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PubMed1993

Single daily ceftriaxone and tobramycin in the empirical management of febrile neutropenic patients: a randomised trial.

A single-institution, randomised pilot trial was conducted to compare the clinical efficacy, microbiological efficacy and possible toxicity of empirical single daily antibiotic administration in febrile neutropenic patients with haematologic disorders (absolute neutrophil count < 1 x 10(9)/l). Upon the development of signs of sepsis, patients received either single daily dose tobramycin (5 mg/kg per day) plus ceftriaxone (2 g/day) (C + T, n = 47) or tobramycin (1.5 mg/kg, every 8 h) plus azlocillin (4 g, every 6 h) (A + T, n = 45). In addition, flucloxacillin (1-2 g, every 4 h) could be added if there was clinical suspicion of staphylococcal infection (17 in each arm). Analysis was performed for the whole group and for the subset which did not receive flucloxacillin. When evaluated at 96 h, 62% of patients randomised to C + T and 67% randomised to A + T had responded (95% confidence interval (CI) for the difference in rates, -25% to +15%). Ninety-six hour response rates for those who did not receive flucloxacillin were 73% and 78%, respectively (95% CI, -17% to +27%). Overall, 42 (89%) and 41 (91%) patients, respectively, eventually became afebrile (95% CI, -14 to 10%) and there was no evidence of altered renal function or electrolyte imbalance in patients randomised to single daily antibiotic therapy compared with the conventional (multi-daily dose) arm. Within 10 days of antibiotic commencement there was 1 death in the C + T arm and 4 deaths in the A + T arm, although overall there were 4 deaths in each arm. Our results suggest that single daily empirical antibiotic therapy with tobramycin and ceftriaxone is efficacious and is not associated with an increased incidence of renal dysfunction or electrolyte imbalance compared with conventional administration schedules of azlocillin plus tobramycin. Single daily therapy has the potential to lead to savings in nursing-staff time and materials and may well contribute to an improved quality of life for febrile neutropenic patients.

Adolescent↗
PubMed2006

Economic evaluation of weekly epoetin alfa versus biweekly darbepoetin alfa for chemotherapy-induced anaemia: evidence from a 16-week randomised trial.

INTRODUCTION: A 16-week, open-label, multicentre, randomised trial of weekly epoetin alfa 40 000 units versus biweekly darbepoetin alfa 200microg among 358 patients with solid-tumour cancers and chemotherapy-induced anaemia demonstrated superior haematological outcomes with epoetin alfa. We sought to compare resource use, costs and clinical outcomes between treatment groups and report the results using a cost-consequences framework. METHODS: Pre-specified methods were used to assign costs (US dollars, year 2004-5 values) to medical resources and patient time using a societal perspective. Costs for inpatient care, outpatient care and physician services were based on US Medicare reimbursement rates. Indirect costs assigned to patient time spent receiving study medication were based on the mean hourly wage in the US. In the base-case analysis, the average wholesale price was used to assign costs to medications. Clinical outcomes included all haemoglobin levels and transfusions recorded throughout the trial. Sensitivity analyses were performed to evaluate the impact of different costing methods, cost sources, perspectives and methods to assign haemoglobin values following a blood transfusion. RESULTS: Over a mean follow-up duration of 11.8 weeks, the average cost of study medications and their administration was the single largest component of total costs and was similar between groups (epoetin alfa 5979 US dollars and darbepoetin alfa 5935 US dollars, difference 44 US dollars; 95% CI -590, 692). There were no significant differences in the proportions of patients hospitalised (epoetin alfa 24.6%, darbepoetin alfa 22.0%; p = 0.57). Patients randomised to epoetin alfa experienced more inpatient days, on average, than patients randomised to darbepoetin alfa (2.6 vs 1.6, 95% CI for the difference, 0.07, 2.27). However, with regard to transfusions, patients in the epoetin alfa arm required fewer units of blood than patients in the darbepoetin alfa arm (0.46 vs 0.88, 95% CI for the difference -0.77, -0.08). Mean total costs, comprising costs for study medications and their administration, inpatient care, transfusions, unplanned radiation therapy, haematology and laboratory services, chemotherapy and non-chemotherapy drugs and indirect costs were 14,976 US dollars in the epoetin alfa arm compared with 14,101 US dollars in the darbepoetin alfa arm, a difference of 875 US dollars (95% CI for difference -849, 2607), of which 98% of the difference was attributable to higher inpatient costs in the epoetin alfa arm (2374 US dollars vs 1520 US dollars; 95% CI for difference -33, 1955). Assessments of multiple clinical measures demonstrated improved outcomes with epoetin alfa relative to darbepoetin alfa. CONCLUSION: Most clinical outcome measures suggested greater improvement with epoetin alfa relative to darbepoetin alfa, but most costs for both agents appeared similar. Decision makers must evaluate the differences in costs and efficacy measures that are most relevant from their perspectives.

Adolescent↗
PubMed1994

Collaborative overview of randomised trials of antiplatelet therapy--I: Prevention of death, myocardial infarction, and stroke by prolonged antiplatelet therapy in various categories of patients. Antiplatelet Trialists' Collaboration.

OBJECTIVE: To determine the effects of "prolonged" antiplatelet therapy (that is, given for one month or more) on "vascular events" (non-fatal myocardial infarctions, non-fatal strokes, or vascular deaths) in various categories of patients. DESIGN: Overviews of 145 randomised trials of "prolonged" antiplatelet therapy versus control and 29 randomised comparisons between such antiplatelet regimens. SETTING: Randomised trials that could have been available by March 1990. SUBJECTS: Trials of antiplatelet therapy versus control included about 70,000 "high risk" patients (that is, with some vascular disease or other condition implying an increased risk of occlusive vascular disease) and 30,000 "low risk" subjects from the general population. Direct comparisons of different antiplatelet regimens involved about 10,000 high risk patients. RESULTS: In each of four main high risk categories of patients antiplatelet therapy was definitely protective. The percentages of patients suffering a vascular event among those allocated antiplatelet therapy versus appropriately adjusted control percentages (and mean scheduled treatment durations and net absolute benefits) were: (a) among about 20,000 patients with acute myocardial infarction, 10% antiplatelet therapy v 14% control (one month benefit about 40 vascular events avoided per 1000 patients treated (2P < 0.00001)); (b) among about 20,000 patients with a past history of myocardial infarction, 13% antiplatelet therapy v 17% control (two year benefit about 40/1000 (2P < 0.00001)); (c) among about 10,000 patients with a past history of stroke or transient ischaemic attack, 18% antiplatelet therapy v 22% control (three year benefit about 40/1000 (2P < 0.00001)); (d) among about 20,000 patients with some other relevant medical history (unstable angina, stable angina, vascular surgery, angioplasty, atrial fibrillation, valvular disease, peripheral vascular disease, etc), 9% v 14% in 4000 patients with unstable angina (six month benefit about 50/1000 (2P < 0.00001)) and 6% v 8% in 16,000 other high risk patients (one year benefit about 20/1000 (2P < 0.00001)). Reductions in vascular events were about one quarter in each of these four main categories and were separately statistically significant in middle age and old age, in men and women, in hypertensive and normotensive patients, and in diabetic and nondiabetic patients. Taking all high risk patients together showed reductions of about one third in non-fatal myocardial infarction, about one third in non-fatal stroke, and about one third in vascular death (each 2P < 0.00001). There was no evidence that non-vascular deaths were increased, so in each of the four main high risk categories overall mortality was significantly reduced. The most widely tested antiplatelet regimen was "medium dose" (75-325 mg/day) aspirin. Doses throughout this range seemed similarly effective (although in an acute emergency it might be prudent to use an initial dose of 160-325 mg rather than about 75 mg). There was no appreciable evidence that either a higher aspirin dose or any other antiplatelet regimen was more effective than medium dose aspirin in preventing vascular events. The optimal duration of treatment for patients with a past history of myocardial infarction, stroke, or transient ischaemic attack could not be determined directly because most trials lasted only one, two, or three years (average about two years). Nevertheless, there was significant (2P < 0.0001) further benefit between the end of year 1 and the end of year 3, suggesting that longer treatment might well be more effective. Among low risk recipients of "primary prevention" a significant reduction of one third in non-fatal myocardial infarction was, however, accompanied by a non-significant increase in stroke. Furthermore, the absolute reduction in vascular events was much smaller than for high risk patients despite a much longer treatment period (4.4% antiplatelet therapy v 4.8% control; five year

Cause of Death↗
PubMed2002

Maintenance infliximab for Crohn's disease: the ACCENT I randomised trial.

BACKGROUND: We did a randomised controlled trial to assess the benefit of maintenance infliximab therapy in patients with active Crohn's disease who respond to a single infusion of infliximab. METHODS: 573 patients with a score of at least 220 on the Crohn's disease activity index (CDAI) received a 5 mg/kg intravenous infusion of infliximab at week 0. After assessment of response at week 2, patients were randomly assigned repeat infusions of placebo at weeks 2 and 6 and then every 8 weeks thereafter until week 46 (group I), repeat infusions of 5 mg/kg infliximab at the same timepoints (group II), or 5 mg/kg infliximab at weeks 2 and 6 followed by 10 mg/kg (group III). The prespecified co-primary endpoints were the proportion of patients who responded at week 2 and were in remission (CDAI <150) at week 30 and the time to loss of response up to week 54 in patients who responded. Analyses of the co-primary endpoints were by intention to treat. FINDINGS: 335 (58%) patients responded to a single infusion of infliximab within 2 weeks. At week 30, 23 of 110 (21%) group I patients were in remission, compared with 44 of 113 (39%) group II (p=0.003) and 50 of 112 (45%) group III (p=0.0002) patients. Thus, patients in groups II and III combined were more likely to sustain clinical remission than patients in group I (odds ratio 2.7, 95% CI 1.6-4.6). Throughout the 54-week trial, the median time to loss of response was 38 weeks (IQR 15 to >54) and more than 54 weeks (21 to >54) for groups II and III, respectively, compared with 19 weeks (10-45) for group I (p=0.002 and p=0.0002, respectively). Infliximab safety was consistent with that seen in other trials of infliximab in Crohn's disease and rheumatoid arthritis. In particular, the incidence of serious infections was similar across treatment groups. INTERPRETATION: Patients with Crohn's disease who respond to an initial dose of infliximab are more likely to be in remission at weeks 30 and 54, to discontinue corticosteroids, and to maintain their response for a longer period of time, if infliximab treatment is maintained every 8 weeks.

Adult↗
PubMed2002

Management of meningitis in children with oral fluid restriction or intravenous fluid at maintenance volumes: a randomised trial.

A multi-centre randomised open trial was done to determine whether moderate oral fluid restriction or intravenous fluid at full maintenance volumes would result in a better outcome for children with bacterial meningitis in Papua New Guinea, and what clinical signs could guide fluid management. Children with clinical signs and cerebrospinal fluid suggestive of bacterial meningitis received either breast milk by nasogastric tube at 60% of normal maintenance volumes (n = 172) or intravenous half-normal saline and 5% dextrose at 100% of normal maintenance volumes (n = 174) for the 1st 48 hrs of treatment. An adverse outcome was death or severe neurological sequelae, and a good outcome was defined as intact survival or survival with at worst mild-to-moderate neurological sequelae. The probability of an adverse outcome was 24.7% in the intravenous group and 33.1% in the oral-restricted group, but the difference was not statistically significant (RR 0.75, 0.53-1.04, p = 0.08). Sunken eyes or reduced skin turgor at presentation were risk factors for an adverse outcome (OR 5.70, 95% CI 2.87-11.29) and were most strongly associated with adverse outcome in the fluid-restricted group. Eyelid oedema during treatment was also a risk factor for an adverse outcome (OR 2.54, 95% CI 1.36-4.75) and eyelid oedema was much more common in the intravenous group (26%) than in the restricted group (5%). For many children with bacterial meningitis in less developed countries, moderate fluid restriction is unnecessary and will be harmful; a normal state of hydration should be achieved but over-hydration should be avoided. Giving 100% of normal maintenance fluids, especially with intravenous hypotonic fluid, will lead to oedema in up to one quarter of children with bacterial meningitis. If additional intravenous fluids are required for children with meningitis, an isotonic solution should be used.

Child↗
PubMed2002

A new generation of artificial ligaments in reconstruction of the anterior cruciate ligament. Two-year follow-up of a randomised trial.

We have undertaken a randomised clinical trial comparing two methods of reconstruction of the anterior cruciate ligament in patients with chronic instability. We used an ipsilateral bone-patellar-tendon-bone autograft in 27 patients and the Ligament Advancement Reinforcement System (LARS) artificial ligament in 26. Assessment before and at two, six, 12 and 24 months after surgery, included the history, physical examination, a modified International Knee Documentation Committee (IKDC) score, the Tegner score, the Knee Injury and Osteoarthritis Outcome Score (KOOS) and instrumented laxity testing. There were no cases of reactive synovitis or of infection of the knee, and there was no difference regarding the failure rate between the two groups. The IKDC showed no significant differences between the two groups at any stage of the follow-up. The KOOS evaluation showed consistently better results in all subscales for the LARS group during the first year of follow-up. After 24 months these differences were no longer evident. Instrument-tested laxity was greater in the LARS group at all stages of follow-up, but the differences were not significant at 24 months. Our findings suggest that at follow-up at 24 months the LARS ligament seems to be a satisfactory treatment option, especially when an early return to high levels of activity is demanded.

Activities of Daily Living↗
PubMed1986

Randomised trial of compliance with screening for colorectal cancer.

A randomised trial of compliance with screening for colorectal cancer by means of the haemoccult test was conducted in Farnborough and Basingstoke districts. In each of the 14 participating practices (41 general practitioners) 25 852 men and women aged between 40 and 70 years were randomly allocated by household to one of six groups. The group determined the method of invitation to screening: a letter and the test were sent to the patient, or a letter with an appointment to attend the surgery was sent, or during a routine consultation the general practitioner invited patients to participate, and some patients received an educational booklet about bowel disorders and screening. Of the 17 824 people who were offered screening, 7545 (42%) complied. Compliance was significantly affected by the method of invitation, but not by whether an educational booklet was received, and was highest (57%) in the group that was offered the haemoccult test during a routine consultation (the "opportunistic" approach). In this group the compliance rate achieved by individual general practitioners ranged from 26% to 82%. Compliance was significantly higher in Farnborough, in the older (55-70) age group, in women, and in households in which two or more people were offered screening. The higher compliance in Farnborough may be explained by the higher proportion of older people and by the higher proportion of people living in households of two or more in the population that was offered screening. The fact that the screening programme in Farnborough was offered to the whole community and that the researcher may have acted as a facilitator were probably also important. One per cent of the patients screened had a positive test, and 24 (38%) of the 63 patients who were positive and were investigated in hospital had neoplastic disease. The yield was 1.2 cancers and 1.2 benign adenomas (1 cm or larger in size) per 1000 people screened. This low yield is likely to be a consequence of the relatively young age group screened.

Adult↗
PubMed2006

Systematic review and meta-analysis of randomised trials and cohort studies of mycophenolate mofetil in lupus nephritis.

Mycophenolate mofetil (MMF) is an immunosuppressant drug being used for induction and maintenance of remission of lupus nephritis in systemic lupus erythematosus. Evidence about its use was sought from full publications and abstracts of randomised trials and cohort studies by using a variety of search strategies. Efficacy and adverse event outcomes were sought. Five randomised trials enrolled patients with World Health Organization (WHO) class III, IV, or V (mostly IV) lupus nephritis, predominantly comparing MMF (1 to 3 g daily) with cyclophosphamide and steroid. Complete response and complete or partial response was significantly more frequent with MMF than with cyclophosphamide, with numbers needed to treat of 8 (95% confidence interval 4.3 to 60) to induce one additional complete or partial response, with wide confidence intervals. Death was reported less frequently with MMF (0.7%, 1 death in 152 patients) than with cyclophosphamide (7.8%, 12 deaths in 154 patients), with a number needed to treat to prevent (NNTp) one death of 14 (8 to 48). Hospital admission was also lower with MMF (1.7% versus 15%; NNTp 7.4 [4.8 to 16]). Serious infections, leucopaenia, amenorrhoea, and hair loss were all significantly less frequent with MMF than with cyclophosphamide, but diarrhoea was significantly more common with MMF. Ten of 18 cohort studies enrolled only patients with lupus nephritis (author-defined or WHO class III to V). Seven of these 10 reported that complete or partial response with MMF (mostly 1 or 2 g daily) with steroid occurred in 121/151 (80%) and that treatment failure or no response occurred in 30/151 (20%). Adverse events were generally similar in cohort studies with and without only patients with lupus nephritis. In all 18 cohorts, gastrointestinal adverse events (diarrhoea, nausea, vomiting) occurred in 30%, infection in 23%, and serious infection in 4.3%. Adverse event discontinuations occurred in 14% and lack of efficacy occurred in 10%. There was a single death with MMF, a mortality rate over the course of 1 year of approximately 0.2%. The results form a basis on which to plan future studies and provide a guide for the use of MMF in lupus nephritis until results of larger studies are available. At least one such study is under way.

Cohort Studies↗
PubMed2006

Do selective cyclo-oxygenase-2 inhibitors and traditional non-steroidal anti-inflammatory drugs increase the risk of atherothrombosis? Meta-analysis of randomised trials.

OBJECTIVE: To assess the effects of selective cyclo-oxygenase-2 (COX 2) inhibitors and traditional non-steroidal anti-inflammatory drugs (NSAIDs) on the risk of vascular events. DESIGN: Meta-analysis of published and unpublished tabular data from randomised trials, with indirect estimation of the effects of traditional NSAIDs. DATA SOURCES: Medline and Embase (January 1966 to April 2005); Food and Drug Administration records; and data on file from Novartis, Pfizer, and Merck. REVIEW METHODS: Eligible studies were randomised trials that included a comparison of a selective COX 2 inhibitor versus placebo or a selective COX 2 inhibitor versus a traditional NSAID, of at least four weeks' duration, with information on serious vascular events (defined as myocardial infarction, stroke, or vascular death). Individual investigators and manufacturers provided information on the number of patients randomised, numbers of vascular events, and the person time of follow-up for each randomised group. RESULTS: In placebo comparisons, allocation to a selective COX 2 inhibitor was associated with a 42% relative increase in the incidence of serious vascular events (1.2%/year v 0.9%/year; rate ratio 1.42, 95% confidence interval 1.13 to 1.78; P = 0.003), with no significant heterogeneity among the different selective COX 2 inhibitors. This was chiefly attributable to an increased risk of myocardial infarction (0.6%/year v 0.3%/year; 1.86, 1.33 to 2.59; P = 0.0003), with little apparent difference in other vascular outcomes. Among trials of at least one year's duration (mean 2.7 years), the rate ratio for vascular events was 1.45 (1.12 to 1.89; P = 0.005). Overall, the incidence of serious vascular events was similar between a selective COX 2 inhibitor and any traditional NSAID (1.0%/year v 0.9%/year; 1.16, 0.97 to 1.38; P = 0.1). However, statistical heterogeneity (P = 0.001) was found between trials of a selective COX 2 inhibitor versus naproxen (1.57, 1.21 to 2.03) and of a selective COX 2 inhibitor versus non-naproxen NSAIDs (0.88, 0.69 to 1.12). The summary rate ratio for vascular events, compared with placebo, was 0.92 (0.67 to 1.26) for naproxen, 1.51 (0.96 to 2.37) for ibuprofen, and 1.63 (1.12 to 2.37) for diclofenac. CONCLUSIONS: Selective COX 2 inhibitors are associated with a moderate increase in the risk of vascular events, as are high dose regimens of ibuprofen and diclofenac, but high dose naproxen is not associated with such an excess.

Anti-Inflammatory Agents, Non-Steroidal↗
PubMed2001

Randomised trials of socially complex interventions: promise or peril?

In the spirit of evidence-based decision making, research findings are increasingly being used to inform practice guidelines and policy making. Whether research informs the process accurately and appropriately depends on the quality of the design. This article examines the assumptions underpinning the randomised trial in relation to its application to evaluating socially complex interventions. Because the properties of the randomised trial are not independent of the characteristics of the interventions being studied, researchers need to be more attentive to selection bias, unmeasured contextual variables and uncontrolled interaction effects that arise because the environment interacts with the intervention. It is recommended that evaluations of socially complex interventions be modified by adding a complex contextual evaluation and using multiple sites.

Evidence-Based Medicine↗
PubMed2004

Increasing response rates to postal questionnaires: a randomised trial of variations in design.

OBJECTIVES: Low response rates to postal questionnaires can threaten the validity of studies by reducing the effective sample size and introducing bias. The identification of methods with which to optimise response rates could, therefore, improve the quality of studies. In an attempt to identify such methods, we undertook a randomised trial of two simple variations in questionnaire design. METHODS: Using a 2 x 2 factorial design, we conducted a randomised trial to test two variations in questionnaire design; the questionnaires were printed on either single-sided or double-sided paper and had either a single- or multiple-booklet layout. Using equal random allocation, 3836 women were randomised to receive one of these questionnaires as part of a study investigating risk factors for osteoporotic fractures. RESULTS: One thousand eight hundred and seventy questionnaires were returned, giving an overall response rate of 48.7%. There were no significant differences in the overall response to each of the four questionnaire designs. When the number of responders who completed at least 50% of each of the three sections was identified, it was found that single-booklet questionnaires had a better response than the multiple-booklet questionnaires and that single-sided questionnaires had a better response than double-sided questionnaires. However, these results were not significant at the 5% level. There were no significant differences in the response to questions on the odd (left-hand side) pages for the single- compared with the double-sided questionnaires. CONCLUSION: As the most cost-effective use of resources, we would advocate the use of double- rather than single-sided questionnaires, and use of a single- rather than multiple-booklet design.

Aged↗
PubMed1998

Randomised trial of effectiveness of second eye cataract surgery.

BACKGROUND: The effectiveness of cataract surgery on one eye is well established, but concerns over health-care expenditure have called into question the value of cataract surgery on the second eye. We examined the effects of second eye surgery in terms of patient perceptions as well as through visual acuity, contrast sensitivity, and stereoacuity tests. METHODS: 208 otherwise healthy patients awaiting second eye cataract surgery were recruited into our randomised trial. At randomisation participants were allocated expedited surgery (planned to take place within 6 weeks) or routine surgery (routine waiting time, 7-12 months). Assessments were made at randomisation and again at review after about 6 months. Eight primary trial outcomes consisted of four questionnaire items and four visual function tests, done with both eyes open. FINDINGS: Traditional clinical tests of success in cataract surgery (visual acuity and contrast sensitivity) showed only slight differences in binocular vision in favour of the expedited-surgery group. There were major benefits for the expedited-surgery group in terms of reported visual symptoms and effects on quality of life. At review, differences in self-reported vision related difficulties between the two groups ranged from 11% (95% CI 4.4-17%, activities) to 30% (19-41%, reading). Stereoacuity was better in the expedited surgery group, the difference between the groups for the proportions with stereoacuity of 3000 s of arc or worse was 58% (47-69%). INTERPRETATION: This trial has shown that there is a clear benefit from second eye cataract surgery.

Adult↗
PubMed2006

Proteinuria, impaired kidney function, and adverse outcomes in people with coronary disease: analysis of a previously conducted randomised trial.

OBJECTIVES: To determine whether data on proteinuria are useful for refining estimates of risk based on kidney function alone, and whether the results of kidney function tests can be a useful adjunct to data on proteinuria. DESIGN: Analysis of data from a randomised trial. Impaired kidney function was defined as low glomerular filtration rate (< 60 ml/min/1.73 m2) and proteinuria (> or = 1+ protein) on dipstick urinalysis. SETTING: Study of cholesterol and recurrent events: a randomised trial of pravastatin 40 mg daily versus placebo. PARTICIPANTS: 4098 men and women with previous myocardial infarction. MAIN OUTCOME MEASURES: All cause mortality and cardiovascular events. RESULTS: 371 participants died in nearly 60 months of follow-up. Compared with participants without proteinuria or impaired kidney function, patients with both characteristics were at high risk (hazard ratio 2.39, 95% confidence interval 1.72 to 3.30), and those with only proteinuria or only impaired kidney function were at intermediate risk (1.69, 1.32 to 2.16; 1.41, 1.12 to 1.79, respectively) of dying from any cause. The results were similar for cardiovascular outcomes, including new cases of heart failure, stroke, and coronary death or non-fatal myocardial infarction. A graded increase in the risk of all cause mortality was seen for severity of renal impairment and degree of proteinuria by dipstick. CONCLUSIONS: The presence or absence of proteinuria on dipstick urinalysis may be used to refine estimates of risk based on kidney function alone.

Female↗
PubMed2000

Pumactant and poractant alfa for treatment of respiratory distress syndrome in neonates born at 25-29 weeks' gestation: a randomised trial.

BACKGROUND: Exogenous surfactant preparations vary in their constitution and biophysical properties. Synthetic and animal-derived preparations lower the rate of death compared with controls. No significant differences in mortality or important long-term clinical outcomes have been shown between them in randomised trials. We did a randomised controlled trial to compare pumactant, a synthetic surfactant, with poractant alfa, an animal-derived surfactant, both of which are widely used in the UK. METHODS: We enrolled 212 neonates born between 25 weeks' and 29 weeks and 6 days' gestation who were intubated for presumed surfactant deficiency and were free from life-threatening malformations. We randomly assigned 105 neonates poractant alfa, and 107 pumactant. The primary outcome was duration of high-dependency care and mortality was a secondary outcome. Analysis was by intention to treat. FINDINGS: Outcome data were analysed for 199 babies. The trial was stopped on the recommendation of the data and safety monitoring committee because mortality assumed a greater importance than the primary outcome. Predischarge mortality differed significantly between groups, in favour of poractant alfa (14.1 vs 31.0%, p=0.006; odds ratio 0.37 [95% CI 0.18-0.76). This difference was sustained after adjustment for centre, gestation, birthweight, sex, plurality, and use of antenatal steroids. INTERPRETATION: Mortality was unexpectedly lower among neonates who received poractant alfa than among those who received pumactant, and was independent of all the variables we investigated. Stopping the trial early may have widened the difference between the treatment groups.

Cause of Death↗
PubMed1994

Indications for fibrinolytic therapy in suspected acute myocardial infarction: collaborative overview of early mortality and major morbidity results from all randomised trials of more than 1000 patients. Fibrinolytic Therapy Trialists' (FTT) Collaborative Group.

Large randomised trials have demonstrated that fibrinolytic therapy can reduce mortality in patients with suspected acute myocardial infarction (AMI). The indications for, and contraindications to, this treatment in some categories of patient are disputed, examples being late presentation, elderly patients, and those in cardiogenic shock. This overview aims to help resolve some of the remaining uncertainties. From all trials of fibrinolytic therapy versus control that randomised more than 1000 patients with suspected AMI, information was sought and checked on deaths during the first 5 weeks and on major adverse events occurring during hospitalisation. The nine trials included 58,600 patients, among whom 6177 (10.5%) deaths, 564 (1.0%) strokes, and 436 (0.7%) major non-cerebral bleeds were reported. Fibrinolytic therapy was associated with an excess of deaths during days 0-1 (especially among patients presenting more than 12 h after symptom onset, and in the elderly) but this was outweighed by a much larger benefit during days 2-35. This "early hazard" should not obscure the very clear overall survival advantage that is produced by fibrinolytic therapy. Benefit was observed among patients presenting with ST elevation or bundle-branch block (BBB)--irrespective of age, sex, blood pressure, heart rate, or previous history of myocardial infarction or diabetes--and was greater the earlier treatment began. Among the 45,000 patients presenting with ST elevation or BBB the relation between benefit and delay from symptom onset indicated highly significant absolute mortality reductions of about 30 per 1000 for those presenting within 0-6 h and of about 20 per 1000 for those presenting 7-12 h from onset, and a statistically uncertain benefit of about 10 per 1000 for those presenting at 13-18 h (with more randomised evidence needed in this latter group to assess reliably the net effects of treatment). Fibrinolytic therapy was associated with about 4 extra strokes per 1000 during days 0-1: of these, 2 were associated with early death and so were already accounted for in the overall mortality reduction, 1 was moderately or severely disabling, and 1 was not. This overview indicates that fibrinolytic therapy is beneficial in a much wider range of patients than is currently given such treatment routinely.

Adult↗
PubMed1998

Does quality of reports of randomised trials affect estimates of intervention efficacy reported in meta-analyses?

BACKGROUND: Few meta-analyses of randomised trials assess the quality of the studies included. Yet there is increasing evidence that trial quality can affect estimates of intervention efficacy. We investigated whether different methods of quality assessment provide different estimates of intervention efficacy evaluated in randomised controlled trials (RCTs). METHODS: We randomly selected 11 meta-analyses that involved 127 RCTs on the efficacy of interventions used for circulatory and digestive diseases, mental health, and pregnancy and childbirth. We replicated all the meta-analyses using published data from the primary studies. The quality of reporting of all 127 clinical trials was assessed by means of component and scale approaches. To explore the effects of quality on the quantitative results, we examined the effects of different methods of incorporating quality scores (sensitivity analysis and quality weights) on the results of the meta-analyses. FINDINGS: The quality of trials was low. Masked assessments provided significantly higher scores than unmasked assessments (mean 2.74 [SD 1.10] vs 2.55 [1.20]). Low-quality trials (score < or = 2), compared with high-quality trials (score > 2), were associated with an increased estimate of benefit of 34% (ratio of odds ratios [ROR] 0.66 [95% CI 0.52-0.83]). Trials that used inadequate allocation concealment, compared with those that used adequate methods, were also associated with an increased estimate of benefit (37%; ROR=0.63 [0.45-0.88]). The average treatment benefit was 39% (odds ratio [OR] 0.61 [0.57-0.65]) for all trials, 52% (OR 0.48 [0.43-0.54]) for low-quality trials, and 29% (OR 0.71 [0.65-0.77]) for high-quality trials. Use of all the trial scores as quality weights reduced the effects to 35% (OR 0.65 [0.59-0.71]) and resulted in the least statistical heterogeneity. INTERPRETATION: Studies of low methodological quality in which the estimate of quality is incorporated into the meta-analyses can alter the interpretation of the benefit of intervention, whether a scale or component approach is used in the assessment of trial quality.

Bias↗
PubMed2001

Surgery for stress incontinence: a non-randomised trial of colposuspension, needle suspension and anterior colporrhaphy.

OBJECTIVE: To compare the outcome, 12 months after surgery, of three principal categories of procedure (colposuspension, needle suspension and anterior colporrhaphy) used for treating stress incontinence. METHODS: A non-randomised trial design comparing 221 colposuspensions, 54 needle suspensions and 130 anterior colporrhaphies performed by 49 surgeons in 18 hospitals in the North Thames health region in 1993-1994. Four outcomes were considered: complications, severity of stress incontinence, social impact of incontinence, and activities of daily living score. Results were adjusted, using logistic regression, for 13 case-mix variables. RESULTS: Significant differences existed between the three procedures in the characteristics of the patients. The cure rate varied by procedure (colposuspension 34% dry; needle suspensions 13%; anterior colporrhaphy 19%). Two thirds of women, however, reported an improvement (colposuspension 75%; needle suspension 68%; anterior colporrhaphy 55%). After adjusting for confounders, colposuspension was significantly more likely to result in an improvement than anterior colporrhaphy (odds ratio 2.2). While this was reflected in improvements in the social life of the women, the difference between procedures did not reach statistical significance (p = 0.05). CONCLUSION: These results suggest surgery for stress incontinence in typical settings is not as good as reported in textbooks. This is mostly because this study was based on women's own reports (and not surgeons' reports) and partly because of the unselected nature of the patients. The information on outcomes given to patients should be reviewed and a large, pragmatic randomised trial including patient-assessed outcomes is needed.

Female↗
PubMed2000

Sample size calculations for cluster randomised trials. Changing Professional Practice in Europe Group (EU BIOMED II Concerted Action).

OBJECTIVES: Cluster randomised trials, in which groups of individuals are randomised, are increasingly being used in the health field. Adopting a clustered approach has implications for the design of such trials, and sample size calculations need to be inflated to accommodate for the clustering effect. Reliable estimates of intracluster correlation coefficients (ICCs) are required for robust sample size calculations to be made; however, little empirical evidence is available on their likely size, and on factors which influence their magnitude. The aim of this study was to generate empirical estimates of ICCs and to explore factors which may affect their magnitude. METHODS: Empirical estimates of ICCs were calculated for both process variables and patient outcomes from a number of datasets of primary and secondary care implementation studies. RESULTS: Estimates of ICCs varied according to setting and type of outcome. Estimates of ICCs for process variables were higher than those for patient outcomes, and estimates derived from secondary care were higher than those from primary care. ICCs for process variables in primary care were of the order of 0.05-0.15, whilst those in secondary care were of the order of 0.3. Estimates for patient outcomes in primary care were generally lower than 0.05. CONCLUSIONS: Adopting cluster randomisation has implications for the design, size and analysis of clinical trials. This study gives an insight into the potential size of ICCs in primary and secondary care, and provides a practical guide to researchers to aid the planning of future studies in this area.

Cluster Analysis↗