What is meant by intention to treat analysis? Survey of published randomised controlled trials

ObjectivesTo assess the methodological quality of intention to treat analysis as reported in randomised controlled trials in four large medical journals.DesignSurvey of all reports of randomised controlled trials published in 1997 in the BMJ, Lancet, JAMA, and New England Journal of Medicine.Results119 (48%) of the reports mentioned intention to treat analysis. Of these, 12 excluded any patients who did not start the allocated intervention and three did not analyse all randomised subjects as allocated. Five reports explicitly stated that there were no deviations from random allocation. The remaining 99 reports seemed to analyse according to random allocation, but only 34 of these explicitly stated this. 89 (75%) trials had some missing data on the primary outcome variable. The methods used to deal with this were generally inadequate, potentially leading to a biased treatment effect. 29 (24%) trials had more than 10% of responses missing for the primary outcome, the methods of handling the missing responses were similar in this subset.ConclusionsThe intention to treat approach is often inadequately described and inadequately applied. Authors should explicitly describe the handling of deviations from randomised allocation and missing responses and discuss the potential effect of any missing response. Readers should critically assess the validity of reported intention to treat analyses.

Key messages

• Intention to treat gives a pragmatic estimate of the benefit of a change in treatment policy rather than of potential benefit in patients who receive treatment exactly as planned
• Full application of intention to treat is possible only when complete outcome data are available for all randomised subjects
• About half of all published reports of randomised controlled trials stated that intention to treat was used, but handling of deviations from randomised allocation varied widely
• Many trials had some missing data on the primary outcome variable, and methods used to deal with this were generally inadequate, potentially leading to bias
• Intention to treat analyses are often inadequately described and inadequately applied

     

Content and quality of 2000 controlled trials in schizophrenia over 50 years

Objective To provide a comprehensive survey of the content and quality of intervention studies relevant to the treatment of schizophrenia.Design Data were extracted from 2000 trials on the Cochrane Schizophrenia Group’s register.Main outcome measures Type and date of publication, country of origin, language, size of study, treatment setting, participant group, interventions, outcomes, and quality of study.Results Hospital based drug trials undertaken in the United States were dominant in the sample (54%). Generally, studies were short (54%<6 weeks), small (mean number of patients 65), and poorly reported (64% had a quality score of ⩽2 (maximum score 5)). Over 600 different interventions were studied in these trials, and 640 different rating scales were used to measure outcome.Conclusions Half a century of studies of limited quality, duration, and clinical utility leave much scope for well planned, conducted, and reported trials. The drug regulatory authorities should stipulate that the results of both explanatory and pragmatic trials are necessary before a compound is given a licence for everyday use.

Key messages

• The advent of randomised controlled trials coincided with many new drug treatments for schizophrenia
• This survey of 2000 randomised controlled trials of treatment for schizophrenia found that the reporting of key aspects of trial methods could easily be improved
• The consistently poor quality of reporting is likely to have resulted in an overoptimistic estimation of the effects of treatments
• Large studies, of long duration, investigating outcomes of importance to clinicians and patients are needed

     

Assessment of the Quality of Reporting in Abstracts of Randomized Controlled Trials Published in Five Leading Chinese Medical Journals

Background

Clear, transparent and sufficiently detailed abstracts of randomized trials (RCTs), published in journal articles are important because readers will often base their initial assessment of a trial on such information. However, little is known about the quality of reporting in abstracts of RCTs published in medical journals in China.

Methods

We identified RCTs abstracts from 5 five leading Chinese medical journals published between 1998 and 2007 and indexed in MEDLINE. We assessed the quality of reporting of these abstracts based on the Consolidated Standards of Reporting Trials (CONSORT) abstract checklist. We also sought to identify whether any differences exist in reporting between the Chinese and English language version of the same abstract.

Results

We identified 332 RCT abstracts eligible for examination. Overall, the abstracts we examined reported 0–8 items as designated in the CONSORT checklist. On average, three items were reported per abstract. Details of the interventions (288/332; 87%), the number of participants randomized (216/332; 65%) and study objectives (109/332; 33%) were the top three items reported. Only two RCT abstracts reported details of trial registration, no abstracts reported the method of allocation concealment and only one mentioned specifically who was blinded. In terms of the proportion of RCT abstracts fulfilling a criterion, the absolute difference (percentage points) between the Chinese and English abstracts was 10% (ranging from 0 to 25%) on average, per item.

Conclusions

The quality of reporting in abstracts of RCTs published in Chinese medical journals needs to be improved. We hope that the introduction and endorsement of the CONSORT for Abstracts guidelines by journals reporting RCTs will lead to improvements in the quality of reporting.     

β Blockade after myocardial infarction: systematic review and meta regression analysis

ObjectivesTo assess the effectiveness of β blockers in short term treatment for acute myocardial infarction and in longer term secondary prevention; to examine predictive factors that may influence outcome and therefore choice of drug; and to examine the clinical importance of the results in the light of current treatment.DesignSystematic review of randomised controlled trials.SettingRandomised controlled trials.SubjectsPatients with acute or past myocardial infarction.Interventionβ Blockers compared with control.Mainoutcome measures All cause mortality and non-fatal reinfarction.ResultsOverall, 5477 of 54 234 patients (10.1%) randomised to β blockers or control died. We identified a 23% reduction in the odds of death in long term trials (95% confidence interval 15% to 31%), but only a 4% reduction in the odds of death in short term trials (−8% to 15%). Meta regression in long term trials did not identify a significant reduction in effectiveness in drugs with cardioselectivity but did identify a near significant trend towards decreased benefit in drugs with intrinsic sympathomimetic activity. Most evidence is available for propranolol, timolol, and metoprolol. In long term trials, the number needed to treat for 2 years to avoid a death is 42, which compares favourably with other treatments for patients with acute or past myocardial infarction.Conclusionsβ Blockers are effective in long term secondary prevention after myocardial infarction, but they are underused in such cases and lead to avoidable mortality and morbidity.

Key messages

• The first randomised trials of β blockade in secondary prevention after myocardial infarction were published in the 1960s
• β blockers were once heralded as a major advance, but their use for secondary prevention has declined in recent years
• Firm evidence shows that long term β blockade remains an effective and well tolerated treatment that reduces mortality and morbidity in unselected patients after myocardial infarction
• The benefits from β blockade compare favourably with other drug treatments for this patient group
• Most evidence is for propranolol, timolol, and metoprolol, whereas atenolol, which is commonly used, is inadequately evaluated for long term use

     

Efficacy,tolerability, and upper gastrointestinal safety of celecoxib for treatment of osteoarthritis and rheumatoid arthritis: systematic review of randomised controlled trials

ObjectiveTo determine the efficacy, gastrointestinal safety, and tolerability of celecoxib (a cyclo-oxygenase 2 (COX 2) inhibitor) used in the treatment of osteoarthritis and rheumatoid arthritis.DesignSystematic review of randomised trials that compared at least 12 weeks'' celecoxib treatment with another non-steroidal anti-inflammatory drug (NSAID) or placebo and reported efficacy, tolerability, or safety. Trials identified from manufacturer and by searching electronic databases and evaluated according to predefined inclusion and quality criteria. Data combined through meta-analysis.Participants15 187 patients with osteoarthritis or rheumatoid arthritis.ResultsNine randomised controlled trials were included. Celecoxib and NSAIDS were equally effective for all efficacy outcomes. Compared with those taking other NSAIDs, in patients taking celecoxib the rate of withdrawals due to adverse gastrointestinal events was 46% lower (95% confidence interval 29% to 58%; NNT 35 at three months), the incidence of ulcers detectable by endoscopy was 71% lower (59% to 79%; NNT 6 at three months), and the incidence of symptoms of ulcers, perforations, bleeds, and obstructions was 39% lower (4% to 61%; NNT 208 at six months). Subgroup analysis of patients taking aspirin showed that the incidence of ulcers detected by endoscopy was reduced by 51% (14% to 72%) in those given celecoxib compared with other NSAIDs. The reduction was greater (73%, 52% to 84%) in those not taking aspirin.ConclusionCelecoxib is as effective as other NSAIDs for relief of symptoms of osteoarthritis and rheumatoid arthritis and has significantly improved gastrointestinal safety and tolerability.

What is already known on this topic

Long term NSAID use is associated with the development of peptic and duodenal ulcersCOX 2 specific inhibitors are claimed to cause fewer gastrointestinal complicationsThe National Institute for Clinical Excellence has recently recommended that COX 2 specific inhibitors are used in patients with arthritis who are at risk of gastrointestinal complications but not in those taking prophylactic aspirin

What this study adds

Systematic review of randomised trials shows that celecoxib is as effective as other NSAIDs for osteoarthritis and rheumatoid arthritisCelecoxib has significantly improved gastrointestinal safety and tolerability compared with standard NSAIDsAn improvement in gastrointestinal safety was still evident in patients who were also taking aspirin     

Influence of data display formats on physician investigators’ decisions to stop clinical trials: prospective trial with repeated measures

ObjectiveTo examine the effect of the method of data display on physician investigators’ decisions to stop hypothetical clinical trials for an unplanned statistical analysis.DesignProspective, mixed model design with variables between subjects and within subjects (repeated measures).SettingComprehensive cancer centre.Participants34 physicians, stratified by academic rank, who were conducting clinical trials.InterventionsParticipants were shown tables, pie charts, bar graphs, and icon displays containing hypothetical data from a clinical trial and were asked to decide whether to continue the trial or stop for an unplanned statistical analysis.ResultsAccuracy of decisions was affected by the type of data display and positive or negative framing of the data. More correct decisions were made with icon displays than with tables, pie charts, and bar graphs (82% v 68%, 56%, and 43%, respectively; P=0.03) and when data were negatively framed rather than positively framed in tables (93% v 47%; P=0.004).ConclusionsClinical investigators’ decisions can be affected by factors unrelated to the actual data. In the design of clinical trials information systems, careful consideration should be given to the method by which data are framed and displayed in order to reduce the impact of these extraneous factors.

Key messages

• In clinical trials formal interim monitoring points, at which statistical tests are conducted, are designated a priori, but investigators also conduct informal interim monitoring, when statistical tests are not used
• This study investigated the effect of the method of displaying results on clinical investigators’ decisions to conduct unplanned analyses of a hypothetical clinical trial
• The method of displaying results significantly influenced the accuracy of decisions, as did the framing of these results (positive or negative)
• The display formats preferred by the clinical investigators did not lead to the most accurate decisions
• Careful consideration should be given to the method of data display in information systems supporting clinical research

     

Human albumin administration in critically ill patients: systematic review of randomised controlled trials

Objective: To quantify effect on mortality of administering human albumin or plasma protein fraction during management of critically ill patients. Design: Systematic review of randomised controlled trials comparing administration of albumin or plasma protein fraction with no administration or with administration of crystalloid solution in critically ill patients with hypovolaemia, burns, or hypoalbuminaemia. Subjects: 30 randomised controlled trials including 1419 randomised patients. Main outcome measure: Mortality from all causes at end of follow up for each trial. Results: For each patient category the risk of death in the albumin treated group was higher than in the comparison group. For hypovolaemia the relative risk of death after albumin administration was 1.46 (95% confidence interval 0.97 to 2.22), for burns the relative risk was 2.40 (1.11 to 5.19), and for hypoalbuminaemia it was 1.69 (1.07 to 2.67). Pooled relative risk of death with albumin administration was 1.68 (1.26 to 2.23). Pooled difference in the risk of death with albumin was 6% (95% confidence interval 3% to 9%) with a fixed effects model. These data suggest that for every 17 critically ill patients treated with albumin there is one additional death. Conclusions: There is no evidence that albumin administration reduces mortality in critically ill patients with hypovolaemia, burns, or hypoalbuminaemia and a strong suggestion that it may increase mortality. These data suggest that use of human albumin in critically ill patients should be urgently reviewed and that it should not be used outside the context of rigorously conducted, randomised controlled trials.

Key messages

• Human albumin solution has been used in the treatment of critically ill patients for over 50 years
• Currently, the licensed indications for use of albumin are emergency treatment of shock, acute management of burns, and clinical situations associated with hypoproteinaemia
• Our systematic review of randomised controlled trials showed that, for each of these patient categories, the risk of death in the albumin treated group was higher than in the comparison group
• The pooled relative risk of death with albumin was 1.68 (95% confidence interval 1.26 to 2.23) and the pooled difference in the risk of death was 6% (3% to 9%) or six additional deaths for every 100 patients treated
• We consider that use of human albumin solution in critically ill patients should be urgently reviewed

     

Vertical transmission rates for HIV in the British Isles: estimates based on surveillance data

ObjectiveTo estimate and interpret time trends in vertical transmission rates for HIV using data from national obstetric and paediatric surveillance registers.DesignProspective study of HIV infected women reported through obstetric surveillance. HIV infection status of the child and onset of AIDS were reported through paediatric surveillance. Rates of vertical transmission and progression to AIDS rate were estimated by methods that take account of incomplete follow up of children with indeterminate infection status and delay in AIDS reporting.SettingBritish Isles.SubjectsPregnant women infected with HIV whose infection was diagnosed before delivery, and their babies.ResultsBy January 1999, 800 children born to diagnosed HIV infected women who had not breast fed had been reported. Vertical transmission rates rose to 19.6% (95% confidence interval 8.0% to 32.5%) in 1993 before falling to 2.2% (0% to 7.8%) in 1998. Between 1995 and 1998 use of antiretroviral treatment increased significantly each year, reaching 97% of live births in 1998. The rate of elective caesarean section remained constant, at around 40%, up to 1997 but increased to 62% in 1998. Caesarean section and antiretroviral treatment together were estimated to reduce risk of transmission from 31.6% (13.6% to 52.2%) to 4.2% (0.8% to 8.5%). The proportion of infected children developing AIDS in the first 6 months fell from 17.7% (6.8% to 30.8%) before 1994 to 7.2% (0% to 15.7%) after, coinciding with increased use of prophylaxis against Pneumocystis carinii pneumonia.ConclusionsIn the British Isles both HIV related morbidity and vertical transmission are being reduced through increased use of interventions.

Key messages

• Reliable estimates of HIV vertical transmission rates can be derived from surveillance data
• Infected pregnant women are increasingly taking up elective caesarean section and antiretroviral treatment to reduce the risk of transmitting HIV to their babies
• Vertical transmission rates have fallen greatly over the past four years and progression to AIDS among infected children may also have slowed
• These benefits can occur only if infected women are diagnosed before or during pregnancy

     

Testing for Helicobacter pylori infection: validation and diagnostic yield of a near patient test in primary care

ObjectiveTo evaluate the performance of a near patient test for Helicobacter pylori infection in primary care.DesignValidation study performed within a randomised trial of four management strategies for dyspepsia.Setting43 general practices around Nottingham.Subjects394 patients aged 18-70 years presenting with recent onset dyspepsia.ResultsWhen used in primary care FlexSure test had a sensitivity and specificity of 67% (95% confidence interval 59% to 75%) and 98% (95% to 99%) compared with a sensitivity and specificity of 92% (87% to 97%) and 90% (83% to 97%) when used previously in secondary care. Of the H pylori test and refer group 14% (28/199) were found to have conditions for which H pylori eradication was appropriate compared with 23% (39/170) of the group referred directly for endoscopy.ConclusionsWhen used in primary care the sensitivity of the FlexSure test was significantly poorer than in secondary care. About a third of patients who would have benefited from H pylori eradication were not detected. Near patient tests need to be validated in primary care before they are incorporated into management policies for dyspepsia.

Key messages

• Near patient tests for H pylori infection have been recommended in the management of dyspepsia in primary care without proper evaluation
• Such tests should have a high sensitivity to avoid missing treatable illness related to infection
• The FlexSure near patient test had a lower sensitivity than previously reported in validation studies performed in secondary care
• Fewer than expected numbers of patients with H pylori related pathology were identified with the FlexSure in primary care

     

Prospective,randomised, double blind trial of prophylaxis with single dose of co-amoxiclav before percutaneous endoscopic gastrostomy

ObjectiveTo determine the efficacy of antibacterial prophylaxis in preventing infectious complications after percutaneous endoscopic gastrostomy.DesignProspective, randomised, placebo controlled, double blind, multicentre study.SettingDepartments of internal medicine at six German hospitals.SubjectsOf 106 randomised adult patients with dysphagia, 97 received study medication, and 84 completed the study. The median age of the patients was 65 years. Most had dysphagia due to malignant disease (65%), and many (76%) had serious comorbidity.InterventionsA single intravenous 2.2 g dose of co-amoxiclav or identical appearing saline was given 30 min before percutaneous endoscopic gastrostomy performed by the thread pull method.ResultsThe incidence of peristomal and other infections within one week after percutaneous endoscopic gastrostomy was significantly reduced in the antibiotic group (8/41 (20%) v 28/43 (65%), P<0.001). Similar results were obtained in an intention to treat analysis. Several peristomal wound infections were of minor clinical significance. After wound infections that required no or only local treatment were excluded from the analysis, antibiotic prophylaxis remained highly effective in reducing clinically important wound infections (1/41 (2%) v 11/43 (26%), P<0.01) and non-wound infections (2 (5%) v 9 (21%), P<0.05).ConclusionsAntibiotic prophylaxis with a single dose of co-amoxiclav significantly reduces the risk of infectious complications after percutaneous endoscopic gastrostomy and should be recommended.

Key messages

• Percutaneous endoscopic gastrostomy for enteral feeding can be associated with substantial rates of infectious complications, notably peristomal wound infection
• Small, single centre studies on prevention of wound infection by antibiotic prophylaxis have given conflicting results
• This prospective, randomised, placebo controlled, double blind, multicentre study showed that a single dose of 2.2 g co-amoxiclav significantly reduced the rate of infection
• The favourable effect of antibiotic prophylaxis included a reduction in the rate of clinically important peristomal wound infection
• Intention to treat analysis indicated a significant reduction in the need for therapeutic antibiotics

     

Career destinations seven years on among doctors who qualified in the United Kingdom in 1988: postal questionnaire survey

ObjectiveTo report the career choices and career destinations in 1995 of doctors who qualified in the United Kingdom in 1988.DesignPostal questionnaire.SettingUnited Kingdom.SubjectsAll doctors who qualified in the United Kingdom in 1988.ResultsOf the 3724 doctors who were sent questionnaires, eight had died and three declined to participate. Of the remaining 3713 doctors, 2885 (77.7%) replied. 16.9% (608/3593; 95% confidence interval 16.1% to 17.8%) of all 1988 qualifiers from medical schools in Great Britain were not working in the NHS in Great Britain in 1995 compared with 17.0% (624/3674; 16.1% to 17.9%) of the 1983 cohort in 1990. The proportion of doctors working in general practice was lower than in previous cohorts. The percentage of women in general practice (44.3% (528/1192)) substantially exceeded that of men (33.1% (443/1340)). 53% (276/522) of the women in general practice and 20% (98/490) of the women in hospital specialties worked part time.ConclusionsConcerns about recruitment difficulties in general practice are justified. Women are now entering general practice in greater numbers than men. There is no evidence of a greater exodus from the NHS from the 1988 qualifiers than from earlier cohorts.

Key messages

• This study reports the career progress to September 1995 of doctors who qualified in 1988
• Loss from the British NHS, at 16.9% (95% confidence interval, 16.1% to 17.8%), was no greater than among earlier qualifiers at the same time after qualification
• The proportion of doctors working in general practice (38%) was lower than in earlier cohorts studied
• In this generation of doctors, women in general practice now outnumber men
• Fifty three per cent of the women in general practice and 20% of the women in hospital specialties were working on a part time or flexible basis

     

Deliberate self harm: systematic review of efficacy of psychosocial and pharmacological treatments in preventing repetition

Objective: To identify and synthesise the findings from all randomised controlled trials that have examined the effectiveness of treatments of patients who have deliberately harmed themselves. Design: Systematic review of randomised controlled trials of psychosocial and physical treatments. Studies categorised according to type of treatment. When there was more than one investigation in a particular category a summary odds ratio was estimated with the Mantel-Haenszel method. Setting: Randomised trials available in electronic databases in 1996, in the Cochrane Controlled Trials Register in 1997, and from hand searching of journals to 1997. Subjects: Patients who had deliberately harmed themselves shortly before entry into the trials with information on repetition of behaviour. The included trials comprised 2452 randomised participants with outcome data. Main outcome measure: Repetition of self harm. Results: 20 trials reported repetition of self harm as an outcome variable, classified into 10 categories. Summary odds ratio (all for comparison with standard aftercare) indicated reduced repetition for problem solving therapy (0.73; 95% confidence interval 0.45 to 1.18) and for provision of an emergency contact card in addition to standard care (0.45; 0.19 to 1.07). The summary odds ratios were 0.83 (0.61 to 1.14) for trials of intensive aftercare plus outreach and 1.19 (0.53 to 2.67) for antidepressant treatment compared with placebo. Significantly reduced rates of further self harm were observed for depot flupenthixol versus placebo in multiple repeaters (0.09; 0.02 to 0.50) and for dialectical behaviour therapy versus standard aftercare (0.24; 0.06 to 0.93). Conclusion: There remains considerable uncertainty about which forms of psychosocial and physical treatments of patients who harm themselves are most effective. Further larger trials of treatments are needed.

Key messages

• A systematic review of the effectiveness of psychosocial and drug treatments of patients who deliberately harm themselves identified 20 randomised controlled trials in which repetition of self harm was reported as an outcome
• Promising results were found for problem solving therapy, provision of a card to allow patients to make emergency contact with services, depot flupenthixol for recurrent self harm, and long term psychological therapy for female patients with borderline personality disorder and recurrent self harm
• Assertive outreach can help to keep patients in treatment
• Nearly all the trials included too few patients to detect clinically significant differences in repetition of self harm, and even synthesis of results by meta-analysis did not have the power to detect such differences
• There is an urgent need for large trials of promising therapies for this substantial clinical population

     

Informing participants of allocation to placebo at trial closure: postal survey

ObjectivesTo assess whether and how investigators of placebo controlled randomised trials inform participants of their treatment allocation at trial closure and to assess barriers to feedback.DesignPostal survey with a semistructured questionnaire.ParticipantsAll investigators who published a placebo controlled randomised trial in 2000 in five leading medical journals, and a random sample of 120 trials listed in the national research register database.Results45% of investigators informed either all or most participants of their treatment allocation, and 55% did not inform any participant or only informed those who asked. The main reasons for not informing participants were that the investigators never considered this option (40%) or to avoid biasing results at study follow up (24%).ConclusionFurther research is required to examine sensitive ways to communicate treatment information to trial participants.

What is already known on this topic

Information is poor on the nature, extent, and effect of informing participants of placebo controlled randomised trials about their treatment allocation at trial closureLess than 50% of participants receiving placebo are informed about their treatment allocation

What this study adds

No standard procedure is available for informing patients of their treatment arm or of study results at the end of a trialEffective and sensitive ways of communicating treatment allocation to participants are required, as is information on the effects on placebo responders     

Randomised,double blind placebo controlled trial of pentoxifylline in the treatment of venous leg ulcers

ObjectiveTo determine whether pentoxifylline 400 mg (Trental 400) taken orally three times daily, in addition to ambulatory compression bandages and dressings, improves the healing rate of pure venous ulcers.DesignRandomised, double blind placebo controlled trial, parallel group study of factorial design, permitting the simultaneous evaluation of alternative pharmaceutical, bandaging, and dressings materials.SettingLeg ulcer clinics of a teaching and a district general hospital in southern Scotland.Participants200 patients with confirmed venous ulcers and in whom other major causal factors were excluded.InterventionsPentoxifylline 400 mg three times daily or placebo.ResultsComplete healing occurred in 65 of the 101 (64%) patients receiving pentoxifylline and 52 of the 99 (53%) patients receiving placebo.ConclusionsThe difference in the healing rates between patients taking pentoxifylline and those taking placebo did not reach statistical significance.

Key messages

• Leg ulcers cost the NHS around £400 million per annum
• 50%-75% of venous leg ulcers can be succesfully treated with dressings and compression bandages but take many months to heal
• A drug that reduced the healing time of venous ulcers would be useful, although no agent has been proved to be effective to date
• Trials with pentoxifylline, a vasoactive drug used in the treatment of peripheral vascular diseases, as an adjunct to the treatment of venous ulcers have been inconclusive
• At the 5% level, pentoxifylline had a non-significant effect on healing rates of pure venous ulcers

     

Systematic review of dietary intervention trials to lower blood total cholesterol in free-living subjects

Objectives: To estimate the efficacy of dietary advice to lower blood total cholesterol concentration in free-living subjects and to investigate the efficacy of different dietary recommendations. Design: Systematic overview of 19 randomised controlled trials including 28 comparisons. Subjects: Free-living subjects. Interventions: Individualised dietary advice to modify fat intake. Main outcome measure: Percentage difference in blood total cholesterol concentration between the intervention and control groups. Results: The percentage reduction in blood total cholesterol attributable to dietary advice after at least six months of intervention was 5.3% (95% confidence interval 4.7% to 5.9%). Including both short and long duration studies, the effect was 8.5% at 3 months and 5.5% at 12 months. Diets equivalent to the step 2 diet of the American Heart Association were of similar efficacy to diets that aimed to lower total fat intake or to raise the polyunsaturated to saturated fatty acid ratio. These diets were moderately more effective than the step 1 diet of the American Heart Association (6.1% v 3.0% reduction in blood total cholesterol concentration; P<0.0001). On the basis of reported food intake, the targets for dietary change were seldom achieved. The observed reductions in blood total cholesterol concentrations in the individual trials were consistent with those predicted from dietary intake on the basis of the Keys equation. Conclusions: Individualised dietary advice for reducing cholesterol concentration is modestly effective in free-living subjects. More intensive diets achieve a greater reduction in serum cholesterol concentration. Failure to comply fully with dietary recommendations is the likely explanation for this limited efficacy.

Key messages

• Results from metabolic ward studies suggest that dietary change can reduce blood cholesterol concentrations by up to 15%
• In free-living subjects the standard step 1 diet of the American Heart Association lowers cholesterol concentration by about 3%, and about another 3% can be achieved with more intensive diets
• Difficulties in complying with the prescribed dietary change explain the failure to achieve the expected reductions in cholesterol concentrations
• It is important to be realistic about the reductions in cardiovascular risk that can be achieved by individual dietary counselling

     

Lowering blood homocysteine with folic acid based supplements: meta-analysis of randomised trials

Objective: To determine the size of reduction in homocysteine concentrations produced by dietary supplementation with folic acid and with vitamins B-12 or B-6. Design: Meta-analysis of randomised controlled trials that assessed the effects of folic acid based supplements on blood homocysteine concentrations. Multivariate regression analysis was used to determine the effects on homocysteine concentrations of different doses of folic acid and of the addition of vitamin B-12 or B-6. Subjects: Individual data on 1114 people included in 12 trials. Findings: The proportional and absolute reductions in blood homocysteine produced by folic acid supplements were greater at higher pretreatment blood homocysteine concentrations (P<0.001) and at lower pretreatment blood folate concentrations (P<0.001). After standardisation to pretreatment blood concentrations of homocysteine of 12 μmol/l and of folate of 12 nmol/l (approximate average concentrations for Western populations), dietary folic acid reduced blood homocysteine concentrations by 25% (95% confidence interval 23% to 28%; P<0.001), with similar effects in the range of 0.5-5 mg folic acid daily. Vitamin B-12 (mean 0.5 mg daily) produced an additional 7% (3% to 10%) reduction in blood homocysteine. Vitamin B-6 (mean 16.5 mg daily) did not have a significant additional effect. Conclusions: Typically in Western populations, daily supplementation with both 0.5-5 mg folic acid and about 0.5 mg vitamin B-12 would be expected to reduce blood homocysteine concentrations by about a quarter to a third (for example, from about 12 μmol/l to 8-9 μmol/l). Large scale randomised trials of such regimens in high risk populations are now needed to determine whether lowering blood homocysteine concentrations reduces the risk of vascular disease.

Key messages

• Higher blood homocysteine concentrations seem to be associated with higher risks of occlusive vascular disease and with lower blood concentrations of folate and vitamins B-12 and B-6
• Proportional and absolute reductions in blood homocysteine concentrations with folic acid supplements are greater at higher pretreatment blood homocysteine concentrations and at lower pretreatment blood folate concentrations
• In typical Western populations, supplementation with both 0.5-5 mg daily folic acid and about 0.5 mg daily vitamin B-12 should reduce blood homocysteine concentrations by about a quarter to a third
• Large scale randomised trials of such regimens in people at high risk are now needed to determine whether lowering blood homocysteine concentrations reduces the risk of vascular disease

     

Trial Publication after Registration in ClinicalTrials.Gov: A Cross-Sectional Analysis

Background

ClinicalTrials.gov is a publicly accessible, Internet-based registry of clinical trials managed by the US National Library of Medicine that has the potential to address selective trial publication. Our objectives were to examine completeness of registration within ClinicalTrials.gov and to determine the extent and correlates of selective publication.

Methods and Findings

We examined reporting of registration information among a cross-section of trials that had been registered at ClinicalTrials.gov after December 31, 1999 and updated as having been completed by June 8, 2007, excluding phase I trials. We then determined publication status among a random 10% subsample by searching MEDLINE using a systematic protocol, after excluding trials completed after December 31, 2005 to allow at least 2 y for publication following completion. Among the full sample of completed trials (n = 7,515), nearly 100% reported all data elements mandated by ClinicalTrials.gov, such as intervention and sponsorship. Optional data element reporting varied, with 53% reporting trial end date, 66% reporting primary outcome, and 87% reporting trial start date. Among the 10% subsample, less than half (311 of 677, 46%) of trials were published, among which 96 (31%) provided a citation within ClinicalTrials.gov of a publication describing trial results. Trials primarily sponsored by industry (40%, 144 of 357) were less likely to be published when compared with nonindustry/nongovernment sponsored trials (56%, 110 of 198; p<0.001), but there was no significant difference when compared with government sponsored trials (47%, 57 of 122; p = 0.22). Among trials that reported an end date, 75 of 123 (61%) completed prior to 2004, 50 of 96 (52%) completed during 2004, and 62 of 149 (42%) completed during 2005 were published (p = 0.006).

Conclusions

Reporting of optional data elements varied and publication rates among completed trials registered within ClinicalTrials.gov were low. Without greater attention to reporting of all data elements, the potential for ClinicalTrials.gov to address selective publication of clinical trials will be limited. Please see later in the article for the Editors'' Summary     

Limits of teacher delivered sex education: interim behavioural outcomes from randomised trial

ObjectiveTo determine whether a theoretically based sex education programme for adolescents (SHARE) delivered by teachers reduced unsafe sexual intercourse compared with current practice.DesignCluster randomised trial with follow up two years after baseline (six months after intervention). A process evaluation investigated the delivery of sex education and broader features of each school.SettingTwenty five secondary schools in east Scotland.Participants8430 pupils aged 13-15 years; 7616 completed the baseline questionnaire and 5854 completed the two year follow up questionnaire.InterventionSHARE programme (intervention group) versus existing sex education (control programme).ResultsWhen the intervention group was compared with the conventional sex education group in an intention to treat analysis there were no differences in sexual activity or sexual risk taking by the age of 16 years. However, those in the intervention group reported less regret of first sexual intercourse with most recent partner (young men 9.9% difference, 95% confidence interval −18.7 to −1.0; young women 7.7% difference, −16.6 to 1.2). Pupils evaluated the intervention programme more positively, and their knowledge of sexual health improved. Lack of behavioural effect could not be linked to differential quality of delivery of intervention.ConclusionsCompared with conventional sex education this specially designed intervention did not reduce sexual risk taking in adolescents.

What is already known on this topic

Despite the widespread assumption that sex education delivered by teachers can reduce sexual risk taking in young people, there have been few randomised trials large enough to show this and none in the United KingdomSeveral quasi-experimental studies have concluded that sex education is effective, but most randomised trials suggest it is not

What this study adds

Improvements in teacher delivered whole class sex education have some beneficial effect on the quality of young people''s sexual relationships but do not influence sexual behaviour