Las diferencias por sexo en la mortalidad tras un síndrome coronario agudo se incrementan en los países de menor riqueza y mayor desigualdad de ingresos / Sex differences in mortality after an acute coronary syndrome increase with lower country wealth and higher income inequality

Introducción y objetivos: Aunque se han comunicado varios factores asociados con las diferencias por sexo en el tratamiento y el pronóstico tras un síndrome coronario agudo (SCA), se sabe poco acerca de la influencia de factores socioeconómicos en las disparidades por sexo. Nuestro objetivo es evaluar el impacto de la riqueza nacional y la desigualdad de ingresos en las diferencias por sexo en la mortalidad tras un SCA. Métodos: Se evaluaron las diferencias entre varones y mujeres en la mortalidad a los 2 años del alta hospitalaria de 23.489 pacientes con SCA de los registros EPICOR y EPICOR Asia. Se utilizaron modelos de regresión de Cox ajustados para evaluar los terciles del producto interior bruto y de desigualdad de ingresos. Resultados: Las mujeres (24,3%) eran de más edad que los varones (65,5 frente a 59,4 años; p <0,001), tenían más comorbilidades, se las revascularizó con menos frecuencia (el 63,6 frente al 75,6%; p <0,001) y recibieron al alta menos tratamientos recomendados por las guías de práctica clínica. Comparadas con los varones, la mortalidad de las mujeres en el seguimiento fue mayor (el 6,4 frente al 4,9%; p <0,001). La asociación entre sexo y mortalidad cambió su dirección desde una hazard ratio (HR)=1,32 (IC95%, 1,17-1,49) en el análisis univariado a HR=0,76 (IC95%, 0,67-0,87) después de ajustar por variables de confusión. Estas diferencias fueron más evidentes a medida que la riqueza de los países se incrementaba (HRpaísesconbajonivelderiqueza=0,85; IC95%, 0,72-1,00; HRpaísesconnivelderiquezaintermedio=0,66; IC95%, 0,50-0,87; HRpaísesconelevadonivelderiqueza=0,60; IC95%, 0,40-0,90; pparatestdetendencia=0,115) y a medida que se equilibraba la desigualdad de ingresos (HRbajoíndicededesigualidad=0,54; IC95%, 0,36-0,81; HRíndicededesigualidadintermedio=0,66; IC95%, 0,50-0,88; HRaltoíndicededesigualidad=0,87; IC95%, 0,74-1,03; pparatestdetendencia=0,031) (AU)

Introduction and objectives: Although several factors associated with sex differences in the management and outcomes after acute coronary syndrome (ACS) have been reported, little is known about the influence of socioeconomic factors on sex disparities. Our aim was to evaluate the influence of country wealth and income inequality on national sex differences in mortality after ACS. Methods: Sex differences in 2-year postdischarge mortality were evaluated in 23 489 ACS patients from the EPICOR and EPICOR Asia registries. Adjusted Cox regression models by country-based terciles of gross national income per capita and income inequality were used. Results: Women (24.3%) were older than men (65.5 vs 59.4 years, P <.001), had more comorbidities, were less often revascularized (63.6% vs 75.6%, P <.001) and received fewer guideline recommended therapies at discharge. Compared with men, a higher percentage of women died during follow-up (6.4% vs 4.9%, P <.001). The association between sex and mortality changed direction from hazard ratio (HR) 1.32 (95%CI, 1.17-1.49) in the univariate assessment to HR 0.76 (95%CI, 0.67-0.87) after adjustment for confounders. These differences were more evident with increasing country wealth (HRlow-incomecountries = 0.85; 95%CI, 0.72-1.00; HRmid-incomecountries = 0.66; 95%CI, 0.50-0.87; HRhigh-incomecountries = 0.60; 95%CI, 0.40-0.90; trend test P = .115) and with decreasing income inequality (HRlow-inequalityindex = 0.54; 95%CI, 0.36-0.81; HRintermediate-inequalityindex = 0.66; 95%CI, 0.50-0.88; HRhigh-inequalityindex = 0.87; 95%CI, 0.74-1.03; trend test P = .031). Conclusions: Women with ACS living in high socioeconomic countries showed a lower postdischarge mortality risk compared with men. This risk was attenuated in countries with poorer socioeconomic background, where adjusted mortality rates were similar between women and men (AU)

Risks to healthcare workers following tracheal intubation of patients with COVID-19: a prospective international multicentre cohort study.

Healthcare workers involved in aerosol-generating procedures, such as tracheal intubation, may be at elevated risk of acquiring COVID-19. However, the magnitude of this risk is unknown. We conducted a prospective international multicentre cohort study recruiting healthcare workers participating in tracheal intubation of patients with suspected or confirmed COVID-19. Information on tracheal intubation episodes, personal protective equipment use and subsequent provider health status was collected via self-reporting. The primary endpoint was the incidence of laboratory-confirmed COVID-19 diagnosis or new symptoms requiring self-isolation or hospitalisation after a tracheal intubation episode. Cox regression analysis examined associations between the primary endpoint and healthcare worker characteristics, procedure-related factors and personal protective equipment use. Between 23 March and 2 June 2020, 1718 healthcare workers from 503 hospitals in 17 countries reported 5148 tracheal intubation episodes. The overall incidence of the primary endpoint was 10.7% over a median (IQR [range]) follow-up of 32 (18-48 [0-116]) days. The cumulative incidence within 7, 14 and 21 days of the first tracheal intubation episode was 3.6%, 6.1% and 8.5%, respectively. The risk of the primary endpoint varied by country and was higher in women, but was not associated with other factors. Around 1 in 10 healthcare workers involved in tracheal intubation of patients with suspected or confirmed COVID-19 subsequently reported a COVID-19 outcome. This has human resource implications for institutional capacity to deliver essential healthcare services, and wider societal implications for COVID-19 transmission.

Blood pressure and risk of dementia and its subtypes: a historical cohort study with long-term follow-up in 2.6 million people.

BACKGROUND AND PURPOSE: Elevated blood pressure (BP) is prevalent and modifiable and has been hypothesized to lead to increased risk of dementia. DATA: Data on 2 593 629 people from the UK Clinical Practice Research Database aged ≥40 years with a BP measurement between 1992 and 2011 and no prior record of dementia were collected. METHODS: Poisson regression models were used to study the association between BP and physician-diagnosed dementia. BP is believed to fall during the prodromal phase of dementia development, so associations were investigated by categories of time since BP measurement (<5, 5-10, >10 years) and by subtypes of dementia. RESULTS: During a median follow-up of 8.2 years, 65 618 cases of dementia were observed: 49 161 Alzheimer's, 13 816 vascular dementia and 2541 other subtypes. For each 10 mmHg higher systolic BP, the future dementia risk was 9.2% (95% confidence interval 8.4%-10.0%) lower, but this association varied markedly by time since BP measurement. Short-term associations with dementia were inverse with a 15.8% (15.5%-17.0%) lower risk 0-5 years after BP measurement and a 5.8% (7.7%-4.4%) lower risk 5-10 years after BP measurement. During the period >10 years after BP measurement, dementia risk was only 1.6% (0.1%-3.0%) lower, with a 4.3% (2.5%-6.0%) lower risk of Alzheimer's disease and a 7.0% (3.8%-10.2%) higher risk of vascular dementia. CONCLUSIONS: Elevated BP is associated with decreased risk of dementia in the short term, possibly due to reverse causation. Long-term associations of BP with dementia are less marked and differ by dementia subtype.

Neural modulation for hypertension and heart failure.

Hypertension (HTN) and heart failure (HF) have a significant global impact on health, and lead to increased morbidity and mortality. Despite recent advances in pharmacologic and device therapy for these conditions, there is a need for additional treatment modalities. Patients with sub-optimally treated HTN have increased risk for stroke, renal failure and heart failure. The outcome of HF patients remains poor despite modern pharmacological therapy and with established device therapies such as CRT and ICDs. Therefore, the potential role of neuromodulation via renal denervation, baro-reflex modulation and vagal stimulation for the treatment of resistant HTN and HF is being explored. In this manuscript, we review current evidence for neuromodulation in relation to established drug and device therapies and how these therapies may be synergistic in achieving therapy goals in patients with treatment resistant HTN and heart failure. We describe lessons learned from recent neuromodulation trials and outline strategies to improve the potential for success in future trials. This review is based on discussions between scientists, clinical trialists, and regulatory representatives at the 11th annual CardioVascular Clinical Trialist Forum in Washington, DC on December 5-7, 2014.

The obesity paradox in heart failure patients with preserved versus reduced ejection fraction: a meta-analysis of individual patient data.

BACKGROUND: In heart failure (HF), obesity, defined as body mass index (BMI) ≥30 kg m(-2), is paradoxically associated with higher survival rates compared with normal-weight patients (the 'obesity paradox'). We sought to determine if the obesity paradox differed by HF subtype (reduced ejection fraction (HF-REF) versus preserved ejection fraction (HF-PEF)). PATIENTS AND METHODS: A sub-analysis of the MAGGIC meta-analysis of patient-level data from 14 HF studies was performed. Subjects were divided into five BMI groups: <22.5, 22.5-24.9 (referent), 25-29.9, 30-34.9 and ≥35 kg m(-2). Cox proportional hazards models adjusted for age, sex, aetiology (ischaemic or non-ischaemic), hypertension, diabetes and baseline blood pressure, stratified by study, were used to examine the independent association between BMI and 3-year total mortality. Analyses were conducted for the overall group and within HF-REF and HF-PEF groups. RESULTS: BMI data were available for 23 967 subjects (mean age, 66.8 years; 32% women; 46% NYHA Class II; 50% Class III) and 5609 (23%) died by 3 years. Obese patients were younger, more likely to receive cardiovascular (CV) drug treatment, and had higher comorbidity burdens. Compared with BMI levels between 22.5 and 24.9 kg m(-2), the adjusted relative hazards for 3-year mortality in subjects with HF-REF were: hazard ratios (HR)=1.31 (95% confidence interval=1.15-1.50) for BMI <22.5, 0.85 (0.76-0.96) for BMI 25.0-29.9, 0.64 (0.55-0.74) for BMI 30.0-34.9 and 0.95 (0.78-1.15) for BMI ≥35. Corresponding adjusted HRs for those with HF-PEF were: 1.12 (95% confidence interval=0.80-1.57) for BMI <22.5, 0.74 (0.56-0.97) for BMI 25.0-29.9, 0.64 (0.46-0.88) for BMI 30.0-34.9 and 0.71 (0.49-1.05) for BMI ≥35. CONCLUSIONS: In patients with chronic HF, the obesity paradox was present in both those with reduced and preserved ventricular systolic function. Mortality in both HF subtypes was U-shaped, with a nadir at 30.0-34.9 kg m(-2).

ASCORE: an up-to-date cardiovascular risk score for hypertensive patients reflecting contemporary clinical practice developed using the (ASCOT-BPLA) trial data.

A number of risk scores already exist to predict cardiovascular (CV) events. However, scores developed with data collected some time ago might not accurately predict the CV risk of contemporary hypertensive patients that benefit from more modern treatments and management. Using data from the randomised clinical trial Anglo-Scandinavian Cardiac Outcomes Trial-BPLA, with 15 955 hypertensive patients without previous CV disease receiving contemporary preventive CV management, we developed a new risk score predicting the 5-year risk of a first CV event (CV death, myocardial infarction or stroke). Cox proportional hazard models were used to develop a risk equation from baseline predictors. The final risk model (ASCORE) included age, sex, smoking, diabetes, previous blood pressure (BP) treatment, systolic BP, total cholesterol, high-density lipoprotein-cholesterol, fasting glucose and creatinine baseline variables. A simplified model (ASCORE-S) excluding laboratory variables was also derived. Both models showed very good internal validity. User-friendly integer score tables are reported for both models. Applying the latest Framingham risk score to our data significantly overpredicted the observed 5-year risk of the composite CV outcome. We conclude that risk scores derived using older databases (such as Framingham) may overestimate the CV risk of patients receiving current BP treatments; therefore, 'updated' risk scores are needed for current patients.

[The Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) statement: guidelines for reporting of observational studies]. / Das Strengthening the Reporting of Observational Studies in Epidemiology (STROBE-) Statement.

Much of biomedical research is observational. The reporting of such research is often inadequate, which hampers the assessment of its strengths and weaknesses and of a study's generalizability. The Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) Initiative developed recommendations on what should be included in an accurate and complete report of an observational study. We defined the scope of the recommendations to cover three main study designs: cohort, case-control, and cross-sectional studies. We convened a 2-day workshop in September 2004, with methodologists, researchers, and journal editors to draft a checklist of items. This list was subsequently revised during several meetings of the coordinating group and in e-mail discussions with the larger group of STROBE contributors, taking into account empirical evidence and methodological considerations. The workshop and the subsequent iterative process of consultation and revision resulted in a checklist of 22 items (the STROBE Statement) that relate to the title, abstract, introduction, methods, results, and discussion sections of articles. Eighteen items are common to all three study designs and four are specific for cohort, case-control, or cross-sectional studies. A detailed Explanation and Elaboration document is published separately and is freely available on the web sites of PLoS Medicine, Annals of Internal Medicine, and Epidemiology. We hope that the STROBE Statement will contribute to improving the quality of reporting of observational studies.

The cost-effectiveness of an early interventional strategy in non-ST-elevation acute coronary syndrome based on the RITA 3 trial.

BACKGROUND: Evidence suggests that an early interventional strategy for patients with non-ST-elevation acute coronary syndrome (NSTE-ACS) can improve health outcomes but also increase costs when compared with a conservative strategy. OBJECTIVE: The aim of this study was to assess the cost-effectiveness of an early interventional strategy in different risk groups from a UK health-service perspective. DESIGN: Decision-analytic model based on randomised clinical trial data. MAIN OUTCOME MEASURES: Costs in UK Sterling at 2003/2004 prices and quality-adjusted life years (QALYs) combined into an incremental cost-effectiveness ratio. METHODS: Data from the third Randomised Intervention Trial of unstable Angina (RITA 3) was employed to estimate rates of cardiovascular death and myocardial infarction, costs and health-related quality of life. Cost-effectiveness was estimated over patients' lifetimes within the decision-analytic model. RESULTS: The mean incremental cost per QALY gained for an early interventional strategy was approximately 55,000 pounds sterling, 22,000 pounds sterling and 12,000 pounds sterling for patients at low, intermediate and high risk, respectively. The early interventional strategy is approximately 1%, 35% and 95% likely to be cost-effective for patients at low, intermediate and high risk, respectively, at a threshold of 20,000 pounds sterling per QALY. The cost-effectiveness of early intervention in low-risk patients is sensitive to assumptions about the duration of the treatment effect. CONCLUSION: An early interventional strategy in patients presenting with NSTE-ACS is likely to be considered cost-effective for patients at high and intermediate risk, but this is less likely to be the case for patients at low risk.

Rosiglitazone RECORD study: glucose control outcomes at 18 months.

AIMS: To compare glucose control over 18 months between rosiglitazone oral combination therapy and combination metformin and sulphonylurea in people with Type 2 diabetes. METHODS: RECORD, a multicentre, parallel-group study of cardiovascular outcomes, enrolled people with an HbA(1c) of 7.1-9.0% on maximum doses of metformin or sulphonylurea. If on metformin they were randomized to add-on rosiglitazone or sulphonylurea (open label) and if on sulphonylurea to rosiglitazone or metformin. HbA(1c) was managed to < or = 7.0% by dose titration. A prospectively defined analysis of glycaemic control on the first 1122 participants is reported here, with a primary outcome assessed against a non-inferiority margin for HbA(1c) of 0.4%. RESULTS: At 18 months, HbA(1c) reduction on background metformin was similar with rosiglitazone and sulphonylurea [difference 0.07 (95% CI -0.09, 0.23)%], as was the change when rosiglitazone or metformin was added to sulphonylurea [0.06 (-0.09, 0.20)%]. At 6 months, the effect on HbA(1c) was greater with add-on sulphonylurea, but was similar whether sulphonylurea was added to rosiglitazone or metformin. Differences in fasting plasma glucose were not statistically significant at 18 months [rosiglitazone vs. sulphonylurea -0.36 (-0.74, 0.02) mmol/l, rosiglitazone vs. metformin -0.34 (-0.73, 0.05) mmol/l]. Increased homeostasis model assessment insulin sensitivity and reduced C-reactive protein were greater with rosiglitazone than metformin or sulphonylurea (all P < or = 0.001). Body weight was significantly increased with rosiglitazone compared with sulphonylurea [difference 1.2 (0.4, 2.0) kg, P = 0.003] and metformin [difference 4.3 (3.6, 5.1) kg, P < 0.001]. CONCLUSIONS: In people with diabetes, rosiglitazone in combination with metformin or sulphonylurea was demonstrated to be non-inferior to the standard combination of metformin + sulphonylurea in lowering HbA(1c) over 18 months, and produces greater improvements in C-reactive protein and basal insulin sensitivity but is also associated with greater weight gain.

Prevalence and prognostic implications of electrocardiographic left ventricular hypertrophy in heart failure: evidence from the CHARM programme.

BACKGROUND: Electrocardiographic left ventricular hypertrophy (ECG LVH) is a powerful independent predictor of cardiovascular morbidity and mortality in hypertension. OBJECTIVE: To determine the contemporary prevalence and prognostic implications of ECG LVH in a broad spectrum of patients with heart failure with and without reduced left ventricular ejection fraction (LVEF). METHODS AND OUTCOME: The Candesartan in Heart failure: Assessment of Reduction in Mortality and morbidity (CHARM) programme randomised 7599 patients with symptomatic heart failure to receive candesartan or placebo. The primary outcome comprised cardiovascular death or hospital admission for worsening heart failure. The relative risk (RR) conveyed by ECG LVH compared with a normal ECG was examined in a Cox model, adjusting for as many as 31 covariates of prognostic importance. RESULTS: The prevalence of ECG LVH was similar in all three CHARM trials (Alternative, 15.4%; Added, 17.1%; Preserved, 14.7%; Overall, 15.7%) despite a more frequent history of hypertension in CHARM-Preserved. ECG LVH was an independent predictor of worse prognosis in CHARM-Overall. RR for the primary outcome was 1.27 (95% confidence interval (CI) 1.04 to 1.55, p = 0.018). The risk of secondary end points was also increased: cardiovascular death, 1.50 (95% CI 1.13 to 1.99, p = 0.005); hospitalisation due to heart failure, 1.19 (95% CI 0.94 to 1.50, p = 0.148); and composite major cardiovascular events, 1.35 (95% CI 1.12 to 1.62, p = 0.002). CONCLUSION: ECG LVH is similarly prevalent in patients with symptomatic heart failure regardless of LVEF. The simple clinical finding of ECG LVH was an independent predictor of a worse clinical outcome in a broad spectrum of patients with heart failure receiving extensive contemporary treatment. Candesartan had similar benefits in patients with and without ECG LVH.

Interventional versus conservative treatment in acute non-ST elevation coronary syndrome: time course of patient management and disease events over one year in the RITA 3 trial.

OBJECTIVE: To determine whether, in acute non-ST elevation coronary syndrome, the benefit from early invasive coronary intervention compared with a conservative strategy of later symptom-guided intervention varies over time. METHODS: In RITA 3 (Randomised Intervention Trial of unstable Angina 3) patients were randomly assigned to coronary angiography (median 2 days after randomisation) and appropriate intervention (n = 895) or to a symptom-guided conservative strategy (n = 915). RESULTS: In the first week patients in both groups were at highest risk of death, myocardial infarction (MI) or refractory angina (incidence rate 40 times higher than in months 5-12 of follow up). There were 22 MIs and 6 deaths in the intervention group (largely due to procedure-related events, 14 MIs and 3 deaths) versus 17 MIs and 3 deaths in the conservative group. In the rest of the year there were an additional 12 versus 27 MIs, respectively (treatment-time interaction p = 0.021). Over one year in the intervention group there was a 43% reduction in refractory angina; 22% of patients underwent coronary artery bypass surgery and 35% underwent percutaneous coronary intervention only, which reduced refractory angina but provoked some early MIs; and 43% were still treated medically, mostly because of a favourable initial angiogram. CONCLUSION: Any intervention policy needs to recognise the high risk of events in the first week and the substantial minority of patients not needing intervention. Intervention may be best targeted at higher risk patients, as the early hazards of the procedure are then offset by reduced subsequent events.

5-year outcome of an interventional strategy in non-ST-elevation acute coronary syndrome: the British Heart Foundation RITA 3 randomised trial.

BACKGROUND: The long-term outcome of an interventional strategy in patients with non-ST-elevation acute coronary syndrome is unknown. We tested whether an interventional strategy (routine angiography followed by revascularisation) was better than a conservative strategy (ischaemia-driven or symptom-driven angiography) over 5 years' follow-up. METHODS: In a multicentre randomised trial, 1810 patients (from 45 hospitals in England and Scotland, UK) with non-ST-elevation acute coronary syndrome were randomly assigned to receive an early intervention (n=895) or a conservative strategy (n=915) within 48 h of the index episode of cardiac pain. In each group, the aim was to provide the best medical treatment, and also to undertake coronary arteriography within 72 h in the interventional strategy with subsequent management guided by the angiographic findings. Analysis was by intention to treat and the primary outcome (composite of death or non-fatal myocardial infarction) had masked independent adjudication. RITA 3 has been assigned the International Standard Randomised Control Trial Number ISRCTN07752711. FINDINGS: At 1-year follow-up, rates of death or non-fatal myocardial infarction were similar. However, at a median of 5 years' follow-up (IQR 4.6-5.0), 142 (16.6%) patients with intervention treatment and 178 (20.0%) with conservative treatment died or had non-fatal myocardial infarction (odds ratio 0.78, 95% CI 0.61-0.99, p=0.044), with a similar benefit for cardiovascular death or myocardial infarction (0.74, 0.56-0.97, p=0.030). 234 (102 [12%] intervention, 132 [15%] conservative) patients died during follow-up (0.76, 0.58-1.00, p=0.054). The benefits of an intervention strategy were mainly seen in patients at high risk of death or myocardial infarction (p=0.004), and for the highest risk group, the odds ratio of death or non-fatal myocardial infarction was 0.44 (0.25-0.76). INTERPRETATION: In patients with non-ST-elevation acute coronary syndrome, a routine invasive strategy leads to long-term reduction in risk of death or non-fatal myocardial infarction, and this benefit is mainly in high-risk patients. The findings provide support for national and international guidelines in the need for more robust risk stratification in acute coronary syndrome.

Rosiglitazone Evaluated for Cardiac Outcomes and Regulation of Glycaemia in Diabetes (RECORD): study design and protocol.

AIMS/HYPOTHESIS: Studies suggest that in addition to blood glucose concentrations, thiazolidinediones such as rosiglitazone improve some cardiovascular (CV) risk factors and surrogate markers, that are abnormal in type 2 diabetes. However, fluid retention might lead to cardiac failure in a minority of people. The aim of the Rosiglitazone Evaluated for Cardiac Outcomes and Regulation of Glycaemia in Diabetes (RECORD) study is to evaluate the long-term impact of these effects on CV outcomes, as well as on long-term glycaemic control, in people with type 2 diabetes. MATERIALS AND METHODS: RECORD is a 6-year, randomised, open-label study in type 2 diabetic patients with inadequate blood glucose control (HbA1c 7.1-9.0%) on metformin or sulphonylurea alone. The study is being performed in 327 centres in Europe and Australasia. After a 4-week run-in, participants were randomised by current treatment stratum to add-on rosiglitazone, metformin or sulphonylurea, with dose titration to a target HbA1c of < or = 7.0%. If confirmed HbA1c rises to > or = 8.5%, either a third glucose-lowering drug is added (rosiglitazone-treated group) or insulin is started (non-rosiglitazone group). The same criterion for failure of triple oral drug therapy in the rosiglitazone-treated group is used for starting insulin in this group. The primary endpoint is the time to first CV hospitalisation or death, blindly adjudicated by a central endpoints committee. The study aim is to evaluate non-inferiority of the rosiglitazone group vs the non-rosiglitazone group with respect to CV outcomes. Safety, tolerability and study conduct are monitored by an independent board. All CV endpoint and safety data are held and analysed by a clinical trials organisation, and are not available to the study investigators while data collection is open. RESULTS: Over a 2-year period a total of 7,428 people were screened in 25 countries. Of these, 4,458 were randomised; 2,228 on background metformin, 2,230 on background sulphonylurea. Approximately half of the participants are male (52%) and almost all are Caucasian (99%). CONCLUSIONS/INTERPRETATION: The RECORD study should provide robust data on the extent to which rosiglitazone, in combination with metformin or sulphonylurea therapy, affects CV outcomes and progression of diabetes in the long term.

Issues in data monitoring and interim analysis of trials.

OBJECTIVES: To address issues about data monitoring committees (DMCs) for randomised controlled trials (RCTs). DATA SOURCES: Electronic databases. Handsearching of selected books. Personal contacts with experts in the field. REVIEW METHODS: Systematic literature reviews of DMCs and small group processes in decision-making; sample surveys of: reports of RCTs, recently completed and ongoing RCTs and policies of major organisations involved in RCTs; case studies of four DMCs; and interviews with experienced DMC members. All focused on 23 prestated questions. RESULTS: Although still a minority, RCTs increasingly have DMCs. There is wide agreement that nearly all trials need some form of data monitoring. Central to the role of the DMC is monitoring accumulating evidence related to benefit and toxicity; variation in emphasis has been reflected in the plethora of names. DMCs for trials performed for regulatory purposes should be aware of any special requirements and regulatory consequences. Advantages were identified for both larger and smaller DMCs. There is general agreement that a DMC should be independent and multidisciplinary. Consumer and ethicist membership is controversial. The chair is recognised as being particularly influential, and likely to be most effective if he or she is experienced, understands both statistical and clinical issues, and is facilitating in style and impartial. There is no evidence available to judge suggested approaches to training. The review suggested that costs should be covered, but other rewards must be so minimal as to not affect decision-making. It is usual to have a minimum frequency of DMC meetings, with evidence that face-to-face meetings are preferable. It is common to have open sessions and a closed session. A report to a DMC should cover benefits and risks in a balanced way, summarised in an accessible style, avoiding excessive detail, and be as current as possible. Disadvantages of blinded analyses seem to outweigh advantages. Information about comparable studies should be included, although interaction with the DMCs of similar ongoing trials is controversial. A range of formal statistical approaches can be used, although this is only one of a number of considerations. DMCs usually reach decisions by consensus, but other approaches are sometimes used. The general, but not unanimous, view is that DMCs should be advisory rather than executive on the basis that it is the trial organisers who are ultimately responsible for the conduct of the trial. CONCLUSIONS: Some form of data monitoring should be considered for all RCTs, with reasons given where there is no DMC or when any member is not independent. An early DMC meeting is helpful, determining roles and responsibilities; planned operations can be agreed with investigators and sponsors/funders. A template for a DMC charter is suggested. Competing interests should be declared. DMC size (commonly three to eight people) is chosen to optimise performance. Members are usually independent and drawn from appropriate backgrounds, and some, particularly the chair, are experienced. A minimum frequency of meetings is usually agreed, with flexibility for more if needed. The DMC should understand and agree the statistical approach (and guidelines) chosen, with both the DMC statistician and analysis statistician competent to apply the method. A DMC's primary purpose is to ensure that continuing a trial according to its protocol is ethical, taking account of both individual and collective ethics. A broader remit in respect of wider ethical issues is controversial; arguably, these are primarily the responsibility of research ethics committees, trial steering committees and investigators. The DMC should know the range of recommendations or decisions open to it, in advance. A record should be kept describing the key issues discussed and the rationale for decisions taken. Errors are likely to be reduced if a DMC makes a thorough review of the evidence and has a clear understanding of how it should function, there is active participation by all members, differences are resolved through discussion and there is systematic consideration of the various decision options. DMCs should be encouraged to comment on draft final trial reports. These should include information about the data monitoring process and detail the DMC membership. It is recommended that groups responsible for data monitoring be given the standard name 'Data Monitoring Committee' (DMC). Areas for further research include: widening DMC membership beyond clinicians, trialists and statisticians; initiatives to train DMC members; methods of DMC decision-making; 'open' data monitoring; DMCs covering a portfolio of trials rather than single trials; DMC size and membership, incorporating issues of group dynamics; empirical study of the workings of DMCs and their decision-making, and which trials should or should not have a DMC.

Do men benefit more than women from an interventional strategy in patients with unstable angina or non-ST-elevation myocardial infarction? The impact of gender in the RITA 3 trial.

AIMS: The RITA 3 trial randomized patients with non-ST-elevation myocardial infarction or unstable angina to strategies of early intervention (angiography followed by revascularization) or conservative care (ischaemia or symptom driven angiography). The aim of this analysis was to investigate the impact of gender on the effect of these two strategies. METHODS AND RESULTS: In total, 1810 patients (682 women and 1128 men) were randomized. The risk factor profile of women at presentation was markedly different to men. There was evidence that men benefited more from an early intervention strategy for death or non-fatal myocardial infarction at 1 year (adjusted odds ratios 0.63, 95% confidence interval 0.41-0.98 for men and 1.79, 95% confidence interval 0.95-3.35 for women; interaction p-value=0.007). Men who underwent the assigned angiogram were more likely to be put forward for coronary artery bypass surgery, even after allowing for differences in disease severity. CONCLUSION: An early intervention strategy resulted in a beneficial effect in men which was not seen in women although caution is needed in interpretation. Further research is needed to evaluate why women do not appear to benefit from early intervention and to identify treatments that improve the prognosis of women.

A comparison of two methods for the estimation of precision with incomplete longitudinal data, jointly modelled with a time-to-event outcome.

Several methods for the estimation and comparison of rates of change in longitudinal studies with staggered entry and informative drop-outs have been recently proposed. For multivariate normal linear models, REML estimation is used. There are various approaches to maximizing the corresponding log-likelihood; in this paper we use a restricted iterative generalized least squares method (RIGLS) combined with a nested EM algorithm. An important statistical problem in such approaches is the estimation of the standard errors adjusted for the missing data (observed data information matrix). Louis has provided a general technique for computing the observed data information in terms of completed data quantities within the EM framework. The multiple imputation (MI) method for obtaining variances can be regarded as an alternative to this. The aim of this paper is to develop, apply and compare the Louis and a modified MI method in the setting of longitudinal studies where the source of missing data is either death or disease progression (informative) or end of the study (assumed non-informative). Longitudinal data are simultaneously modelled with the missingness process. The methods are illustrated by modelling CD4 count data from an HIV-1 clinical trial and evaluated through simulation studies. Both methods, Louis and MI, are used with Monte Carlo simulations of the missing data using the appropriate conditional distributions, the former with 100 simulations, the latter with 5 and 10. It is seen that naive SEs based on the completed data likelihood can be seriously biased. This bias was largely corrected by Louis and modified MI methods, which gave broadly similar estimates. Given the relative simplicity of the modified MI method, it may be preferable.

Neonatal head circumference, neonatal weight, and risk of hayfever, asthma and eczema in a large cohort of adolescents from Sheffield, England.

BACKGROUND: Neonatal physical characteristics, including head circumference and birth weight, have been hypothesized to be markers of in utero thymic development. Greater head circumference and lower birth weight have been linked in previous studies to subsequent development of asthma, and greater birth weight has been associated with subsequent development of eczema. OBJECTIVE: To investigate potential associations between neonatal head circumference and weight and hayfever, asthma and eczema in a cohort of adolescents from Sheffield, England. METHODS: Responses to a questionnaire inquiring about physician-diagnosed hayfever, asthma and eczema among adolescents in Sheffield, England, were linked to previously recorded measurements of weight at birth and at 1 month and head circumference at 1 month. Logistic regression methods were used to relate diagnoses to neonatal measurements and potential confounders. RESULTS: The cohort consisted of 10,809 adolescents, of whom 16.5% reported hayfever, 18.0% asthma, and 16.2% eczema. After adjusting for sex, age at the time of the questionnaire, maternal age and gestational age at birth, number of older and younger siblings, time since birth of next older sibling, neonatal sickness, type of neonatal feeding, and maternal and paternal educational backgrounds, hayfever was the only disease associated with neonatal measurements. Comparing the highest with the lowest fifths of distributions, lifetime prevalence of hayfever was positively associated with neonatal head circumference (adjusted odds ratio 1.23, 95% CI 1.03 to 1.47) and with birth weight (1.17, 0.99 to 1.39). Hayfever was inversely related to the ratio of head circumference to birth weight (0.89, 0.75 to 1.05) and to gestational age. The associations with head circumference and birth weight were not substantially altered by further adjustment for gestational age. CONCLUSION: Greater neonatal head circumference may be associated with an increased risk of hayfever, but the inverse relationship between hayfever prevalence and the ratio of head circumference to birth weight challenges the prior hypothesis that greater head circumference relative to body mass reflects abnormal thymic development in utero, increasing the likelihood of allergic sensitization.

Interventional versus conservative treatment for patients with unstable angina or non-ST-elevation myocardial infarction: the British Heart Foundation RITA 3 randomised trial. Randomized Intervention Trial of unstable Angina.

BACKGROUND: Current guidelines suggest that, for patients at moderate risk of death from unstable coronary-artery disease, either an interventional strategy (angiography followed by revascularisation) or a conservative strategy (ischaemia-driven or symptom-driven angiography) is appropriate. We aimed to test the hypothesis that an interventional strategy is better than a conservative strategy in such patients. METHODS: We did a randomised multicentre trial of 1810 patients with non-ST-elevation acute coronary syndromes (mean age 62 years, 38% women). Patients were assigned an early intervention or conservative strategy. The antithrombin agent in both groups was enoxaparin. The co-primary endpoints were a combined rate of death, non-fatal myocardial infarction, or refractory angina at 4 months; and a combined rate of death or non-fatal myocardial infarction at 1 year. Analysis was by intention to treat. FINDINGS: At 4 months, 86 (9.6%) of 895 patients in the intervention group had died or had a myocardial infarction or refractory angina, compared with 133 (14.5%) of 915 patients in the conservative group (risk ratio 0.66, 95% CI 0.51-0.85, p=0.001). This difference was mainly due to a halving of refractory angina in the intervention group. Death or myocardial infarction was similar in both treatment groups at 1 year (68 [7.6%] vs 76 [8.3%], respectively; risk ratio 0.91, 95% CI 0.67-1.25, p=0.58). Symptoms of angina were improved and use of antianginal medications significantly reduced with the interventional strategy (p<0.0001). INTERPRETATION: In patients presenting with unstable coronary-artery disease, an interventional strategy is preferable to a conservative strategy, mainly because of the halving of refractory or severe angina, and with no increased risk of death or myocardial infarction.

Coronary angioplasty versus medical therapy for angina. Health service costs based on the second Randomized Intervention Treatment of Angina (RITA-2) trial.

AIMS: The second Randomized Intervention Treatment of Angina (RITA-2) trial compares an initial strategy of PTCA with continued medical management in patients with arteriographically proven coronary artery disease. This paper employs resource use data collected in the trial to compare the health service costs of the two strategies over 3 years follow-up. METHODS AND RESULTS: 1018 patients were randomized, 504 to PTCA and 514 to continued medical management. Health service resource use data were collected prospectively on all patients. Hospital unit costs were estimated in collaboration with five U.K. centres. PTCA patients underwent more subsequent coronary arteriograms, but subsequent (non-randomized) PTCAs were more common in patients randomized to medical management (118 procedures in 102 patients) compared to those randomized to PTCA (73 procedures in 62 patients). The likelihood of undergoing CABG was similar in the two groups. The use of antianginal medications was higher in patients randomized to an initial strategy of medical management. There was an overall mean additional cost per patient over 3 years in patients randomized to PTCA of pound 2685 (95% CI pound 2074- pound 3322). CONCLUSIONS: In RITA-2, the cost of an initial strategy of PTCA exceeded the cost of an initial strategy of medical management by 74% over 3 years.