(53): 1-52, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34505829

RESUMO

BACKGROUND: The use of placebo comparisons for randomised trials assessing the efficacy of surgical interventions is increasingly being considered. However, a placebo control is a complex type of comparison group in the surgical setting and, although powerful, presents many challenges. OBJECTIVES: To provide a summary of knowledge on placebo controls in surgical trials and to summarise any recommendations for designers, evaluators and funders of placebo-controlled surgical trials. DESIGN: To carry out a state-of-the-art workshop and produce a corresponding report involving key stakeholders throughout. SETTING: A workshop to discuss and summarise the existing knowledge and to develop the new guidelines. RESULTS: To assess what a placebo control entails and to assess the understanding of this tool in the context of surgery is considered, along with when placebo controls in surgery are acceptable (and when they are desirable). We have considered ethics arguments and regulatory requirements, how a placebo control should be designed, how to identify and mitigate risk for participants in these trials, and how such trials should be carried out and interpreted. The use of placebo controls is justified in randomised controlled trials of surgical interventions provided that there is a strong scientific and ethics rationale. Surgical placebos might be most appropriate when there is poor evidence for the efficacy of the procedure and a justified concern that results of a trial would be associated with a high risk of bias, particularly because of the placebo effect. CONCLUSIONS: The use of placebo controls is justified in randomised controlled trials of surgical interventions provided that there is a strong scientific and ethics rationale. Feasibility work is recommended to optimise the design and implementation of randomised controlled trials. An outline for best practice was produced in the form of the Applying Surgical Placebo in Randomised Evaluations (ASPIRE) guidelines for those considering the use of a placebo control in a surgical randomised controlled trial. LIMITATIONS: Although the workshop participants involved international members, the majority of participants were from the UK. Therefore, although every attempt was made to make the recommendations applicable to all health systems, the guidelines may, unconsciously, be particularly applicable to clinical practice in the UK NHS. FUTURE WORK: Future work should evaluate the use of the ASPIRE guidelines in making decisions about the use of a placebo-controlled surgical trial. In addition, further work is required on the appropriate nomenclature to adopt in this space. FUNDING: Funded by the Medical Research Council UK and the National Institute for Health Research as part of the Medical Research Council-National Institute for Health Research Methodology Research programme.


Assuntos
Efeito Placebo , Humanos , Projetos de Pesquisa
2.
Colorectal Dis ; 23(11): 2821-2833, 2021 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-34331836

RESUMO

AIM: Parastomal hernia (PSH) is a common complication following stoma creation. Previous reviews found mesh reinforcement during initial stoma creation beneficial in reducing PSH incidence. Since then, several multicentre randomised controlled trials (RCTs) produced widely ranging results rendering previous findings debatable. This current review assessed whether combining the latest larger multicentre RCTs would alter the previous findings. METHODS: The Cochrane Library, MEDLINE and Embase were searched from the respective dates of inception until 15 January 2021. RCTs were included if they compared mesh with no mesh during initial stoma creation in adult patients to prevent PSH. Included RCTs were summarised narratively and meta-analysed to estimate the relative risk (RR) of PSH incidence (primary analysis), peristomal complications and PSH repair (secondary analyses). Several subgroup analyses were performed, including mesh type (synthetic/biologic), surgical technique (open/laparoscopic) and mesh position (sublay/intraperitoneal). RESULTS: Thirteen RCTs were included in the primary meta-analysis (1070 patients); PSH incidence was reduced in patients with mesh compared with patients without mesh at maximal follow-up (RR = 0.54; 95% CI 0.39-0.77; I2  = 67%; P < 0.01). The number of PSH repairs was fewer in patients who had mesh (RR = 0.63; 0.35-1.14; I2  = 6%; P = 0.39), with no difference in peristomal complications (RR = 0.96; 0.55-1.70; I2  = 0%; P = 0.71), comparing with no mesh. Subgroup analyses suggested that placing synthetic mesh using an open sublay technique might be more beneficial. CONCLUSIONS: Prophylactic mesh reinforcement during initial stoma creation reduces PSH incidence and potentially its repair, without an increase in peristomal complications. However, substantial heterogeneity among included RCTs limits confidence in the results.

3.
Colorectal Dis ; 23(11): 2967-2979, 2021 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-34331840

RESUMO

AIM: Parastomal hernia (PSH) is a common problem following colostomy. Using prophylactic mesh during end colostomy creation may reduce PSH incidence, but concerns exist regarding the optimal type of mesh, potential long-term complications, and cost-effectiveness of its use. We evaluated the cost-effectiveness of mesh prophylaxis to prevent PSH in patients undergoing end colostomy creation for rectal cancer. METHODS: We developed a decision-analytical model, stratified by rectal cancer stages I-IV, to estimate the lifetime costs, quality-adjusted life-years (QALYs) and net monetary benefits (NMBs) of synthetic, biologic and no mesh from a UK NHS perspective. We pooled the mesh-related relative risks of PSH from 13 randomised controlled trials (RCTs) and superimposed these on the baseline (no mesh) risk from a population-based cohort. Uncertainty was assessed in sensitivity analyses. RESULTS: Synthetic mesh was less costly and more effective than biologic and no mesh to prevent PSH for all rectal cancer stages. At the willingness-to-pay threshold of £20,000/QALY, the incremental NMBs (95% CI) ranged between £1,706 (£1,692 to £1,720) (stage I) and £684 (£678 to £690) (stage IV) for synthetic versus no mesh, and £2,038 (£1,997 to £2,079) (stage I) and £1,671 (£1,653 to £1,689) (stage IV) for synthetic versus biologic mesh. Synthetic mesh was more cost-effective than no mesh unless the relative risk of PSH was ≥0.95 for stages I-III and ≥0.93 for stage IV. [Correction added on 05 October 2021 after first online publication: The estimation of health outcomes (QALYs) for all three interventions evaluated (synthetic mesh; biologic mesh; no mesh) have been corrected in this version.] CONCLUSIONS: Synthetic mesh was the most cost-effective strategy to prevent the formation of PSH in patients after end colostomy for any rectal cancer stage; however, conclusions are dependent on which subset of RCTs are considered to provide the most robust evidence.

4.
Resuscitation ; 167: 1-9, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-34126133

RESUMO

AIM: Optimal airway management during out-of-hospital cardiac arrest (OHCA) is uncertain. Complications from tracheal intubation (TI) may be avoided with supraglottic airway (SGA) devices. The AIRWAYS-2 cluster randomised controlled trial (ISRCTN08256118) compared the i-gel SGA with TI as the initial advanced airway management (AAM) strategy by paramedics treating adults with non-traumatic OHCA. This paper reports the trial cost-effectiveness analysis. METHODS: A within-trial cost-effectiveness analysis of the i-gel compared with TI was conducted, with a six-month time horizon, from the perspective of the UK National Health Service (NHS) and personal social services. The primary outcome measure was quality-adjusted life years (QALYs), estimated using the EQ-5D-5L questionnaire. Multilevel linear regression modelling was used to account for clustering by paramedic when combining costs and outcomes. RESULTS: 9296 eligible patients were attended by 1382 trial paramedics and enrolled in the AIRWAYS-2 trial (4410 TI, 4886 i-gel). Mean QALYs to six months were 0.03 in both groups (i-gel minus TI difference -0.0015, 95% CI -0.0059 to 0.0028). Total costs per participant up to six months post-OHCA were £3570 and £3413 in the i-gel and TI groups respectively (mean difference £157, 95% CI -£270 to £583). Based on mean difference point estimates, TI was more effective and less costly than i-gel; however differences were small and there was great uncertainty around these results. CONCLUSION: The small differences between groups in QALYs and costs shows no difference in the cost-effectiveness of the i-gel and TI when used as the initial AAM strategy in adults with non-traumatic OHCA.


Assuntos
Reanimação Cardiopulmonar , Serviços Médicos de Emergência , Parada Cardíaca Extra-Hospitalar , Adulto , Análise Custo-Benefício , Humanos , Intubação Intratraqueal , Parada Cardíaca Extra-Hospitalar/terapia , Medicina Estatal
5.
JMIR Res Protoc ; 10(5): e22533, 2021 May 31.
Artigo em Inglês | MEDLINE | ID: mdl-34057417

RESUMO

BACKGROUND: Barth syndrome is a rare, life-threatening, X-linked recessive genetic disease that predominantly affects young males and is caused by abnormal mitochondrial lipid metabolism. Currently, there is no definitive treatment for Barth syndrome other than interventions to ameliorate acute symptoms, such as heart failure, cardiac arrhythmias, neutropenia, and severe muscle fatigue. Previous mechanistic studies have identified the lipid-lowering drug bezafibrate as a promising potential treatment; however, to date, no human trials have been performed in this population. OBJECTIVE: The aim of this study is to determine whether bezafibrate (and resveratrol in vitro) will increase mitochondrial biogenesis and potentially modify the cellular ratio of monolysocardiolipin (MLCL) to tetralinoleoyl-cardiolipin (L4-CL), ameliorating the disease phenotype in those living with the disease. METHODS: The CARDIOMAN (Cardiolipin Manipulation) study is a UK single-center, double-blinded, randomized, placebo-controlled crossover study investigating the efficacy of bezafibrate in participants with Barth syndrome. Treatment was administered in two 15-week phases with a minimum washout period of 1 month between the phases where no treatment was administered. The primary outcome is peak oxygen consumption (VO2 peak). Secondary outcomes include MLCL/L4-CL ratio and CL profile in blood cells, amino acid expression, phosphocreatine to adenosine triphosphate ratio in cardiac muscle and skeletal muscle oxidative function on phosphorus-31 magnetic resonance spectroscopy, quality of life using the Pediatric Quality of Life Inventory questionnaire, absolute neutrophil count, cardiac function and rhythm profiles at rest and during exercise, and mitochondrial organization and function assessments. Outcomes were assessed at baseline and during the final week of each treatment phase. RESULTS: A total of 12 patients were scheduled to participate across three consecutive research clinics between March and April 2019. In total, 11 participants were recruited, and the follow-up was completed in January 2020. Data analysis is ongoing, with publication expected in 2021. CONCLUSIONS: This trial was approved by the United Kingdom National Research Ethics Service Committee and the Medicines and Healthcare products Regulatory Agency. The feasibility of the CARDIOMAN study will help to inform the future conduct of randomized controlled trials in rare disease populations as well as testing the efficacy of bezafibrate as a potential treatment for the disease and advancing the mechanistic understanding of Barth syndrome. TRIAL REGISTRATION: International Standard Randomized Controlled Trial Number (ISRCTN): 58006579; https://www.isrctn.com/ISRCTN58006579. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/22533.

6.
Semin Arthritis Rheum ; 51(3): 601-606, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-33875246

RESUMO

OBJECTIVES: To develop an operational definition of contextual factors (CF) [1]. METHODS: Based on previously conducted interviews, we presented three CF types in a Delphi survey; Effect Modifying -, Outcome Influencing - and Measurement Affecting CFs. Subsequently, a virtual Special Interest Group (SIG) session was held for in depth discussion of Effect Modifying CFs. RESULTS: Of 161 Delphi participants, 129 (80%) completed both rounds. After two rounds, we reached consensus (≥70% agreeing) for all but two statements. The 45 SIG participants were broadly supportive. CONCLUSION: Through consensus we developed an operational definition of CFs, which was well received by OMERACT members.


Assuntos
Reumatologia , Consenso , Humanos , Avaliação de Resultados em Cuidados de Saúde , Projetos de Pesquisa , Inquéritos e Questionários
7.
Colorectal Dis ; 23(7): 1900-1908, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-33686656

RESUMO

AIM: Abdominal surgery sometimes necessitates the creation of a stoma, which can cause future complications including parastomal hernia (PSH), an incisional hernia adjacent to and related to the stoma. PSH affects approximately 40% of patients within 2 years of stoma formation. Complications of PSH reduce a patient's quality of life and can be severe (e.g. bowel obstruction). PSHs are difficult to manage and can recur after surgical repair. Therefore, it is very important to prevent a PSH. Surgeons create stomas in different ways and both patient and surgical factors are believed to influence the development of PSH. The aim of the CIPHER study is to investigate the influence of different surgical techniques on the development of PSH. METHOD: The UK cohort study to investigate the prevention of parastomal hernia (the CIPHER study) aims to recruit 4000 patients undergoing elective or expedited surgery with the intention of forming an ileostomy or colostomy, irrespective of the primary indication for the planned surgery. For each patient, surgeons will describe their methods of trephine formation, mesh reinforcement of the stoma trephine, use of the stoma as a specimen extraction site and wound closure. The primary outcome will be incident PSH during follow-up, defined as symptoms of PSH (custom-designed questionnaire) and anatomical PSH, ascertained by independent reading of usual care CT scans. Secondary outcomes will include surgical site infection, the Comprehensive Complication Index, quality of life (EQ-5D-5L and SF-12), PSH repair and use of NHS resources. RESULTS: Results of the study will be submitted for publication in peer-reviewed journals. All publications relating to the results of CIPHER will use a corporate authorship, 'The CIPHER Study Investigators' with named writing committee members. CONCLUSION: The CIPHER study will be the first to investigate detailed surgical methods of stoma formation in a large, representative cohort of patients with a range of primary indications, both cancer and noncancer.


Assuntos
Hérnia Ventral , Hérnia Incisional , Estomas Cirúrgicos , Estudos de Coortes , Colostomia , Hérnia Ventral/etiologia , Hérnia Ventral/cirurgia , Humanos , Hérnia Incisional/etiologia , Hérnia Incisional/prevenção & controle , Recidiva Local de Neoplasia , Qualidade de Vida , Telas Cirúrgicas , Estomas Cirúrgicos/efeitos adversos , Reino Unido
8.
Eye (Lond) ; 35(2): 592-600, 2021 02.
Artigo em Inglês | MEDLINE | ID: mdl-32367004

RESUMO

AIMS: This study aims to quantify the diagnostic test-accuracy of three visual function self-monitoring tests for detection of active disease in patients with neovascular age-related macular degeneration (nAMD) when compared with usual care. An integrated qualitative study will investigate the acceptability of these home-based testing strategies. METHODS: All consenting participants are provided with an equipment pack containing an iPod touch with two vision test applications installed and a paper journal of reading tests. Participants self-monitor their vision at home each week with all three tests for 12-18 months. Usual care continues over this period. Key eligibility criteria are: age ≥50 years; at least one eye with AMD with ≥6-≤42 months since first AMD treatment; and vision not worse than Snellen 6/60, LogMAR 1.04 or 33 letters. The primary outcome, and reference standard, is diagnosis of active disease during usual care monitoring in the Hospital Eye Service. Secondary outcomes include duration of study participation, ability of participants to do the tests, adherence to weekly testing and acceptability of the tests to participants. CONCLUSIONS: Recruitment is in progress at five NHS centres. Challenges in procuring equipment, setting up the devices and transporting devices containing lithium batteries to participating sites delayed the start of recruitment. The study will describe the performance of the tests self-administered at home in detecting active disease compared to usual care monitoring. It will also describe the feasibility of the NHS implementing patient-administered electronic tests or similar applications at home for monitoring health.


Assuntos
Degeneração Macular , Degeneração Macular Exsudativa , Humanos , Degeneração Macular/diagnóstico , Pessoa de Meia-Idade , Acuidade Visual , Degeneração Macular Exsudativa/diagnóstico
9.
Ann Rheum Dis ; 80(2): 242-249, 2021 02.
Artigo em Inglês | MEDLINE | ID: mdl-33055082

RESUMO

OBJECTIVES: The Outcome Measures in Rheumatology Initiative established the Contextual Factors Working Group to guide the understanding, identification and handling of contextual factors for clinical trials. In clinical research, different uses of the term 'contextual factors' exist. This study explores the perspectives of researchers (including clinicians) and patients in defining 'contextual factor' and its related terminology, identifying such factors and accounting for them in trials across rheumatology. METHODS: We conducted individual semistructured interviews with researchers (including clinicians) who have experience within the field of contextual factors in clinical trials or other potentially relevant areas, and small focus group interviews with patients with rheumatic conditions. We transcribed the interviews and applied qualitative content analysis. RESULTS: We interviewed 12 researchers and 7 patients. Researcher's and patient's descriptions of contextual factors were categorised into two broad themes, each comprising two contextual factors types. The 'treatment effect' theme focused on factors explaining variations in treatment effects (A) among patients and (B) among studies. The 'outcome measurement' theme focused on factors that explain (C) variations in the measurement result itself (apart from actual changes/differences in the outcome) and (D) variations in the outcome itself (beside treatment of interest). Methods for identifying and handling contextual factors differed among these themes and types. CONCLUSIONS: Two main themes for contextual factors with four types of contextual factors were identified based on input from researchers and patients. This will guide operationalisation of contextual factors. Further research should refine our findings and establish consensus among relevant stakeholders.


Assuntos
Ensaios Clínicos como Assunto/psicologia , Pesquisadores/psicologia , Reumatologistas/psicologia , Reumatologia/normas , Terminologia como Assunto , Consenso , Feminino , Grupos Focais , Humanos , Masculino , Pessoa de Meia-Idade , Avaliação de Resultados em Cuidados de Saúde , Pesquisa Qualitativa , Projetos de Pesquisa , Doenças Reumáticas/psicologia
10.
J Am Heart Assoc ; 9(24): e016495, 2020 12 15.
Artigo em Inglês | MEDLINE | ID: mdl-33305660

RESUMO

Background To assess differences in platelet inhibition during ticagrelor monotherapy (TIC) or dual therapy with ticagrelor and aspirin (TIC+ASP) in patients after percutaneous coronary intervention using a comprehensive panel of functional tests. Methods and Results In a single-center parallel group, open label, randomized controlled trial, 110 participants were randomized to receive either TIC (n=55) or TIC+ASP (n=55) for 4 weeks. The primary outcome was the platelet aggregation response with 10 µmol/L thrombin receptor activation peptide-6 (TRAP-6). The secondary outcomes were platelet aggregation responses and binding of surface activation markers with a panel of other activators. The mean percentage aggregation for 10 µmol/L TRAP-6 was similar for the TIC and TIC+ASP groups (mean difference+4.29; 95% CI, -0.87 to +9.46). Aggregation was higher in the TIC group compared with the TIC+ASP group with 1 µg/mL (+6.47; +2.04 to +10.90) and 0.5 µg/mL (+14.00; +7.63 to +20.39) collagen related peptide. Aggregation responses with 5 µmol/L TRAP-6, 5 µmol/L or 2.5 µmol/L thromboxane A2 receptor agonist and surface activation marker binding with 5 µmol/L TRAP-6 or 0.5 µg/mL collagen related peptide were the same between the treatment groups. Conclusions Patients with PCI show similar levels of inhibition of most platelet activation pathways with TIC compared with dual therapy with TIC + ASP. However, the greater aggregation response with collagen related peptide during TIC indicates incomplete inhibition of glycoprotein VI (collagen) receptor-mediated platelet activation. This difference in pharmacodynamic response to anti-platelet medication may contribute to the lower bleeding rates observed with TIC compared with dual antiplatelet therapy in recent clinical trials. Registration Information URL: https://www.isrctn.com; Unique Identifier ISRCTN84335288.


Assuntos
Síndrome Coronariana Aguda/tratamento farmacológico , Quimioterapia Combinada/efeitos adversos , Intervenção Coronária Percutânea/efeitos adversos , Antagonistas do Receptor Purinérgico P2Y/farmacologia , Ticagrelor/farmacologia , Síndrome Coronariana Aguda/sangue , Idoso , Ácido Araquidônico/sangue , Aspirina/uso terapêutico , Quimioterapia Combinada/métodos , Terapia Antiplaquetária Dupla/efeitos adversos , Terapia Antiplaquetária Dupla/métodos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Fragmentos de Peptídeos/efeitos dos fármacos , Agregação Plaquetária/efeitos dos fármacos , Inibidores da Agregação Plaquetária/uso terapêutico , Testes de Função Plaquetária/métodos , Antagonistas do Receptor Purinérgico P2Y/administração & dosagem , Antagonistas do Receptor Purinérgico P2Y/uso terapêutico , Receptores de Tromboxano A2 e Prostaglandina H2/agonistas , Ticagrelor/administração & dosagem , Ticagrelor/uso terapêutico
12.
Cochrane Database Syst Rev ; 10: CD013101, 2020 10 12.
Artigo em Inglês | MEDLINE | ID: mdl-33045104

RESUMO

BACKGROUND: Corticosteroids are routinely given to children undergoing cardiac surgery with cardiopulmonary bypass (CPB) in an attempt to ameliorate the inflammatory response. Their use is still controversial and the decision to administer the intervention can vary by centre and/or by individual doctors within that centre. OBJECTIVES: This review is designed to assess the benefits and harms of prophylactic corticosteroids in children between birth and 18 years of age undergoing cardiac surgery with CPB. SEARCH METHODS: We searched CENTRAL, MEDLINE, Embase and Conference Proceedings Citation Index-Science in June 2020. We also searched four clinical trials registers and conducted backward and forward citation searching of relevant articles. SELECTION CRITERIA: We included studies of prophylactic administration of corticosteroids, including single and multiple doses, and all types of corticosteroids administered via any route and at any time-point in the perioperative period. We excluded studies if steroids were administered therapeutically. We included individually randomised controlled trials (RCTs), with two or more groups (e.g. multi-drug or dose comparisons with a control group) but not 'head-to-head' trials without a placebo or a group that did not receive corticosteroids. We included studies in children, from birth up to 18 years of age, including preterm infants, undergoing cardiac surgery with the use of CPB. We also excluded studies in patients undergoing heart or lung transplantation, or both; studies in patients already receiving corticosteroids; in patients with abnormalities of the hypothalamic-pituitary-adrenal axis; and in patients given steroids at the time of cardiac surgery for indications other than cardiac surgery. DATA COLLECTION AND ANALYSIS: We used the Covidence systematic review manager to extract and manage data for the review. Two review authors independently assessed studies for inclusion, extracted data, and assessed risks of bias. We resolved disagreements by consensus or by consultation with a third review author. We assessed the certainty of evidence with GRADE. MAIN RESULTS: We found 3748 studies, of which 888 were duplicate records. Two studies had the same clinical trial registration number, but reported different populations and interventions. We therefore included them as separate studies. We screened titles and abstracts of 2868 records and reviewed full text reports for 84 studies to determine eligibility. We extracted data for 13 studies. Pooled analyses are based on eight studies. We reported the remaining five studies narratively due to zero events for both intervention and placebo in the outcomes of interest. Therefore, the final meta-analysis included eight studies with a combined population of 478 participants. There was a low or unclear risk of bias across the domains. There was moderate certainty of evidence that corticosteroids do not change the risk of in-hospital mortality (five RCTs; 313 participants; risk ratio (RR) 0.83, 95% confidence interval (CI) 0.33 to 2.07) for children undergoing cardiac surgery with CPB. There was high certainty of evidence that corticosteroids reduce the duration of mechanical ventilation (six RCTs; 421 participants; mean difference (MD) 11.37 hours lower, 95% CI -20.29 to -2.45) after the surgery. There was high-certainty evidence that the intervention probably made little to no difference to the length of postoperative intensive care unit (ICU) stay (six RCTs; 421 participants; MD 0.28 days lower, 95% CI -0.79 to 0.24) and moderate-certainty evidence that the intervention probably made little to no difference to the length of the postoperative hospital stay (one RCT; 176 participants; mean length of stay 22 days; MD -0.70 days, 95% CI -2.62 to 1.22). There was moderate certainty of evidence for no effect of the intervention on all-cause mortality at the longest follow-up (five RCTs; 313 participants; RR 0.83, 95% CI 0.33 to 2.07) or cardiovascular mortality at the longest follow-up (three RCTs; 109 participants; RR 0.40, 95% CI 0.07 to 2.46). There was low certainty of evidence that corticosteroids probably make little to no difference to children separating from CPB (one RCT; 40 participants; RR 0.20, 95% CI 0.01 to 3.92). We were unable to report information regarding adverse events of the intervention due to the heterogeneity of reporting of outcomes. We downgraded the certainty of evidence for several reasons, including imprecision due to small sample sizes, a single study providing data for an individual outcome, the inclusion of both appreciable benefit and harm in the confidence interval, and publication bias. AUTHORS' CONCLUSIONS: Corticosteroids  probably do not change the risk of mortality for children having heart surgery using CPB at any time point. They probably reduce the duration of postoperative ventilation in this context, but have little or no effect on the total length of postoperative ICU stay or total postoperative hospital stay. There was inconsistency in the adverse event outcomes reported which, consequently, could not be pooled. It is therefore impossible to provide any implications and policy-makers will be unable to make any recommendations for practice without evidence about adverse effects. The review highlighted the need for well-conducted RCTs powered for clinical outcomes to confirm or refute the effect of corticosteroids versus placebo in children having cardiac surgery with CPB. A core outcome set for adverse event reporting in the paediatric major surgery and intensive care setting is required.


Assuntos
Corticosteroides/uso terapêutico , Procedimentos Cirúrgicos Cardíacos/métodos , Ponte Cardiopulmonar/efeitos adversos , Inflamação/prevenção & controle , Adolescente , Corticosteroides/efeitos adversos , Viés , Procedimentos Cirúrgicos Cardíacos/mortalidade , Ponte Cardiopulmonar/mortalidade , Causas de Morte , Criança , Pré-Escolar , Dexametasona/uso terapêutico , Máquina Coração-Pulmão/efeitos adversos , Mortalidade Hospitalar , Humanos , Hidrocortisona/uso terapêutico , Lactente , Recém-Nascido , Inflamação/etiologia , Unidades de Terapia Intensiva Pediátrica/estatística & dados numéricos , Tempo de Internação , Metilprednisolona/uso terapêutico , Ensaios Clínicos Controlados Aleatórios como Assunto , Respiração Artificial/estatística & dados numéricos
13.
Resuscitation ; 157: 74-82, 2020 12.
Artigo em Inglês | MEDLINE | ID: mdl-33010371

RESUMO

AIM: The AIRWAYS-2 cluster randomised controlled trial compared the i-gel supraglottic airway device (SGA) with tracheal intubation (TI) as the first advanced airway management (AAM) strategy used by Emergency Medical Service clinicians (paramedics) treating adult patients with non-traumatic out-of-hospital cardiac arrest (OHCA). It showed no difference between the two groups in the primary outcome of modified Rankin Scale (mRS) score at 30 days/hospital discharge. This paper reports outcomes to 6 months. METHODS: Paramedics from four ambulance services in England were randomised 1:1 to use an i-gel SGA (759 paramedics) or TI (764 paramedics) as their initial approach to AAM. Adults who had a non-traumatic OHCA and were attended by a participating paramedic were enrolled automatically under a waiver of consent. Survivors were invited to complete questionnaires at three and six months after OHCA. Outcomes were analysed using regression methods. RESULTS: 767/9296 (8.3%) enrolled patients survived to 30 days/hospital discharge and 317/767 survivors (41.3%) consented and were followed-up to six months. No significant differences were found between the two treatment groups in the primary outcome measure (mRS score: 3 months: odds ratio (OR) for good recovery (i-gel/TI, OR) 0.89, 95% CI 0.69-1.14; 6 months OR 0.91, 95% CI 0.71-1.16). EQ-5D-5L scores were also similar between groups and sensitivity analyses did not alter the findings. CONCLUSION: There were no statistically significant differences between the TI and i-gel groups at three and six months. We therefore conclude that the initially reported finding of no significant difference between groups at 30 days/hospital discharge was sustained when the period of follow-up was extended to six months.


Assuntos
Reanimação Cardiopulmonar , Serviços Médicos de Emergência , Parada Cardíaca Extra-Hospitalar , Adulto , Manuseio das Vias Aéreas , Inglaterra , Humanos , Intubação Intratraqueal , Parada Cardíaca Extra-Hospitalar/terapia
14.
JAMA Ophthalmol ; 138(10): 1043-1051, 2020 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-32816002

RESUMO

Importance: When initiating anti-vascular endothelial growth factor (VEGF) treatment for patients with neovascular age-related macular degeneration (nAMD), knowledge of prognostic factors is important for advising patients and guiding treatment. We hypothesized that eyes with greater fluctuation in retinal thickness over time have worse outcomes than eyes with less variation. Objective: To investigate whether visual and anatomic outcomes in eyes with nAMD initiating anti-VEGF treatment are associated with fluctuations in retinal thickness. Design, Setting, and Participants: In this study using data from the Comparison of Age-Related Macular Degeneration Treatments Trials (CATT) and the Inhibition of VEGF in Age-Related Choroidal Neovascularization (IVAN) randomized clinical trial, people with previously untreated nAMD were included. Data were collected from February 2008 to November 2012, and data were analyzed from April 2017 to April 2020. Main Outcomes and Measures: Foveal center point thicknesses (FCPTs) were extracted from 1165 study eyes from CATT and 566 study eyes from the IVAN trial, excluding those with 3 measurements or less. For each eye, the SD of FCPT was calculated. Eyes were grouped by FCPT SD quartile. Associations of FCPT SD quartile with outcomes were quantified at month 24 or the last available visit by linear or logistic regression, adjusting for baseline best-corrected visual acuity (BCVA) and randomized allocations to drug and treatment regimen, for BCVA, development of fibrosis, and development of macular atrophy. Results: Of the 1731 included patients, 1058 (61.1%) were female, and the mean (SD) age was 78.6 (7.4) years. The median (interquartile range) FCPT SD was 40.2 (27.1-61.2) in the IVAN cohort and 59.0 (38.3-89.4) in the CATT cohort. After adjustment for baseline BCVA and trial allocations, BCVA worsened significantly across the quartiles of FCPT SD; the difference between the first and fourth quartiles was -6.27 Early Treatment Diabetic Retinopathy Study letters (95% CI, -8.45 to -4.09). The risk of developing fibrosis and macular atrophy also increased across FCPT SD quartiles. Odds ratios ranged from 1.40 (95% CI, 1.03 to 1.91) for quartile 2 to 1.95 (95% CI, 1.42 to 2.68) for quartile 4 for fibrosis and from 1.32 (95% CI, 0.90 to 1.92) for quartile 2 to 2.10 (95% CI, 1.45 to 3.05) for quartile 4 for macular atrophy. Conclusions and Relevance: Greater variation in retinal thickness in eyes with nAMD during treatment with anti-VEGF was associated with worse BCVA and development of fibrosis and macular atrophy in these post hoc analyses, despite protocol-directed treatment frequency. Practitioners may want to consider variation in retinal thickness when advising patients about their prognosis.


Assuntos
Bevacizumab/administração & dosagem , Ranibizumab/administração & dosagem , Retina/patologia , Acuidade Visual/fisiologia , Degeneração Macular Exsudativa/diagnóstico , Idoso , Inibidores da Angiogênese/administração & dosagem , Feminino , Humanos , Masculino , Tomografia de Coerência Óptica/métodos , Resultado do Tratamento , Fator A de Crescimento do Endotélio Vascular/antagonistas & inibidores , Degeneração Macular Exsudativa/tratamento farmacológico , Degeneração Macular Exsudativa/fisiopatologia
15.
J Clin Epidemiol ; 125: 16-25, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32416338

RESUMO

BACKGROUND AND OBJECTIVE: Randomized trials included in meta-analyses are often affected by bias caused by methodological flaws or limitations, but the degree of bias is unknown. Two proposed methods adjust the trial results for bias using empirical evidence from published meta-epidemiological studies or expert opinion. METHODS: We investigated agreement between data-based and opinion-based approaches to assessing bias in each of four domains: sequence generation, allocation concealment, blinding, and incomplete outcome data. From each sampled meta-analysis, a pair of trials with the highest and lowest empirical model-based bias estimates was selected. Independent assessors were asked which trial within each pair was judged more biased on the basis of detailed trial design summaries. RESULTS: Assessors judged trials to be equally biased in 68% of pairs evaluated. When assessors judged one trial as more biased, the proportion of judgments agreeing with the model-based ranking was highest for allocation concealment (79%) and blinding (79%) and lower for sequence generation (59%) and incomplete outcome data (56%). CONCLUSION: Most trial pairs found to be discrepant empirically were judged to be equally biased by assessors. We found moderate agreement between opinion and data-based evidence in pairs where assessors ranked one trial as more biased.


Assuntos
Ensaios Clínicos Controlados Aleatórios como Assunto/normas , Projetos de Pesquisa/normas , Atitude , Viés , Humanos , Julgamento , Metanálise como Assunto
16.
Ophthalmology ; 127(9): 1191-1200, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32359843

RESUMO

PURPOSE: To describe visual outcomes, frequency of treatment and monitoring visits, and anti-vascular endothelial growth factor drugs used in usual care in participants who exited a trial in which treatment for neovascular age-related macular degeneration (nAMD) was initiated with bevacizumab or ranibizumab. DESIGN: Multicenter cohort study up to 7 years after trial exit. PARTICIPANTS: Patients enrolled in the Inhibition of VEGF in Age-related choroidal Neovascularisation (IVAN) trial; after excluding participants from 2 sites and who died or withdrew during the trial, 537 were included in this follow-up cohort. METHODS: Data were collected between May 26, 2016, and August 24, 2017. Distance visual acuity (DVA) (letters read) in both eyes and treatments for nAMD administered to either eye at all usual care visits were extracted from medical records of all participants until the point of data collection (duration of study eye monitoring). MAIN OUTCOME MEASURES: Rate of change of DVA during active surveillance of the study eye (study eye monitoring), estimated using a multivariable linear random effects model. Other outcome measures were visit and treatment frequency and switches in anti-vascular endothelial growth factor (VEGF) drug. RESULTS: Data were obtained for 99% (532/537) of eligible participants. The median duration of study eye monitoring after IVAN exit was 3.3 years (interquartile range [IQR], 1.3-4.7), and median DVA was 58.0 letters (IQR, 34.0-73.0). Study eye DVA deteriorated by 4.3 (95% confidence interval [CI], 3.7-4.9) letters per year. Injection rate did not influence the rate of change in DVA after adjusting for key covariates. After IVAN exit, 174 participants (32%) received no treatment; 332 of 358 (93%) were treated first with ranibizumab, 78 (23%) of whom switched to aflibercept. The DVA was similar among participants who switched or did not switch at the end of study monitoring. CONCLUSIONS: Approximately 5 years after the IVAN study finished, with unprecedented completeness of follow-up for such a trial, the trajectory of functional decline in the study eye was shown to be greater than that previously reported for incomplete trial cohorts. Anti-VEGF injection rates and treatment switches were not important factors in determining visual acuity outcomes.


Assuntos
Inibidores da Angiogênese/uso terapêutico , Neovascularização de Coroide/tratamento farmacológico , Acuidade Visual/fisiologia , Degeneração Macular Exsudativa/tratamento farmacológico , Idoso , Idoso de 80 Anos ou mais , Bevacizumab/uso terapêutico , Neovascularização de Coroide/fisiopatologia , Feminino , Seguimentos , Humanos , Injeções Intravítreas , Masculino , Pessoa de Meia-Idade , Participação do Paciente , Ranibizumab/uso terapêutico , Perfil de Impacto da Doença , Inquéritos e Questionários , Resultado do Tratamento , Fator A de Crescimento do Endotélio Vascular/antagonistas & inibidores , Degeneração Macular Exsudativa/fisiopatologia
17.
Lancet ; 395(10226): 828-838, 2020 03 07.
Artigo em Inglês | MEDLINE | ID: mdl-32145797

RESUMO

Placebo comparisons are increasingly being considered for randomised trials assessing the efficacy of surgical interventions. The aim of this Review is to provide a summary of knowledge on placebo controls in surgical trials. A placebo control is a complex type of comparison group in the surgical setting and, although powerful, presents many challenges. This Review outlines what a placebo control entails and present understanding of this tool in the context of surgery. We consider when placebo controls in surgery are acceptable (and when they are desirable) in terms of ethical arguments and regulatory requirements, how a placebo control should be designed, how to identify and mitigate risk for participants in these trials, and how such trials should be done and interpreted. Use of placebo controls is justified in randomised controlled trials of surgical interventions provided there is a strong scientific and ethical rationale. Surgical placebos might be most appropriate when there is poor evidence for the efficacy of the procedure and a justified concern that results of a trial would be associated with high risk of bias, particularly because of the placebo effect. Feasibility work is recommended to optimise the design and implementation of randomised controlled trials. This Review forms an outline for best practice and provides guidance, in the form of the Applying Surgical Placebo in Randomised Evaluations (known as ASPIRE) checklist, for those considering the use of a placebo control in a surgical randomised controlled trial.


Assuntos
Placebos , Ensaios Clínicos Controlados Aleatórios como Assunto , Procedimentos Cirúrgicos Operatórios , Guias como Assunto , Humanos , Ensaios Clínicos Controlados Aleatórios como Assunto/ética , Ensaios Clínicos Controlados Aleatórios como Assunto/normas , Projetos de Pesquisa
18.
J Orthop ; 19: 93-97, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32021044

RESUMO

Introduction: This study aimed to determine the practicality and estimate the effect of administering pre-operative blood product resuscitation to a consecutive, prospectively recruited cohort of 100 patients admitted to a single centre with a hip fracture with all other treatment unchanged. Method: 100 patients aged 65 years or over admitted acutely to our unit with unilateral fractured femoral neck during the study period were included in this study, regardless of cognitive function. Patients were excluded only if there were relevant medical comorbidities or consent was declined. Each patient was resuscitated with a single unit of packed red cells in the immediate perioperative period in addition to standard care. The primary outcome was to establish the feasibility of the study protocol employed in using blood products to resuscitate eligible patients and recording reasons for any failures to include eligible patients. Additional data regarding mortality at 30 days following injury, subsequent blood product use, any transfusion related adverse reactions and total blood product use was measured. Results: We were able to show that it is safe and practicable to deliver blood as an early resuscitative strategy in the frail elderly hip fracture population. The mortality rate of the study cohort was 3%. No adverse reaction was observed in any of the 99 patients given blood as a result of the resuscitation strategy and no morbidity was seen that could be attributed to the effect of giving blood. The total amount of blood received by comparable cohorts in the study period and the two preceding years were similar. Conclusions: The study suggests that in the hip fracture population it is both practical and beneficial to move away from reactive transfusion regimens, and instead centre efforts instead on optimal resuscitation at the initial presentation.

19.
Lancet ; 395(10220): 294-303, 2020 01 25.
Artigo em Inglês | MEDLINE | ID: mdl-31982075

RESUMO

BACKGROUND: In chronic central serous chorioretinopathy (CSCR), fluid accumulates in the subretinal space. CSCR is a common visually disabling condition that develops in individuals up to 60 years of age, and there is no definitive treatment. Previous research suggests the mineralocorticoid receptor antagonist, eplerenone, is effective for treating CSCR; however, this drug is not licensed for the treatment of patients with CSCR. We aimed to evaluate whether eplerenone was superior to placebo in terms of improving visual acuity in patients with chronic CSCR. METHODS: This randomised, double-blind, parallel-group, multicentre placebo-controlled trial was done at 22 hospitals in the UK. Participants were eligible if they were aged 18-60 years and had had treatment-naive CSCR for 4 months or more. Patients were randomly assigned (1:1) to either the eplerenone or the placebo group by a trial statistician through a password-protected system online. Allocation was stratified by best-corrected visual acuity (BCVA) and hospital. Patients were given either oral eplerenone (25 mg/day for 1 week, increasing to 50 mg/day for up to 12 months) plus usual care or placebo plus usual care for up to 12 months. All participants, care teams, outcome assessors, pharmacists, and members of the trial management group were masked to the treatment allocation. The primary outcome was BCVA, measured as letters read, at 12 months. All outcomes apart from safety were analysed on a modified intention-to-treat basis (participants who withdrew consent without contributing a post-randomisation BCVA measurement were excluded from the primary analysis population and from most secondary analysis populations). The trial is registered with ISRCTN, ISRCTN92746680, and is completed. FINDINGS: Between Jan 11, 2017, and Feb 22, 2018, we enrolled and randomly assigned 114 patients to receive either eplerenone (n=57) or placebo (n=57). Three participants in the placebo group withdrew consent without contributing a post-randomisation BCVA measurement and were excluded from the primary outcome analysis population. All patients from the eplerenone group and 54 patients from the placebo group were included in the primary outcome. Modelled mean BCVA at 12 months was 79·5 letters (SD 4·5) in the placebo group and 80·4 letters (4·6) in the eplerenone group, with an adjusted estimated mean difference of 1·73 letters (95% CI -1·12 to 4·57; p=0·24) at 12 months. Hyperkalaemia occurred in eight (14%) patients in each group. No serious adverse events were reported in the eplerenone group and three unrelated serious adverse events were reported in the placebo group (myocardial infarction [anticipated], diverticulitis [unanticipated], and metabolic surgery [unanticipated]). INTERPRETATION: Eplerenone was not superior to placebo for improving BCVA in people with chronic CSCR after 12 months of treatment. Ophthalmologists who currently prescribe eplerenone for CSCR should discontinue this practice. FUNDING: Efficacy and Mechanism Evaluation Programme, and National Institute for Health Research and Social Care.


Assuntos
Coriorretinopatia Serosa Central/tratamento farmacológico , Eplerenona/uso terapêutico , Antagonistas de Receptores de Mineralocorticoides/uso terapêutico , Adulto , Coriorretinopatia Serosa Central/fisiopatologia , Doença Crônica , Método Duplo-Cego , Eplerenona/efeitos adversos , Feminino , Seguimentos , Humanos , Masculino , Adesão à Medicação/estatística & dados numéricos , Pessoa de Meia-Idade , Antagonistas de Receptores de Mineralocorticoides/efeitos adversos , Resultado do Tratamento , Acuidade Visual/efeitos dos fármacos , Adulto Jovem
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