Felicity Clemens

Efficacy and economic assessment of conventional ventilatory support versus extracorporeal membrane oxygenation for severe adult respiratory failure (CESAR): a multicentre randomised controlled trial

BACKGROUND Severe acute respiratory failure in adults causes high mortality despite improvements in ventilation techniques and other treatments (eg, steroids, prone positioning, bronchoscopy, and inhaled nitric oxide). We aimed to delineate the safety, clinical efficacy, and cost-effectiveness of extracorporeal membrane oxygenation (ECMO) compared with conventional ventilation support. METHODS In this UK-based multicentre trial, we used an independent central randomisation service to randomly assign 180 adults in a 1:1 ratio to receive continued conventional management or referral to consideration for treatment by ECMO. Eligible patients were aged 18-65 years and had severe (Murray score >3.0 or pH <7.20) but potentially reversible respiratory failure. Exclusion criteria were: high pressure (>30 cm H(2)O of peak inspiratory pressure) or high FiO(2) (>0.8) ventilation for more than 7 days; intracranial bleeding; any other contraindication to limited heparinisation; or any contraindication to continuation of active treatment. The primary outcome was death or severe disability at 6 months after randomisation or before discharge from hospital. Primary analysis was by intention to treat. Only researchers who did the 6-month follow-up were masked to treatment assignment. Data about resource use and economic outcomes (quality-adjusted life-years) were collected. Studies of the key cost generating events were undertaken, and we did analyses of cost-utility at 6 months after randomisation and modelled lifetime cost-utility. This study is registered, number ISRCTN47279827. FINDINGS 766 patients were screened; 180 were enrolled and randomly allocated to consideration for treatment by ECMO (n=90 patients) or to receive conventional management (n=90). 68 (75%) patients actually received ECMO; 63% (57/90) of patients allocated to consideration for treatment by ECMO survived to 6 months without disability compared with 47% (41/87) of those allocated to conventional management (relative risk 0.69; 95% CI 0.05-0.97, p=0.03). Referral to consideration for treatment by ECMO led to a gain of 0.03 quality-adjusted life-years (QALYs) at 6-month follow-up [corrected]. A lifetime model predicted the cost per QALY of ECMO to be pound19 252 (95% CI 7622-59 200) at a discount rate of 3.5%. INTERPRETATION We recommend transferring of adult patients with severe but potentially reversible respiratory failure, whose Murray score exceeds 3.0 or who have a pH of less than 7.20 on optimum conventional management, to a centre with an ECMO-based management protocol to significantly improve survival without severe disability. This strategy is also likely to be cost effective in settings with similar services to those in the UK. FUNDING UK NHS Health Technology Assessment, English National Specialist Commissioning Advisory Group, Scottish Department of Health, and Welsh Department of Health.

Gender Differences in the Management and Clinical Outcome of Stable Angina

Background— We sought to examine the impact of gender on the investigation and subsequent management of stable angina and to assess gender differences in clinical outcome at 1 year. Methods and Results— The Euro Heart Survey of Stable Angina enrolled patients with a clinical diagnosis of stable angina on initial assessment by a cardiologist. Baseline clinical details and cardiac investigations planned or performed within a 4-week period of the assessment were recorded, and follow-up data were collected at 1 year. A total of 3779 patients were included in the survey; 42% were female. Women were less likely to undergo an exercise ECG (odds ratio, 0.81; 95% CI, 0.69 to 0.95) and less likely to be referred for coronary angiography (odds ratio, 0.59; 95% CI, 0.48 to 0.72). Antiplatelet and statin therapies were used significantly less in women than in men, both at initial assessment and at 1 year, even in those in whom coronary disease had been confirmed. Women with confirmed coronary disease were less likely to be revascularized than their male counterparts and were twice as likely to suffer death or nonfatal myocardial infarction during the 1-year follow-up period (hazard ratio, 2.09; 95% CI, 1.13 to 3.85), even after multivariable adjustment for age, abnormal ventricular function, severity of coronary disease, and diabetes. Conclusions— Significant gender bias has been identified in the use of investigations and evidence-based medical therapy in stable angina. Women were also less likely to be revascularized. The observed bias is of particular concern in light of the adverse prognosis observed among women with stable angina and confirmed coronary disease.

A proposed charter for clinical trial data monitoring committees: helping them to do their job well

Formal monitoring of data from randomised controlled trials (RCTs) is becoming more common. Wide variation exists in the structure and organisation of data monitoring committees (DMCs), with little guidance on how they should operate. We used various strategies to consider the behavioural, procedural, and organisational aspects of data monitoring in RCTs: systematic reviews of DMCs and small group processes in decision making; surveys of reports of RCTs, recently completed and ongoing RCTs, and the policies of major organisations connected with RCTs; detailed case studies of four DMCs that faced difficult decisions; and interviews with experienced DMC members. The findings aided the development of a template for a charter for DMCs. We summarise the findings and outline the key considerations at every stage of the data monitoring process. Widespread use of a charter for the structure and organisation of DMCs would promote a systematic and transparent approach, and enable them to operate more effectively and efficiently.Formal monitoring of data from randomised controlled trials (RCTs) is becoming more common. Wide variation exists in the structure and organisation of data monitoring committees (DMCs), with little guidance on how they should operate. We used various strategies to consider the behavioural, procedural, and organisational aspects of data monitoring in RCTs: systematic reviews of DMCs and small group processes in decision making; surveys of reports of RCTs, recently completed and ongoing RCTs, and the policies of major organisations connected with RCTs; detailed case studies of four DMCs that faced difficult decisions; and interviews with experienced DMC members. The findings aided the development of a template for a charter for DMCs. We summarise the findings and outline the key considerations at every stage of the data monitoring process. Widespread use of a charter for the structure and organisation of DMCs would promote a systematic and transparent approach, and enable them to operate more effectively and efficiently.

Predicting prognosis in stable angina—results from the Euro heart survey of stable angina: prospective observational study

Abstract Objectives To investigate the prognosis associated with stable angina in a contemporary population as seen in clinical practice, to identify the key prognostic features, and from this to construct a simple score to assist risk prediction. Design Prospective observational cohort study. Setting Pan-European survey in 156 outpatient cardiology clinics. Participants 3031 patients were included on the basis of a new clinical diagnosis by a cardiologist of stable angina with follow-up at one year. Main outcome measure Death or non-fatal myocardial infarction. Results The rate of death and non-fatal myocardial infarction in the first year was 2.3 per 100 patient years; the rate was 3.9 per 100 patient years in the subgroup (n = 994) with angiographic confirmation of coronary disease. The clinical and investigative factors most predictive of adverse outcome were comorbidity, diabetes, shorter duration of symptoms, increasing severity of symptoms, abnormal ventricular function, resting electrocardiogaphic changes, or not having any stress test done. Results of non-invasive stress tests did not significantly predict outcome in the population who had tests done. A score was constructed using the parameters predictive of outcome to estimate the probability of death or myocardial infarction within one year of presentation with stable angina. Conclusions A score based on the presence of simple, objective clinical and investigative variables makes it possible to discriminate effectively between very low risk and very high risk patients and to estimate the probability of death or non-fatal myocardial infarction over one year.

Randomised controlled trial and parallel economic evaluation of conventional ventilatory support versus extracorporeal membrane oxygenation for severe adult respiratory failure (CESAR).

OBJECTIVES To determine the comparative effectiveness and cost-effectiveness of conventional ventilatory support versus extracorporeal membrane oxygenation (ECMO) for severe adult respiratory failure. DESIGN A multicentre, randomised controlled trial with two arms. SETTING The ECMO centre at Glenfield Hospital, Leicester, and approved conventional treatment centres and referring hospitals throughout the UK. PARTICIPANTS Patients aged 18-65 years with severe, but potentially reversible, respiratory failure, defined as a Murray lung injury score > or = 3.0, or uncompensated hypercapnoea with a pH < 7.20 despite optimal conventional treatment. INTERVENTIONS Participants were randomised to conventional management (CM) or to consideration of ECMO. MAIN OUTCOME MEASURES The primary outcome measure was death or severe disability at 6 months. Secondary outcomes included a range of hospital indices: duration of ventilation, use of high frequency/oscillation/jet ventilation, use of nitric oxide, prone positioning, use of steroids, length of intensive care unit stay, and length of hospital stay - and (for ECMO patients only) mode (venovenous/veno-arterial), duration of ECMO, blood flow and sweep flow. RESULTS A total of 180 patients (90 in each arm) were randomised from 68 centres. Three patients in the conventional arm did not give permission to be followed up. Of the 90 patients randomised to the ECMO arm, 68 received that treatment. ECMO was not given to three patients who died prior to transfer, two who died in transit, 16 who improved with conventional treatment given by the ECMO team and one who required amputation and could not therefore be heparinised. Ninety patients entered the CM (control) arm, three patients later withdrew and refused follow-up (meaning that they were alive), leaving 87 patients for whom primary outcome measures were available. CM consisted of any treatment deemed appropriate by the patients intensivist with the exception of extracorporeal gas exchange. No CM patients received ECMO, although one received a form of experimental extracorporeal arteriovenous carbon dioxide removal support (a clear protocol violation). Fewer patients in the ECMO arm than in the CM arm had died or were severely disabled 6 months after randomisation, [33/90 (36.7%) versus 46/87 (52.9%) respectively]. This equated to one extra survivor for every six patients treated. Only one patient (in the CM arm) was known to be severely disabled at 6 months. Patients allocated to ECMO incurred average total costs of 73,979 pounds compared with 33,435 pounds for those undergoing CM (UK prices, 2005). A lifetime model predicted the cost per quality-adjusted life-year (QALY) of ECMO to be 19,252 pounds (95% confidence interval 7622 pounds to 59,200 pounds) at a discount rate of 3.5%. Lifetime QALYs gained were 10.75 for the ECMO group compared with 7.31 for the conventional group. Costs to patients and their relatives, including out of pocket and time costs, were higher for patients allocated to ECMO. CONCLUSIONS Compared with CM, transferring adult patients with severe but potentially reversible respiratory failure to a single centre specialising in the treatment of severe respiratory failure for consideration of ECMO significantly increased survival without severe disability. Use of ECMO in this way is likely to be cost-effective when compared with other technologies currently competing for health resources. TRIAL REGISTRATION Current Controlled Trials ISRCTN47279827.

Use of recombinant activated factor VII in primary postpartum hemorrhage - The northern European registry 2000-2004

OBJECTIVE: To collect data from nine European countries for cases of obstetric hemorrhage between 2000 and 2004 in which recombinant activated factor VII (rFVIIa) was used. METHODS: The cases were identified through national surveys. Standardized case report forms included sociodemographic details, past medical and obstetric history, and details of the progress and management of labor in which the postpartum hemorrhage occurred. Clinicians were asked to describe subjectively the effect of rFVIIa administration using two mutually exclusive categories: 1) bleeding reduced or 2) bleeding unchanged or worse. RESULTS: A total of 113 forms were returned (88%) with 97 (86%) classified as treatment, and 16 (14%) as “secondary prophylaxis.” Clinicians noted improvements after a single dose for 80% of women in the treatment group, and for 75% in the secondary “prophylaxis” group. However, rFVIIa failed in 15 cases (13.8%). Few serious adverse events were noted related to rFVIIa administration; there were four cases of thromboembolism, one myocardial infarction, and one skin rash. CONCLUSION: Clinical reports and hematologic data suggest improvement for more than 80% of women after rFVIIa administration and few adverse effects. LEVEL OF EVIDENCE: II

Inorganic arsenic and basal cell carcinoma in areas of Hungary, Romania, and Slovakia: A case-control study

Background: Inorganic arsenic (iAs) is a potent carcinogen, but there is a lack of information about cancer risk for concentrations < 100 μg/L in drinking water. Objectives: We aimed to quantify skin cancer relative risks in relation to iAs exposure < 100 μg/L and the modifying effects of iAs metabolism. Methods: The Arsenic Health Risk Assessment and Molecular Epidemiology (ASHRAM) study, a case–control study, was conducted in areas of Hungary, Romania, and Slovakia with reported presence of iAs in groundwater. Consecutively diagnosed cases of basal cell carcinoma (BCC) of the skin were histologically confirmed; controls were general surgery, orthopedic, and trauma patients who were frequency matched to cases by age, sex, and area of residence. Exposure indices were constructed based on information on iAs intake over the lifetime of participants. iAs metabolism status was classified based on urinary concentrations of methylarsonic acid (MA) and dimethylarsinic acid (DMA). Associations were estimated by multivariable logistic regression. Results: A total of 529 cases with BCC and 540 controls were recruited for the study. BCC was positively associated with three indices of iAs exposure: peak daily iAs dose rate, cumulative iAs dose, and lifetime average water iAs concentration. The adjusted odds ratio per 10-μg/L increase in average lifetime water iAs concentration was 1.18 (95% confidence interval: 1.08, 1.28). The estimated effect of iAs on cancer was stronger in participants with urinary markers indicating incomplete metabolism of iAs: higher percentage of MA in urine or a lower percentage of DMA. Conclusion: We found a positive association between BCC and exposure to iAs through drinking water with concentrations < 100 μg/L.

A randomised controlled trial investigating the effect of n-3 long-chain polyunsaturated fatty acid supplementation on cognitive and retinal function in cognitively healthy older people: the Older People And n-3 Long-chain polyunsaturated fatty acids (OPAL) study protocol [ISRCTN72331636].

The number of individuals with age-related cognitive impairment is rising dramatically in the UK and globally. There is considerable interest in the general hypothesis that improving the diet of older people may slow the progression of cognitive decline. To date, there has been little attention given to the possible protective role of n-3 long-chain polyunsaturated fatty acids (n-3 LCPs) most commonly found in oily fish, in age-related loss of cognitive function. The main research hypothesis of this study is that an increased dietary intake of n-3 LCPs will have a positive effect on cognitive performance in older people in the UK.To test this hypothesis, a double-blind randomised placebo-controlled trial will be carried out among adults aged 70–79 years in which the intervention arm will receive daily capsules containing n-3 LCP (0.5 g/day docosahexaenoic acid and 0.2 g/day eicosapentaenoic acid) while the placebo arm will receive daily capsules containing olive oil. The main outcome variable assessed at 24 months will be cognitive performance and a second major outcome variable will be retinal function. Retinal function tests are included as the retina is a specifically differentiated neural tissue and therefore represents an accessible window into the functioning of the brain.The overall purpose of this public-health research is to help define a simple and effective dietary intervention aimed at maintaining cognitive and retinal function in later life. This will be the first trial of its kind aiming to slow the decline of cognitive and retinal function in older people by increasing daily dietary intake of n-3 LCPs. The link between cognitive ability, visual function and quality of life among older people suggests that this novel line of research may have considerable public health importance.

Inadequate control of heart rate in patients with stable angina: results from the European heart survey.

Aims To examine resting heart rate (HR) in a population presenting with stable angina in relation to prior and subsequent pharmacological treatment, comorbid conditions and clinical outcome. Methods and results The European Heart Survey was a prospective, observational, cohort study of 3779 patients with stable angina newly presenting to cardiology services. Mean baseline resting HR was 73 beats/min (bpm) and 52.3% of patients had a baseline HR > 70 bpm. Over half of patients were on no chronotropic medication at baseline. Patients with chronic respiratory disease or diabetes had higher resting HRs (75–76 bpm), and were more likely to have been receiving calcium channel blockers at baseline assessment. Overall, β-blockers were the most common treatment administered following cardiologist assessment, but were used less frequently in patients with chronic respiratory disease and diabetes, and the dosages used were less than that found to be effective in clinical trials. Mean daily doses of metoprolol, bisoprolol, carvedilol, and atenolol were 75 mg, 6 mg, 19 mg and 55 mg, respectively. Higher HR at baseline was associated with higher rates of cardiovascular mortality and hospitalisation for heart failure. Conclusion Control of ischaemic symptoms through heart rate modification in patients with angina is currently inadequate, both by primary referring physicians and cardiologists. Given the adverse outcome associated with higher resting heart rates in this as in other studies, and the availability of specific HR reducing strategies, attention should be given to achieving optimal HR control.

Data monitoring in randomized controlled trials: surveys of recent practice and policies

Background Data Monitoring Committees (DMCs) are increasingly involved in the conduct of randomized controlled trials, but there is little documented evidence of what they do. Three interlinked surveys were carried out as part of the DAMOCLES project to explore recent and current DMC practice and policy. Methods 1) A questionnaire about DMC practice was sent to sample of 45 authors of trials published in selected journals in 2000. The sample was stratified by centre (single/multiple), disease area, and presence of DMC. 2) A sample of investigators in trials ongoing in the United Kingdom in 2001–02 was also sent a questionnaire about DMC practice. The sample was drawn from trials funded by the Medical Research Council, the United Kingdom Department of Healths Health Technology Assessment Programme, and a local and a multicentre research ethics committee. The sample was additionally stratified by funder (public/industry), centre (single/ multiple), and disease area. 3) A sample of major organisations involved in randomised controlled trials was sent a questionnaire about DMC policies. Results Information about DMC practice from the first survey was obtained from 31 trials (69%), of which four had a DMC. Information about DMC practice from the second survey was obtained about 36 trials (90%), of which 20 had a DMC. Information about DMC policy from the third survey was obtained from 25 out of 25 organisations. There was general agreement about the sorts of trials particularly needing independent DMCs, but there were few uniform approaches to their modes of functioning, and few of the organisations surveyed had developed formal policies. Conclusions The roles of existing DMCs and policies governing DMC functioning vary widely across trials and organisations that sponsor or oversee trials, both within the UK and internationally. These findings reinforce previous calls for development of such policies across a wider range of organisations, better means to monitor their implementation within trials, and wider use of structured “charters”, which set out DMC modus operandi in advance.