Systematic review: patient adherence to TB treatments

A range of factors influence patients' adherence to the lengthy and complex treatment regimens used for tuberculosis (TB), according to a systematic review of the evidence, and better knowledge of these may allow the development of interventions to reduce barriers to adherence. The authors of the review note that TB remains a major contributor to the global burden of disease, and requires treatment with multiple drugs for prolonged courses. As a result, up to half of patients do not complete the course of treatment leading to prolonged infection, the development of resistant organisms, and adverse outcomes for both individual and their society. This review aimed to identify research on factors that both hinder and encourage patients to adhere to their treatment, with the objective of informing the development of new interventions to improve adherence.

The authors carried out a comprehensive literature search for studies that examined adherence or non-adherence to preventive or curative TB treatments and described the perspectives of patients, care givers, or health care providers. Both qualitative and quantitative studies were included, and unpublished work was considered. The only major limitation was the exclusion of papers not published in English due to resource constraints.

Over 7,000 citations were scanned and 2,162 potentially relevant abstracts obtained. Of these, 626 were considered potentially eligible after review of the abstracts and scanned in full to produce 66 potentially eligible studies: exclusion of duplicate and ineligible papers, left 44 for final review and assessment. They ranged in publication date from 1969 to 2005, covered most geographical areas, and involved about 3,213 individuals. Eligible studies were used to develop a model of factors related to treatment adherence: studies were analysed to identify relevant themes and concepts, and categories were developed from these to represent related themes and concepts. Eight major themes were identified across the studies, including organisation of treatment and care; interpretations of illness and wellness; the financial burden of treatment; knowledge, attitudes, and beliefs about treatment; law and immigration; personal characteristics and adherence behaviour; side effects; and family, community, and household support. The authors used these to produce a synthesis describing how four major factors interact to affect adherence to TB treatment: structural factors, including poverty and gender discrimination; the social context; health service factors; and personal factors. They discuss these in some depth, noting areas of interaction between different factors. Finally, they suggest some implications of the study for policy and practice. They note that the results are limited by the underlying data. Additionally, most studies were carried out in developing countries and are thus most relevant to these; nevertheless, studies in more developed countries had similar findings so the overall results may be applicable to them also.

Overall, the authors conclude that adherence to TB medication is complex and dynamic, with a wide range of factors impacting on patients' treatment-taking behaviour. They suggest that their analysis could help in the development of both patient-centred and structural interventions to assist adherence.

PLoS Med 2007; 4(7): e238. doi:10.1371/journal.pmed.0040238 (link to free full text)

Medical knowledge of the general public is seriously limited.

A survey from Switzerland suggests that the general public, including those with some medical knowledge, has very limited knowledge about important signs and risk factors of major medical conditions. The authors suggest that everyone needs a set level of health knowledge about major medical conditions, both to reduce their risk of developing them and increase their chance of seeking medical help when appropriate. They therefore carried out a survey to determine whether ordinary people had this level of knowledge for four conditions. They defined a 'minimum medical knowledge' (MMK) set for chronic obstructive pulmonary disease (COPD), HIV infection, heart attack and stroke, using several experts each field, and developed a questionnaire to determine how much people knew of this. They hypothesised that people with personal experience or some degree of medical training would reach this level more often than those without. The survey was carried out by face to face interview with randomly chosen participants in six busy locations in Zurich. Basic questions included level of education, medical or paramedical background, and personal experience of the conditions involved within their social environment.

Of 272 people approached, 185 (68%) were willing to take part; mean age was 37, and the gender balance was about equal; 84 (46%) had education to degree level, 34 (18%) some medical or paramedical background, and 96 (52%) had some personal experience of one of the conditions. No subject scored 100% MMK: the mean score was 32% and the highest score achieved was 72% (with the minimum 0%). Those with a degree and those with personal experience only scored marginally higher than the mean, as did those with a medical or paramedical background.

The authors conclude that in this population they found a considerable level of ignorance in relation to the symptoms of and risks for frequently found and important illnesses; unexpectedly, personal or professional exposure to the illnesses made only a small difference. They comment that there is little published data in this area, but suggest that they would have expected their results to be better as in the Swiss healthcare system good health knowledge could reduce personal financial costs. In systems where patients have no co-payments, the level of knowledge may be even lower. They suggest that further research is needed, especially comparing different health systems.

BMC Medicine 2007; 5: 14. doi:10.1186/1741-7015-5-14 (link to full text, freely available)

Dexamethasone safer than betamethasone for preterm neonates?

According to the results of a trial published in Obstetrics and Gynecology, the use of antenatal dexamethasone is associated with a lower rate of neonatal intraventricular haemorrhage than betamethasone, although both agents are effective at reducing overall neonatal morbidity and mortality.

In the double-blind Antenatal Betamethasone Compared with Dexamethasone (Betacode) trial, investigators randomised women at risk for preterm delivery to treatment with antenatal betamethasone (n=100) or dexamethasone (n=105). Exclusion criteria included clinical chorioamnionitis, foetal structural and chromosomal abnormalities, prior antenatal steroid exposure, and steroid use for other indications.

The main results were as follows:

• There were no significant differences between the groups in rate of respiratory distress syndrome, need for vasopressor therapy, necrotising enterocolitis, retinopathy of prematurity, patent ductus arteriosus, neonatal sepsis, and neonatal mortality
• There were 6 cases of intraventricular haemorrhage in infants of the 105 women randomised to dexamethasone (5.7%) compared with 17 cases among infants of the 100 women treated with antenatal betamethasone (17.0%) (RR 2.97, 95% CI 1.22-7.24, P=0.02). Dexamethasone was therefore associated with an absolute risk reduction in the rate of intraventricular haemorrhage of 11.3 % (95% CI 2.7-11.9%), with a number needed to treat of 9 (95% CI 5-37).
• There were 6 brain lesions of any kind (6.7%) in infants of women receiving dexamethasone and 18 cases of any type of brain lesion in the infants of women receiving betamethasone (18.0%) (RR 2.7, 95% CI 1.18-6.19, P=0.02)

The authors state that their study "largely supports the continuing use of both betamethasone and dexamethasone in the treatment of women at risk of preterm delivery…However, dexamethasone seems to be more effective in reducing the rate of intraventricular haemorrhage compared with betamethasone”.

An accompanying editorial discusses the study.

[Editor's note: this summary was taken from the abstract only, as the full text was not accessible at the time of posting]

Obstet Gynecol 2007; 110: 26-30 (link to abstract) Obstet Gynecol 2007; 110: 7-9 (editorial; link to full text, available to subscribers only)

Treating rheumatoid arthritis

BMJ editorial: Treating rheumatoid arthritis.

The authors of this editorial discuss the use of anti-TNF agents in the treatment of rheumatoid arthritis (RA). They refer to recent trials in this area of practice, one which suggested that these agents may produce remission in patients if used early. Questioning whether patients with a poor prognosis should receive anti-TNF as first line treatment, the authors conclude: “If the cost of the drugs was minimal, the only relevant comparator would be combination regimens with corticosteroids and methotrexate as the anchoring drugs. Cost effectiveness analyses are under way and will influence how widespread such an approach is likely to be. The success of the treatment-to-target strategy supports its use in clinical practice whenever possible. The data also suggest that patients with rheumatoid arthritis can achieve remission, but for them to cease treatment and remain in remission they must be treated early on in the disease process. However, sufficient uncertainty exists to warrant further double blinded trials and analyses of their costs.”

BMJ 2007; 335: 56-7 (link to extract)

HRT increases cardiovascular and thromboembolic risk when started many years after menopause.

According to data from WISDOM, a RCT of HRT (Hormone Replacement Therapy) in postmenopausal women, treatment started many years after the menopause increases cardiovascular and thromboembolic risk.

This multicentre, randomised, double blind study involved postmenopausal women aged 50-69 years, from general practices in UK (384), Australia (91), and New Zealand (24). The participants were randomised to 10 years of treatment with oestrogen only therapy (conjugated equine oestrogens 0.625 mg OD) or combined HRT (conjugated equine oestrogens plus medroxyprogesterone acetate 2.5/5.0 mg OD). The primary outcomes were major cardiovascular disease, osteoporotic fractures, and breast cancer. Secondary outcomes included other cancers, death from all causes, venous thromboembolism (VTE), cerebrovascular disease, dementia, and quality of life. After a median follow-up of 11.9 months, the trial was prematurely closed during recruitment, after the publication of early results from the women's health initiative study. At that stage, 56,583 had been screened, 8980 entered run-in, and 5692 (26% of target of 22,300) had started treatment.

When combined HRT (n=2196) was compared with placebo (n=2189), there was a statistically significant increase in the number of major cardiovascular events (7 v 0, p = 0.016) and VTE (22 v 3, hazard ratio 7.36; 95% CI, 2.20 to 24.60). There were no statistically significant differences in numbers of breast or other cancers, cerebrovascular events, fractures and overall deaths. There were also no significant differences in outcomes between combined or oestrogen only HRT.
The study concluded that these findings are consistent with those of the women's health initiative study and secondary prevention studies. In addition, the researchers call for further study of the long term risks and benefits of starting HRT near the menopause, when the effect may be different.

BMJ, published early online 11 July 2007; doi:10.1136/bmj.39266.425069.AD (link to abstract)

FDA issues US safety information for Rocephin (ceftriaxone sodium) after adverse incidents in neonates

Roche and the FDA have informed healthcare professionals of revisions to various sections of the US prescribing information for Rocephin™ (ceftriaxone) for injection, following new post-marketing information.

In the past few years, isolated neonatal deaths associated with calcium-ceftriaxone precipitates in the lungs and kidneys have been described worldwide. In some of these cases ceftriaxone and the calcium-containing solutions or medications were administered by different routes and at different times. For this reason, ceftriaxone must not be mixed or administered simultaneously with calcium-containing solutions or products, even via different infusion lines. Calcium-containing solutions or products must not be administered within 48 hours of last administration of ceftriaxone.

In addition, new text has been added to more prominently reinforce that hyperbilirubinaemic neonates (especially prematures) should not be treated with Rocephin, as in vitro studies have shown that ceftriaxone can displace bilirubin from its binding to serum albumin, and therefore bilirubin encephalopathy may develop in these patients.

More information is available from FDA Medwatch

Selenium supplements don't prevent type-2 diabetes, and may increase risk

Secondary analysis of an existing study has found that taking selenium supplements does not appear to prevent type-2 diabetes, and may even increase risk for the disease. There is epidemiological and experimental evidence to suggest that dietary intake of antioxidants, including selenium, may protect against type-2 diabetes, however there have been no long-term randomised controlled trials on this.

The authors of this paper used data from an existing long-term controlled trial of selenium supplementation on cancer incidence to investigate whether any effect on diabetes risk could be shown. The study was an investigation into whether such supplements reduced the risk of non-melanoma skin cancer in people living in areas of the US with low selenium consumption. Participants were recruited from dermatology clinics between 1983 and 1991, and were randomised to receive identical tablets containing a high-selenium yeast (equivalent to 200microgm daily) or an ordinary yeast control. For this analysis, the authors assessed the incidence of type-2 diabetes throughout the blinded phase of the trial (1983-1996) in participants who did not have it at baseline. Diabetes was assessed by self-report, corroborated by medical records.

The study involved 1,312 participants, of whom 1,202 did not have type-2 diabetes at baseline: there were no statistically significant baseline differences between the selenium and control groups. Average follow-up was 7.7 years, and over this time 97 new cases of type-2 diabetes were identified. This gives a rate similar to that found in other studies of largely white populations, however there was a statistically significant imbalance between the selenium and control groups: of the 97 cases, 58 developed in the selenium group and 39 in the placebo group. These give incidences of 12.6 vs. 8.4 cases per 1000 patient-years respectively and a hazard ration of 1.55 (95% CI 1.03 to 2.33).

The authors conclude that selenium supplementation in this group of people from low-selenium areas of the US did not appear to reduce risk for type-2 diabetes. In contrast, those in the supplement group had a statistically significant increase in risk that persisted across subgroups. When risk was analysed by baseline selenium level, the risk increased with greater baseline levels. They caution that their study has limitations: for example, incidence of diabetes was a secondary outcome of the study, it was self-reported, and the numbers were relatively small so a few more cases in the placebo group would attenuate the association. Nevertheless, it was a placebo-controlled study with good adherence to treatment.

An accompanying editorial discusses the study and its potential implications. The authors note that selenium-containing supplements are widely used in the US, and that while it is an essential micronutrient, it has a narrow therapeutic range. Further trials are need to investigate this possible link; meanwhile, those whose diet provides adequate daily supplies should not take supplements except as part of a controlled trial.

Ann Intern Med 2007; 147: 217-23 (published online in advance of print, link to abstract); Ann Intern Med 2007; 147(4) (Editorial, published online in advance of print; link to full text, may be restricted to subscribers)

Most respiratory tract infections in children are viral, and antibiotics have minimal effects

A prospective study in children presenting to their GPs with 'more than a simple cold' found that a demonstrable viral cause could be shown in over three-quarters: antibiotic treatment had minimal effects except in those shown to have influenza. For many years, GPs have been encouraged to avoid prescribing antibiotics for 'simple coughs and colds' to reduce the spread of resistance; prescribing has been reduced, but has not declined further of late. Much of the evidence supporting these recommendations has weaknesses, such as excluding younger children and those with more severe symptoms.

This study aimed to address some of these issues. GPs were asked to identify children presenting with cough and fever and considered to have more severe symptoms, for whom they would consider prescribing an antibiotic: the study looked at the aetiology and times course of the infection in these children.

Participants were children aged 6 months to 12 years with a cough, fever reported within past 72 hours, symptom severity suggesting a respiratory tract infection more than a simple cold, and for whom the GP considered prescribing an antibiotic. Those actually studied had a nasopharyngeal aspirate taken for viral identification (by PCR) and both GP and parents were asked to rate the severity of illness on a 0 to 10 scale. The child's illness was tracked using a parental symptom diary. Outcomes included cause, severity and time-course of illness, and the effects of antibiotics where prescribed.

A total of 425 children were initially selected, of whom 408 were analysed (most common reason for exclusion was lack of parental consent to sampling). In these, a probable viral cause of infection was identified in 77% (316/408), with the main virus identified being influenza (33%), respiratory syncytial virus (RSV, 14%), parainfluenza (14%), and human metapneumovirus (8%). Those with RSV infection were assessed as most severely ill by GPs (mean score 5), however there was considerable overlap between scores. Clinical symptoms identified the virus in 45% of cases.

Duration and severity scores of illness were very similar for all viruses, with the median symptom scores substantially the same on each day, and scores falling to a median of 0 by nine days from presentation. About a third of children (34.1%) were prescribed an antibiotic, most often in human metapneumovirus and RSV infections, however antibiotic prescription had no significant impact on rate of recovery. There was no effect on duration of fever overall with antibiotics, however there was an indication that antibiotics may reduce duration of fever in those with influenza virus infection.

The authors conclude that the use of molecular diagnostic technology and nasopharyngeal aspirates allowed identification of a probable cause for infection in a much higher proportion of cases than in previous studies. It shows that in the majority of children with 'more than a simple cold' for whom an antibiotic would be considered, the infection has a viral aetiology. In this study, prescribing an antibiotic made no difference to the overall time course of the illness. Their results, therefore, underpin existing guidance that these infections in the community are predominantly viral: in the absence of any significant respiratory difficulty they are self-limiting and do not require antibiotics. The consistent time course of illness found with all infections allows a reliable prognosis to be given. They discuss the specific observation of a reduction in duration of fever in influenza infections, and suggest that this is consistent with reports of 10-17% secondary bacterial infection rate in children with 'flu: this observation would support a trial of early use of antibiotics in children with flu.

Arch Dis Child 2007; 92: 594-7 (link to abstract)

Antimicrobial prophylaxis does not reduce recurrent UTI risk in children (but does increase resistance)

Prophylactic antibiotics for children thought to be at risk of recurrent urinary tract infection (UTI) do not appear to influence risk of recurrence, but do increase the risk of infection with resistant bacteria according to the results of a cohort study published in JAMA today. The authors note that there it little primary care-based data on the incidence of recurrent UTI, and that most available data is derived from secondary care populations. US guidelines on the management of children with a first UTI recommend imaging for vesicoureteral reflux (VUR) and prophylactic antibiotic treatment if this is present: these recommendations are based on theory, however, and there is little evidence for them. Some recent research suggests that antibiotic prophylaxis is ineffective in this situation, and there is concern over the development of resistance. This study aimed, therefore, to gather data on the risk factors for recurrent UTI in children in primary care, to determine whether antimicrobial prophylaxis altered the risk of recurrence, and to examine risk factors for development of bacterial resistance.

The authors assembled a cohort of children aged six and under at entry who had been diagnosed with a first episode of UTI in 27 paediatric practices in three US states between mid-2001 and mid-2006. The practices share a common health record, and were located in urban, suburban, and semi-rural areas; the record includes demographic, administrative, and laboratory data as well as clinical data. The initial cohort comprised all children aged under six with two or more clinic visits; those with a diagnosis of UTI were analysed further. Exclusion criteria included previous UTI, and underlying conditions that could increase UTI risk. Primary outcome was time to recurrent UTI.

A total of 74,974 children had two or more clinic visits over the study period, and of these, 666 had a first UTI with no co-morbid conditions to give a first-UTI incidence in otherwise healthy children of 0.007 per person-year. Of these, 55 had less than two weeks observation and could not be analysed, leaving 611 for final analysis. Most of the 611 were female (88.9%) and aged two to six years. Two-thirds had not been screened for VUR and most (79.1%) did not receive antimicrobial prophylaxis. There were 83 (3.6%) who had a recurrent UTI to give a recurrence rate of 0.12 per person-year, and 51 recurrences were caused by an organism resistant to any antimicrobial. Factors that increased risk of recurrence included age, and severe (grade 4 to 5) VUR, but not less severe VUR (grade 1 to 3). Antimicrobial prophylaxis had no effect on risk of recurrence, however it was associated with increased risk of recurrence with resistant bacteria (odds ratio 7.5, 95% CI 1.60 to 35.17).

The authors conclude that in their study population, antimicrobial prophylaxis in children with UTI was not associated with a reduction in risk of recurrence, however it was associated with an increase in the risk of infection with resistant bacteria. They note that their study is the first to produce an estimate of the incidence of recurrent UTI in children in a primary care setting: their value for first UTI is consistent with previously published population-based estimates, however the value for recurrence is much lower than that previously published and derived from referral populations. The results also provide other valuable data on factors affecting risk of UTI recurrence in children. Further studies are needed to expand their results, and to study the risks and benefits of antimicrobial prophylaxis in this patient group.

JAMA 2007; 298; 179-86 (link to abstract)

Medication errors in paediatric care: how they happen and how to reduce them.

Medication errors in paediatric care: how they happen and how to reduce them

A systematic review published in Quality and Safety in Health Care has evaluated peer reviewed knowledge on children’s medication errors and recommendations to improve paediatric medication safety.
The review included data from 31 articles that reported paediatric medication errors. According to the researchers, the distributional epidemiological estimates of the relative percentages of paediatric error types were: prescribing 3–37%, dispensing 5–58%, administering 72–75%, and documentation 17–21%.

The concluded that “Medication errors occur across the entire spectrum of prescribing, dispensing, and administering, and have a myriad of non-evidence based potential reduction strategies. Further research in this area needs a firmer standardisation for items such as dose ranges and definitions of medication errors, broader scope beyond inpatient prescribing errors, and prioritisation of implementation of medication error reduction strategies”.

Qual Safety Health Care 2007; 16: 116-26 (link to abstract)

Dietary counselling for weight loss - moderate effects, but the evidence is not strong.

Dietary counselling for weight loss - moderate effects, but the evidence is not strong

Dietary counselling is modestly effective for encouraging weight loss, but its effects seem to wane with time, according to this meta-analysis: the available evidence is, however, mostly of only poor to fair quality. The authors of this study note that obesity-related health problems are a major health-issue: in the US, around 65% of adults are overweight and around half of these are obese (defined as a BMI >30kg/m2). Previous reviews have indicated that dietary counselling can produce appreciable weight loss, however they are not clear on the extent of weight loss achievable, especially long term. This analysis aimed to update the evidence.

The authors carried out a literature search for randomised trials that investigated the effect of dietary counselling on BMI, compared to a controls (generally usual care or a minimal intervention). The starting point for the search was a previous major systematic review published in 1998. Exclusion criteria included studies in children, those where mean baseline BMI was less than 25, those lasting less than 12 weeks, and those not reporting effects at 16 weeks or more. For analysis, the net change in BMI (change from baseline in study group less change from baseline in controls) and its SE were extracted from the published data. Study quality was assessed as good, fair, or poor.

The initial literature search identified over 13,000 citations, of which 102 were potentially eligible: 56 were excluded because they did not fit the defined eligibility criteria, leaving 46 for analysis. There were 63 study groups, 26 involving diet only and 37 diet and exercise; these involved about 6,400 participants who received dietary counselling and about 5,500 controls. A wide range of different methods of delivering the interventions were used, including group meetings, individual meetings, a combination of these, and the internet. Only four studies (9%) were considered to be good quality, 63% were fair quality, and 28% were poor quality (mainly due to very high rates of withdrawal, incomplete reporting, and unclear analyses).

Analysis indicated a maximum net treatment effect of just under 2 BMI units over 12 months. This was equivalent roughly to 6% body-weight loss or 5kg at one year. Effects were shown during the active phases of interventions, with slow weight regain during maintenance. There was some indication that combining dietary counselling with exercise improved outcomes, but the difference was not statistically significant in most studies. The data available suggests that overall, after the intervention is finished, patients will return to their previous weight after about five to six years. The authors comment that their analysis adds new information to previous reviews, however there are significant limitations because of deficiencies in the underlying data. The trials were statistically and clinically heterogeneous, making analysis and interpretation difficult; there were also problems with missing data, which may be accounted for in ways that could either overestimate or underestimate the treatment effect. They conclude that their analysis shows dietary counselling-based weight loss shows modest effects relative to usual care, with diminishing returns over the course of the intervention. While the changes may appear modest, these may still have clinically significant effects: good quality trials to investigate this are needed.

Ann Intern Med 2007; 147: 41-50 (link to abstract)

Comment why do recommendations on aspirin for people with diabetes differ?

Comment why do recommendations on aspirin for people with diabetes differ?

In this article published early online in the European Heart Journal, the authors discuss how recommendations made by major European and US scientific societies on the use of aspirin for the primary prevention of CV disease in diabetics are ‘totally divergent’. The US statement recommends the use of aspirin for primary prevention in all individuals aged >40 or with additional risk factors. In contrast, in the European guidelines there is no mention of aspirin for the primary prevention of myocardial infarction or CV death, while it is recommended for the prevention of stroke.

The authors comment: ‘existing knowledge is mainly derived from dated trials, including small numbers of patients, and hardly representing current strategies for the management of CV risk factors. The high level of uncertainty regarding the balance between benefits and risks of aspirin therapy have important implications for clinical practice, auditing activities, and the design and conduct of randomized clinical trials’.

Eur Heart J, published early online 29 June 2007; doi:10.1093/eurheartj/ehm248 (link to abstract)

Meta-analysis: low-dose aspirin (modestly) reduces risk of pre-eclampsia.

A large meta-analysis of patient-level data has found that low-dose aspirin given to pregnant woman at risk of pre-eclampsia modestly but consistently reduced their risk of adverse outcomes. Pre-eclampsia affects between 2% and 8% of pregnancies and can have severe adverse effects on both mother and baby. While the cause is not yet known, abnormalities of clotting and platelet function occur and suggest the potential for benefit from anti-platelet drugs: many studies have been carried out over the past two decades, but their results have not been clear-cut. Previous systematic reviews suggested a benefit overall, however there was still controversy. The authors of this meta-analysis aimed to used patient-level data from as many previous trials as possible in an attempt to clarify the situation.

They carried out a comprehensive literature search using a relevant secondary database that is regularly updated from other databases. Eligible studies were randomised controlled trials of women at risk of pre-eclampsia treated for primary prevention with one or more anti-platelet agents, against controls of placebo or no treatment. Where potentially eligible trials included both primary and secondary prevention arms, only patients in the primary prevention arm were included in the analysis. Variables for the analysis were pre-specified, and anonymised data for patients in all eligible trials was requested from the original study authors; this was re-coded if necessary, checked for consistency, corrected where necessary, and finally agreed with the original authors. Four primary outcomes were defined: pre-eclampsia, death in utero or before hospital discharge, delivery pre-term at less than 34 weeks gestation, and infant small for gestational age. These were combined as an additional composite outcome - 'pregnancy with serious adverse outcome' (pregnancy where the mother dies or develops pre-eclampsia or if any baby is preterm, small for gestational age, or does not survive to discharge from hospital). Results were analysed on an intention to treat basis, but analysis for each outcome was restricted to trials having at least 80% of the data available for that outcome. Analyses compared the effect of the anti-platelet agent against placebo or no treatment for each outcome.

There were 115 trials identified initially, of which 50 were excluded as having no comparison group or treating women with established eclampsia only and two were excluded because patients were not truly randomised. Of the 63 remaining, including a total of 38,026 women, data could not be obtained for 27 (accounting for about 10% of the total participants; trial authors not traceable n=7, refused n=1, original data lost or irretrievable n=17, or not supplied n=2). This left 36 trials involving 34,288 women for which data could be analysed. Of these, 31, including 32,217 women and their 32,819 babies, were primary prevention studies and were thus included in this analysis. In 27, accounting for the great majority of the data, aspirin was given alone (dose 50mg to 150mg daily). Three small trials used only other anti-platelet drugs, and three tested aspirin and dipyridamole in combination. Just over half the women included were in their first pregnancy, 70% were aged 20 to 35, and 90% had at least one risk factor. Overall, 8% developed pre-eclampsia.

Compared to control, treatment with an anti-platelet agent was associated with a small but robust reduction in the relative risk of both pre-eclampsia (RR 0.90, 95% CI 0.84 to 0.97, p=0.004) and preterm birth before 34 weeks' gestation (RR 0.90, 95% CI 0.83 to 0.98, p=0.011). They also reduced the risk of the composite outcome to a similar extent (RR 0.90, 95% CI 0.85 to 0.96, p=0.001). There were also similar reductions in the other two primary outcomes (baby small for age, stillborn, or died before discharge), however these were not statistically significant. Maternal outcomes were similar for the two groups, with no significant increase in bleeding in the anti-platelet group. Subgroup analyses did not reveal any subgroup in which there was particular benefit.

The authors conclude that the data shows that treatment with an anti-platelet drug, mainly aspirin, reduces the risk of pre-eclampsia and some adverse pregnancy outcomes by about 10%. It is not possible to determine from the available data whether any particular subgroup benefits, although as the risk reduction is relative the absolute benefit will depend on a woman's underlying risk. The trials recruited mainly women at low to moderate risk of pre-eclampsia, so the data for women at high risk is limited. The analysis does not suggest that aspirin treatment is associated with significant adverse effects, although because some of the data on post-partum haemorrhage is uncertain, this outcome needs to be treated with caution.

An accompanying Comment discusses the paper and its implications. They authors discuss the possible mechanism of the benefit, and suggest questions that still need answers. They agree with the trial authors that use will depend on the mother's pre-existing risk level, and should be after full discussion of the potential risks and benefits. There have been a number of media reports of this study, and UK experts caution that pregnant women should not start taking aspirin without discussion with their doctor.

Lancet, published early online 18 May 2007; DOI:10.1016/S0140-6736(07)60712-0 (link to abstract); Lancet, published early online 18 May 2007; DOI:10.1016/S0140-6736(07)60713-2 (Comment; link to full text, available to subscribers only); BBC News report.

Public Health Link: Update on seizures of cannabis contaminated with glass particles.

The Department of Health has released this update to a previous alert issued in 2007 on the potential health harms associated with the use of cannabis contaminated with glass particles. The following advice is based on emerging information from the Forensic Science Service, which includes analysis of seizures of cannabis:

• Contaminated cannabis has been in circulation since at least July 2006 and in significant numbers since at least November 2006.
• Contaminated cannabis has been found in approximately 5-10% of herbal cannabis seizure cases examined; the proportions in seized cannabis in February (4.6%) and March (5.9%) are lower than that in January (9.6%), which may indicate that the market is changing in response to the media and concerns of users.
• Glass-contaminated cannabis has now been found in most parts of the UK, but not in Wales, and with no recent seizures in Northern Ireland; there is evidence to support the view that contaminated cannabis is being imported, probably from the Netherlands.
• The reason for adding the glass particles remains uncertain, but it still seems likely that they are added to improve the apparent quality and weight.
• Internet cannabis forums are now reporting the appearance of cannabis contaminated with much finer particles that are not easily detected as a gritty feeling; and if growers are using much smaller particles of glass beads, this could, theoretically increase the health risk of smoking contaminated cannabis.

The main alert and information for patients provided in January 2007, advising to stop or reduce use, and to avoid any further use of samples where there is suspicion of actual contamination, still stands. The wording of each has been updated to reflect the information that there are internet reports of samples with finer glass that may not be identifiable by a feeling of grittiness.

This alert can be found via the DoH Public Health Link; the previous one referred to is here.

Review: Syndrome of inappropriate antidiuresis

The New England Journal of Medicine features a review of the syndrome of inappropriate antidiuresis (SIAD), beginning with a case vignette, a discussion of the clinical problem, diagnosis, evidence supporting various treatment strategies, and ends with the authors' clinical recommendations on the management of the case.

The review notes that the only definitive treatment of SIAD is elimination of its underlying cause; the most important factors dictating management are the severity of the hyponatraemia, its duration, and the presence or absence of symptoms.

The aim of treating symptomatic patients with severe hyponatraemia known to have developed acutely (within 48 hours) is to increase serum sodium level by 1-2mmol/L/h by infusing 3% saline; concomitant furosemide is recommended by some, though others advise avoiding it, or reserving it for patients with extracellular-fluid volume expansion. In addition, the magnitude of correction during the first 24 hours should be no more than 8-10 mmol/L, and no more than 18-25 mmol/L during the first 48 hours, even when the hyponatraemia is acute. An increase in serum sodium levels of < 10 mmol/L is usually sufficient to reduce symptoms and prevent complications.

Most cases of hyponatraemia of long or unclear duration are chronic and minimally symptomatic. Unlike those with acute hyponatraemia, these patients have a documented risk of osmotic demyelination if serum sodium is corrected by more than 12 mmol/L over 24 hours; this disorder begins with lethargy and affective changes (generally after initial improvement of neurological symptoms with treatment), followed by mutism or dysarthria, spastic quadriparesis, and pseudobulbar palsy. To balance the risks of chronic hyponatraemia vs risks of rapid correction, many authorities recommend a modest rate of correction (increase in serum sodium 0.5-1.0 mmol/L/h), using lower rates of saline infusion for patients with symptomatic hyponatraemia of unknown duration. Many limit correction to 8 mmol/L over 24 hours and 18 mmol/l over 48 hours; close monitoring of the rate of correction (every 2 to 3 hours) is recommended to avoid overcorrection.

Asymptomatic patients with chronic hyponatraemia have a low risk of serious neurological problems, but are at risk of osmotic demyelination with rapid correction. Oral intake of urea (30 g per day) is effective but is poorly tolerated; demeclocycline (300 to 600 mg BD) reduces urinary osmolality and increases serum sodium levels, but its effects can be variable and it can cause nephrotoxicity, whilst lithium is no longer recommended.

A new therapeutic option for SIAD is conivaptan, a vasopressin-receptor antagonist approved by the FDA in 2007 for IV treatment of hypervolaemic hyponatraemia; drugs in development include the oral selective vasopressin V2 receptor antagonists tolvaptan and satavaptan.

Other topics discussed include reversal of osmotic demyelination that develops during the treatment of hyponatraemia, differentiating SIAD from Cerebral Salt Wasting, a syndrome of hyponatraemia and extracellular-fluid volume depletion in patients with insults to the CNS, and the prevention of postoperative hyponatraemia.

N Engl J Med 2007; 356: 2064-72 (link to extract).

Clinical Review: Management of genital herpes

A review in the BMJ looks at the management of genital herpes using the latest evidence based guidelines from the British Association for Sexual Health and HIV (BASHH), the Centers for Disease Control and Prevention (CDC), and other expert committees.

The following questions are addressed:

• What causes genital herpes and how is infection acquired?
• What is the prevalence of genital herpes in the UK and worldwide?
• How do patients present?
• How do I make a diagnosis of genital herpes?
• How do I manage patients with genital herpes?
• How do I manage patients with asymptomatic HSV infection?
• What are the important points to discuss when counselling patients?
• How do I manage genital herpes in a pregnant woman?
• What is the interaction between genital HSV-2 and HIV?
• How do I manage genital herpes in HIV positive or immunocompromised patients?
• What about a vaccine?

BMJ 2007; 334:1048-52 (link to extract)

Effect of a weight-loss diet may depend on individual insulin secretion

A study comparing two weight-loss diets found that a one providing a low glycaemic load gave better outcomes than a low fat diet in individuals with high insulin secretion. The authors of the study note that clinical trials of weight loss diets have given inconsistent results and suggest that this may be because inherent physiological differences in participants could modify their response to particular regimens. They suggest that insulin secretion could be such a modifying factors, and therefore studied the effects of two different diets in a group of individuals whose insulin response to a glucose load had been measured. Their hypothesis was that those with a high insulin secretion may be most sensitive to a glycaemic load. The study diets were designed as low glycaemic load / higher fat (40% carbohydrate and 35% fat), and low fat / higher glycaemic load (55% carbohydrate and 20% fat). Participants were overweight or obese young adults who were randomised to one or other diet after having a standard oral glucose tolerance test. They had a six-month intensive intervention period followed by a twelve-month follow-up, and were assessed at 6, 12, and 18 months. Primary outcomes were body weight, body fat percentage, and cardiovascular risk factor levels.

A total of 227 individuals were assessed for eligibility, of whom 73 were randomised (15 male, 58 female); 52 completed the 18 month follow-up. Baseline measurements were broadly similar for the two groups. Overall changes in body weight and body fat percentage were similar for both diets, with mean loss in weight of around 2 to 3kg at 18 months and 1 to 1.5 reduction in body fat percentage. The effect was modified by insulin secretion level, however: those with high levels had greater weight loss ((–5.8 vs –1.2 kg; P = .004) and loss of body fat (–2.6% vs –0.9%; P = .03) with the low glycaemic load diet compared to the low-fat diet. Across the whole cohort, the low glycaemic load diet improved levels of triglycerides and HDL cholesterol, and the low fat diet improved levels of LDL cholesterol.

The authors conclude that variability in the results from weight loss trials may be due to the influence of hormonal factors. In individuals with a high insulin response to a glucose load, a low glycaemic load diet may be particularly valuable. In all dieters, low glycaemic load diets are likely to improve HDL cholesterol and triglyceride levels, whereas low fat diets will improve LDL cholesterol levels.

JAMA 2007; 297; 2092-102 (link to abstract)

US recommendations: treatment of hypertension in the prevention and management of IHD

This scientific statement is from the American Heart Association Council for High Blood Pressure Research and the Councils on Clinical Cardiology and Epidemiology and Prevention. It summarises the published data relating to the treatment of hypertension in the context of ischaemic heart disease (IHD) prevention and management. The authors pose a number of significant questions relating to the treatment of hypertension to reduce coronary artery disease (CAD), including appropriate target BP levels in different patients, whether effects on blood pressure alone are the most important factor, whether any drug types have particular efficacy in specific circumstances, and which drugs should be used in patients with established CAD. It attempts, on the basis of the best available evidence, to develop guidance that will be appropriate for both blood pressure reduction and the management of CAD in adults, and its main recommendations are summarised in tabular form.

Circulation, published early online 14 May 2007; doi:10.1161/CIRCULATIONAHA.107.183885 (link to full text, available free at time of posting)

US recommendations on acute coronary care in the elderly with myocardial infarction

This 2-part American Heart Association scientific statement summarises evidence on patient heterogeneity, clinical presentation, and treatment of non–ST-elevation ACS in relation to age (<65,>/=85 years), and summarises evidence on presentation and treatment of ST-segment–elevation myocardial infarction in relation to age (<65,>/=85 years). The primary goal is to identify the areas in which sufficient evidence is available to guide practice, as well as to determine areas that warrant further study. The two reviews discuss the evidence behind reperfusion therapy, and adjunctive treatment with agents such as antiplatelet therapy, antithrombin, and adjunctive therapy with beta-blockers, renin–angiotensin blockade, nitrates, and statins.

non-ST elevation acute coronary syndrome statement: Circulation 2007; 115: 2549-69;
STEMI statement: Circulation 2007; 115: 2570-89 (links to abstracts, full text freely available at time of posting)

Irish regulatory authorities withdraw NSAID due to liver problems.

The Irish medicines regulatory authority, the Irish Medicines Board, have requested the immediate withdrawal from the market of nimesulide, a relatively COX-2 selective NSAID, due to reports of liver toxicity. The drug has been marketed in Ireland since 1995, but is not and has never been licensed in the UK.

According to the Board, there have been 53 liver-related adverse effect reports relating to nimesulide since it was launched in Ireland, including nine cases of liver failure - three fatal. Six patients have required liver transplant. [Editor's note: these figures relate to a population of about 4 million.]

Nimesulide is marketed in Ireland under the brand names Aulin, Mesulid, and Mesine; it is also marketed under a wide range of brand names in a number of other European countries and elsewhere in the world. UK patients will not have received the drug unless prescribed it abroad.

Announcement from the Irish Medicines Board (IMB home page).

High use of multivitamin supplements associated with increased fatal prostate cancer risk.

Analysis of data from a large US cohort suggests that regular use of high dose multivitamin supplements is associated with an increased risk of advanced and fatal prostate cancer. The authors of the analysis note that some previous epidemiological studies have linked high intake of vitamin and mineral supplements with an increase in risk of fatal prostate cancer. In this analysis they aimed to study the potential link further and clarify whether an effect on earlier prostate cancer was present.

They used data from a large prospective cohort study, the US National Institutes of Health (NIH)–AARP Diet and Health Study. Participants in this study were selected from 3.5 million residents of six US states, aged 50 to 71 years: at enrolment, they completed questionnaires on usual dietary intake, vitamin supplement use, demographic factors, and health-related behaviours. Major exclusions for the current analysis were women and participants not free from cancer at enrolment. Outcomes were relative risk of total, localised, advanced, and fatal prostate cancer according to level of multivitamin supplement use over five years follow-up, or six years for fatal cancers.

The initial cohort included 567,169 individuals, of whom 295,344 were eligible men. About a third (36%) reported consistent daily use of some type of multivitamin, and 5% were heavy users (more than seven times per week). Analysis of potential confounding factors found that multivitamin use was associated with a range of healthy lifestyle factors (e.g. less current smoking, greater frequency of exercise, healthy diet choices etc.). During the five-year non-fatal cancer follow-up period, 10,241 participants were diagnosed with incident prostate cancer, including 8,765 localized and 1,476 advanced cancer. Over the extended six-year follow-up, there were 179 fatal prostate cancers in the cohort.

There was no significant association between multivitamin use and risk of localised prostate cancer, with relative risks (RR) for all levels of use being similar to never-use (the reference). Heavy use, however, was associated with significantly increased risks of advanced (RR = 1.32, 95% CI = 1.04 to 1.67) and fatal (RR = 1.98, 95% CI = 1.07 to 3.66) prostate cancer. Subgroup analysis found that the positive associations with excessive use were strongest in men with a family history of prostate cancer or who took individual micronutrient supplements, including selenium, beta-carotene, or zinc; however numbers in some of these groups were small and thus confidence intervals wide.

The authors conclude that their analysis shows that multivitamin use does not protect against prostate cancer. It supports previous work, however, in indicating an association between heavy use of multivitamin supplements and increased risk of advanced and fatal prostate cancer. They caution that the association with heavy use may be related to confounding factors, such as an increased likelihood of screening in heavy users, or increased intake as a preventive attempt in those with a positive family history, nevertheless it is of potential concern and should be investigated further.

J Nat Cancer Inst 2007; 99: 754-64 (link to abstract);
BBC News report

Pharmacist intervention can improve medication adherence in patients with heart failure

An educational intervention delivered by pharmacists can improve patients' adherence to medication for heart failure, but only as long as it is ongoing according to a controlled trial from the US. A major proportion of the cost of caring for patients with heart failure comes from the treatment of exacerbations: appropriate medication can reduce the frequency of exacerbations, however regimens are often complex with a number of drugs to be taken. Patients may find adherence to such regimens difficult, and this study aimed to determine whether an educational intervention delivered by the pharmacist dispensing the patient's routine medication could improve adherence. It was carried out in a large academic primary care centre in an economically disadvantaged area and involved patients with heart failure seen by general medical or cardiology clinics or after hospital discharge, who were randomised to intervention or usual care. Patients receiving their care from the centre get prescribed medicines from a central pharmacy or one of several associated satellites. For the purpose of the study, the central pharmacy was moved to be adjacent to the general medicine clinics treating heart failure patients: it was staffed with two pharmacists, the study pharmacist who saw all intervention patients, and another pharmacist who saw usual care group.

The study pharmacist reviewed each intervention patient's medication history and their level of medication knowledge and skills. Based on this, they were provided with personalised verbal and written education about their medication and how to take it. Primary outcomes were medication adherence (measured using electronic container lids) and clinical exacerbations requiring emergency department treatment or hospitalisation. Study duration was one year overall, with a nine month intervention period and three months post-intervention.

A total of 314 patients were randomised from 1,512 potentially eligible. Study patients were slightly younger (63 vs. 67) and more likely to be women (67% vs. 59%) than those in the potentially eligible group, however they were similar to heart failure patients seen by the centre overall (n=3,034). Of the study group, 192 were randomised to usual care and 122 to the intervention. Adherence to medication was significantly greater in the intervention group than in the control: 78.8% vs. 67.9% (difference 10.9 percentage points; 95% CI, 5.0 to 16.7 percentage points) actually took their medication and 53.1% vs. 47.2% (difference, 5.9 percentage points; 95% CI, 0.4 to 11.5 percentage points) took their medication near the scheduled times. The effect dissipated fairly rapidly, however, as the differences were not significant by the end of the post-intervention period. Patients in the intervention group were 19.4% less likely to have an exacerbation requiring emergency department visit or hospitalisation (incidence rate ratio, 0.82; 95% CI, 0.73 to 0.93) and had lower healthcare costs over the study period.

Based on their results, the authors conclude that a pharmacist intervention for outpatients with heart failure can improve medication adherence. This can reduce exacerbations and consequently costs, however it probably requires to be ongoing as the effect dissipated rapidly after the end of the study. The cost of the intervention was associated mainly with setting it up, and as more patients received it the cost per patient reduced: the authors calculate that it gave a return on investment of 14 times. They suggest that the results are consistent with those of previous studies looking at similar pharmacist and multidisciplinary interventions, however the interventions in this study was less comprehensive or intensive than most previous work.

Ann Intern Med 2007; 146: 714-25 (link to abstract)

Supplementation with calcium and vitamin D prevents postmenopausal weight gain?

The authors of this study note that there is a ‘propensity toward postmenopausal gains in fat mass and replacement of lean tissue with adipose tissue’, and data show that the proportion of obese (BMI>30) women between the ages of 50 and 79 years in the US increased by nearly 50% during the 1990s. There are some preliminary data to suggest that calcium and vitamin D may have a role in effective weight management - calcium and 1,25-hydroxyvitamin D regulate lipid metabolism in adipose cells, and calcium may decrease fatty acid absorption through the formation of calcium and fatty acid "soaps" in the intestine.

A total of 36,282 postmenopausal women who were already enrolled in the dietary modification and/or hormone therapy arms of the Women's Health Initiative clinical trial entered into the calcium plus cholecalciferol (vitamin D) randomised trial, which was designed to test whether calcium plus cholecalciferol supplementation would reduce the incidence of hip fracture and colorectal cancer. Personal use of calcium (up to 1000 mg/d) and cholecalciferol (up to 600 IU/d and, after 1999, up to 1000 IU/d) was allowed. Women were randomised at their first or second annual visit to receive 1000 mg of elemental calcium plus 400 IU of cholecalciferol (vitamin D) (n=18,176) or placebo (n=18,106) daily. The primary outcome was weight change, assessed annually for an average of 7 years; all participants with at least 1 weight change measurement were included in the intent-to-treat analysis.

The two groups were similar at baseline in terms of demographic, medical, and lifestyle characteristics, including intake of calcium. The main findings were:

• Women randomised to supplementation had smaller average annual weight gains than women assigned to placebo, with a mean difference between the groups of –0.13 kg (95% CI –0.21 to –0.05; P=0.001).
• For women who were the most adherent (consuming >80% of their pills during follow-up); the mean difference in annual weight gain was –0.14 kg in favour of the supplementation (P<0.001).>
• Women who entered the trial with intakes of calcium lower than the current RDI (<1200>1200 mg)

The authors conclude that ‘even though the overall mean weight change difference between groups was small, women in the active intervention who had inadequate baseline dietary calcium had an 11% lower risk of weight gain during the first 3 years of the trial compared with women with calcium-deficient diets in the placebo group’. They recommend that current dietary recommendations are adhered to, and ‘postmenopausal women should continue to be advised to consume 1200 mg/d of calcium as recommended by of the Food and Nutrition Board of the National Academy of Sciences’.

Arch Intern Med 2007; 167: 893-902 (link to abstract)

PPIs increase the risk of community-acquired pneumonia?

The authors of this study note that there is some previous trial evidence to suggest that proton pump inhibitor (PPI) therapy may be associated with a dose-dependant increased risk of community-acquired pneumonia (CAP). This relationship was also seen with histamine 2 receptor antagonists (H2RA), therefore it was postulated that the effect may be related to acid suppression per se.

In this population-based case-control study, the authors sought to confirm the possible association between PPI use and CAP, to identify risk factors, and to evaluate potential non-causal associations between the use of PPIs and CAP. They used data from four databases in Denmark, and identified 7,642 cases of CAP (discharge diagnosis) during 2000 through 2004. A total of 34,176 controls were randomly selected, and matched by age (in 10-year bands) and sex to the cases with a 4:1 ratio. Exposure status (i.e. use of PPIs) of the cases and the control subjects was determined from prescription data extracted from a pharmacoepidemiological database. Individuals were defined as a current user if they had redeemed a prescription for a PPI during the past 90 days before the index date; past users were those who had redeemed a prescription for a PPI more than 90 days before the index date. The primary endpoint was any admission with a discharge diagnosis of CAP.

The analysis found that:

• A total of 817 (10.7%) of the cases and 1584 (4.6%) of the controls were current users of PPIs; the adjusted odds ratio (OR) associating current use of PPIs with CAP was 1.5 (95% CI, 1.3-1.7). No dose-response relationship was found.
• Use of H2RAs (OR, 1.10; 95% CI, 0.8-1.3), and past use of PPIs (OR, 1.2; 95% CI, 0.9-1.6) were not associated with an increased risk of CAP.
• Analyses found that groups seeming to be at particular risk include those who had recently initiated PPI therapy (OR, 5.0; 95% 2.1-11.7), and those below 40 years of age (OR, 2.3; 95% CI, 1.3-4.0)

The authors discuss some of the possible confounders, including alcoholism and smoking (known risk factors of CAP; no data available on the smoking status or alcohol consumption of the patients) and frailty (users of PPIs are frailer than others and more often suffer from chronic diseases). They note that gastroesophageal reflux disease itself might explain an excess of CAP among PPI users, but that the individuals included in the study were taking PPIs for a range of indications therefore ‘a strong confounding by reflux is unlikely’.

Arch Intern Med 2007; 167: 950-5 (link to abstract)

NICE issues draft public health guidance on smoking cessation services.

NICE issues draft public health guidance on smoking cessation services.

The National Institute for Health and Clinical Excellence (NICE) has published draft guidance on smoking cessation services, intended for NHS and non-NHS professionals who have a direct or indirect role in smoking cessation services. The interventions discussed include pharmacotherapies, individual behavioural counselling, group behaviour therapy, brief interventions, telephone counselling and quitlines, and self-help material.

When finalised, this guidance will supersede and replace NICE technology appraisal 39: ‘Guidance on the use of nicotine replacement therapy (NRT) and bupropion for smoking cessation’. It cross- references and is consistent with ‘Brief interventions and referral for smoking cessation in primary care and other settings’ (NICE public health intervention guidance 1) and ‘Workplace interventions to promote smoking cessation’ (public health intervention guidance 5).

The closing date for comments is 8th June 2007, and the next Programme Development Group meeting will be held on 6th June 2007.

The draft guidance is available from the NICE website here.

New UK guidelines on irritable bowel syndrome.

New UK guidelines on irritable bowel syndrome.

The British Society of Gastroenterology has issued comprehensive new guidelines on the management of irritable bowel syndrome (IBS). These cover the diagnosis and management of this common condition, affecting 5-11% of the population. Most sufferers will present to their GP, however a significant proportion - from around 33% up to 90% in some studies - will self-manage.

The guidelines cover the diagnosis of IBS, which is made easier by the availability of agreed diagnostic criteria (Rome-III criteria). They also detail alarm features that suggest the possibility of an alternative diagnosis requiring further investigation. Diagnosis should include looking for adverse psychological features, as these will affect response to treatment if present.

Management is multi-factorial and no single treatment benefits more than 20% of patients. Psychological therapies and correction of any concomitant anxiety or depression are valuable in many patients. Although many drug therapies have been tried, the evidence for most is limited; however there is some evidence of benefit in appropriate patients for antispasmodics, soluble fibre, 5-HT3 antagonists, 5-HT4 antagonists, SSRI, and tricyclic antidepressives. There is a great need for ways of identifying which patients will respond best to specific therapies. (437 references)

Gut, published early online 8 May 2007; doi:10.1136/gut.2007.119446 (link to abstract); the guidelines will become freely available from the British Society of Gastroenterology website here (not yet available at time of posting).

Rosiglitazone decreases bone formation in healthy postmenopausal women?

A study published in the Journal of Clinical Endocrinology & Metabolism has investigated whether rosiglitazone inhibits bone formation. This small 14-wk randomised, double-blind, placebo-controlled trial included 50 otherwise healthy postmenopausal women who received rosiglitazone 8mg/day. The women were included if they were more than 5 year post-menopausal, and aged older than 55 years.

The primary end points of the study were the two specific markers of bone formation, osteocalcin and procollagen type-I N-terminal propeptide (P1NP). The researchers reported that the osteoblast markers P1NP and osteocalcin declined by 13% (P < 0.005 vs. placebo) and 10% (P = 0.04 vs. placebo), respectively, in the rosiglitazone group. These changes were evident by 4 weeks and persisted for the duration of the study.

From these preliminary findings, they concluded that short-term therapy with rosiglitazone may have detrimental effects on bone formation, and advise that skeletal end points should be included in future long-term studies of thiazolidinedione use.

[Editor's comment: both rosiglitazone and pioglitazone were the subject of FDA warnings to US health professionals recently, noting an increased risk of fractures in women taking these drugs during trials compared to comparator drugs. This paper provides some theoretical support to the trial data.]

J Clin Endocrinol Metab 2007; 92: 1305-10 (link to abstract).

Review: Thiazolidinediones in patients with type 2 diabetes mellitus and heart failure.

In this article, the authors review the significant findings related to the use of thiazolidinediones (TZDs) in the treatment of patients with type 2 diabetes mellitus and heart failure. They cover the following areas:

• Benefits of TZDs on cardiovascular surrogate endpoints
• Weight gain
• Oedema
• Heart failure
• Observational studies
• Prospective clinical trial (PROactive)

The authors note that ‘because of the potential for fluid retention and worsening oedema, clinical studies have excluded patients with New York Heart Association (NYHA) functional class III or IV heart failure. In patients at risk for heart failure or those who have NYHA functional class I or II symptoms, initiation of therapy should be at the lower dose for TZDs with close monitoring of weight gain, oedema, and other signs of worsening heart failure … patients with NYHA functional class III or IV heart failure should not receive TZDs’.

Am J Health Syst Pharm 2007; 64: 931-6 (link to abstract)

FDA proposes new warnings about suicidal thinking and behaviour in young adults on antidepressants.

The FDA is proposing that manufacturers of all antidepressants update the existing black box warning on their products' labelling to include warnings about increased risks of suicidal thinking and behaviour, in young adults aged 18 to 24 during initial treatment (first 1 -2 months). The proposed labelling changes will also include a statement that scientific data did not show this increased risk in adults older than 24, and that adults aged 65 and older taking antidepressants have a decreased risk of suicidality.

The proposed warnings emphasise that depression and certain other serious psychiatric disorders are themselves the most important causes of suicide. The proposed labelling changes apply to the entire category of antidepressants, as available data are not sufficient to exclude any single medication from the increased risk of suicidality.

In 2005, the FDA had started a comprehensive review of 295 individual antidepressant trials that included over 77,000 adult patients with major depressive disorder and other psychiatric disorders, to examine the risk of suicidality in adults prescribed antidepressants. In 2006, its Psychopharmacologic Drugs Advisory Committee agreed that labelling changes were needed to inform health care professionals about the increased risk of suicidality in younger adults using antidepressants. The manufacturers will now have 30 days to submit their revised product labels and revised Medication Guides to the FDA for review.

[Editor's comment: note that the data that form the basis of this warning relate to suicidality - suicidal thoughts and behaviour - but not completed suicide. There have not been enough patients included in controlled trials to get reliable data on completed suicide, however the majority of the relevant data - admittedly all epidemiological, and thus less robust than randomised controlled trials - does not show any increase in completed suicide associated with antidepressive use: in general, there is an inverse relationship overall with a suggestion of an increase in the first few weeks of treatment. A large study that included data from the period before treatment found the month before treatment to be the highest risk.]

The FDA proposals are available here.

Review: Photoprotection

A review on photoprotection published early online in the Lancet examines environmental photoprotection, photoprotective clothing, sunscreens, controversies of sunscreens and clinical recommendations.

The key points from the article are as follows:

• Behavioural measures such as wearing sun protective clothes and a hat, and reducing sun exposure to a minimum, must be preferred to sunscreens.
• For improved protection, especially if midday summer exposure or tropical exposure is unavoidable, coverage of as much of the skin surface as possible, and correct application of a highly protective sunscreen over the remainder of the exposed skin, is very effective.
• Application of a liberal quantity of sunscreen is by far the most important factor for effectiveness of the sunscreen, followed by uniformity of application and specific absorption spectrum of the agent used.
• Application of organic sunscreens to exposed sites should be done 15–30 minutes before going out into the sun.
• Waterproof or water-resistant sunscreens should be used to diminish the need for reapplication after swimming followed by towelling, friction with clothing or sand, and sweating.
• The better protection against UVB provided by high SPF sunscreens (SPF > 15) has not been clearly proven to further protect against skin cancer, but the overall data has shown that a high SPF is preferable to low SPF sunscreen.
• Broad-spectrum sunscreens with adequate UVA protection should be used, but there is no clear definition of what is “adequate.”
• Sunscreens should not be abused in an attempt to increase time in the sun to a maximum.
• Year-round daily use of sunscreen for people living in countries of low insolation, eg, UK and northern Europe can not be recommended, and sunscreens are best avoided during October to March.
• There is some evidence that year-round application of sunscreens can be beneficial in preventing cancer and solar elastosis in areas of high insolation, such as Queensland, Australia, and Texas, USA.

[Editor's comment: media reports have picked up on the variable protection provided by different fabrics: unfortunately, the best protection seems to come from thicker, dark coloured, denim, wool, and synthetic (e.g. polyester) fabrics!]

Lancet, published early online 3 May 2007; DOI:10.1016/S0140-6736(07)60638-2
BBC News report.

Incidence of haemorrhagic stroke increased in the elderly; maybe related to aspirin use

The rate of haemorrhagic stroke in older people has not fallen over the past 25 years, in comparison to younger people in whom there has been a marked reduction: use of antithrombotic drugs seems to be a major factor associated with the difference according to a study published early online by the Lancet Neurology. Previous studies in the UK have concluded that rates of fatal haemorrhagic stroke have fallen for a number of years: this is consistent with better control of hypertension, the major risk factor. These studies have not, however, included people over 75 due to difficulties in reliable death certificate data. As the main causes may differ in this population, data cannot be extrapolated from the younger group. This paper reports an analysis of data from two separate studies of roughly the same population separated by two decades, investigating the incidence of stroke by age and risk factors.

The studies that provided the data were the Oxford Community Stroke Project (OCSP; 1981–86) and the Oxford Vascular Study (OXVASC; 2002–06): these covered substantially the same population, and data for the OSCP could be re-analysed to include the same practices involved in OXVASC. Analysis thus used data on 91,108 individuals from OXVASC and 87,861 from OCSP (both estimated mid-study values); the populations were similar, although the proportion of people aged over 75 increased by about a third with time. Both studies used the same definition for intracerebral haemorrhage, and CT imaging was used in both for the majority of cases (imaging, autopsy or both used in 89% for OCSP and 96% in OXVASC). Incidence rates for all and fatal intracerebral haemorrhages was calculated for both studies, and age specific rates were calculated for above and below 75 years. Incidences were also calculated for moderate to severe hypertension (both uncontrolled and controlled) and use of antithrombotic drugs (low-dose aspirin, clopidogrel, or warfarin).

There were 512 eligible strokes in the OXVASC population, and 557 in OCSP. In both studies, the rate of haemorrhagic stroke was 10% (52 and 55 respectively) - about half were fatal. Comparing the two populations, there was a suggestion of a decrease in rate overall (rate ration 0.72, 95% CI 0.49 to 1.05, p=0.08: this was accounted for by a significant reduction in the rate for people aged under 75 (RR 0.53, 95% CI 0.29 to 0.95; p=0.03), as there was no significant reduction in those aged over 75. There were fewer events associated with hypertension (RR 0.37, 95% CI 0.20 to 0.69; p=0.002), but more associated with antithrombotic use (RR 7.4, 95% CI 1.7 to 32; p=0.007): there was a significant rise in the proportion of people taking antithrombotic drugs before their stroke, from 4% to 41%. About one third of antithrombotic-associated strokes were preceded by warfarin use and two-thirds with aspirin or clopidogrel. In those aged over 75, there was also an increase in bleeds thought to be related to amyloid angiopathy.

The authors conclude that there has been a substantial fall in the incidence of haemorrhagic strokes due to hypertension over the past 25 years, however the incidence has not fallen overall. This is in part associated with antithrombotic use. While drug use would not have been directly causal in all these cases, estimates based on published data suggest that about 20% of haemorrhagic strokes in people over 75 are due to antithrombotic treatment. They note that despite the fall in younger patients, hypertension was still the most common cause in this age group.

This study has been widely reported in the media. Expert commentators note that the figures suggest that the risks from taking antithrombotic medications probably outweighs the benefit in healthy older people, however those prescribed these drugs to prevent stroke due to an underlying medical condition should continue to take them.

[Editor's comment: while the media reports concentrate on aspirin, given that there were probably many more people taking this (or clopidogrel) than warfarin, the absolute risk with warfarin will be significantly greater.]

Lancet Neurology, published early online 1 May 2007; DOI:10.1016/S1474-4422(07)70107-2 (link to abstract);
BBC News report;
the Stroke Association have issued a response

Letter in BMJ: Dependence on OTC drugs.

The authors of a letter in the BMJ call for large scale research to investigate the extent of dependence on over the counter (OTC) drugs, in particular, those containing codeine. They cite 3 recent cases of addiction to Nurofen Plus (ibuprofen and codeine phosphate), whereby the patients began using the drug as recommended but their use of it increased as dependence developed. The authors note that although codeine phosphate is available on prescription only, it can still be bought OTC in combination with other analgesics.

Speaking to BBC news, one of the authors (a GP) said that she did not think the drugs were unsafe, or that they should be banned. She said, “Thousands and thousands of people take these drugs and don't have any problems. It's a very small minority who do. But our anxiety is that it's a problem which is not being picked up by the public or doctors, and that we're just seeing the tip of the iceberg."

Br Med J 2007; 334: 917-8 (link to extract);
BBC News report

DTB review: Update on drugs for hyperactivity in childhood.

The authors of this DTB review update a previous review from 2001, focusing on the newer products for attention deficit hyperactivity disorder (ADHD). The following topics are covered in the review:

• Background
• The drugs (methylphenidate, dexamfetamine, atomoxetine)
• Efficacy of drug treatment
• Safety issues
• Cost

The authors suggest that drug treatment should be managed under the supervision of a specialist and should only be used as an adjunct to other interventions, for example behavioural and educational. They conclude:

“Current evidence suggests that the drugs licensed for such use in children and adolescents (methylphenidate, dexamfetamine and atomoxetine) are effective in tackling core symptoms of ADHD. However, it does not allow clear distinction between the drugs in terms of efficacy. The longer history of use with methylphenidate is a compelling reason for preferring it as a first choice. Modified-release methylphenidate is more expensive than the immediate-release forms, but avoids midday doses and, therefore, the need to take this controlled-drug to school. Dexamfetamine is an alternative for children unresponsive to methylphenidate. Atomoxetine is a comparatively new treatment. Unlike methylphenidate and dexamfetamine, it is not a controlled drug. However, its long-term safety is not clear, so its use should be reserved for patients in whom stimulants are contraindicated or cause unwanted effects.”

Drug Therap Bull May 2007: Vol. 45(5)

Clinical update: Intravenous iron for anaemia.

Clinical update: Intravenous iron for anaemia.

A Comment article in today's Lancet discusses the use of parenteral iron in patients with iron-deficiency anaemia. The authors assert that this form of therapy is underused, due to concerns over the toxicity of one particular preparation; they consider that using current preparations and appropriate regimens it is safe and effective. Parenteral iron has been considered dangerous and a therapy of last resort because the only preparation available for many years, high-molecular-weight iron dextran, was occasionally associated with anaphylactic reactions. There are now four parenteral iron preparations available, the other three - low-molecular-weight iron dextran, and two iron salts, ferric gluconate and iron saccharate - being associated with a much lower incidence of adverse effects.

The authors discuss the situations in which parenteral iron is appropriate, and how these may affect the choice of preparation and regimen. Iron dextran, preferably the low-molecular-weight form, may be given as a total dose infusion: a test dose is usually specified, however the authors report no untoward events with experience of over 20,000 doses and question the need for this if the low-molecular-weight form is used. This and the iron salts can be given as short infusions containing 100 to 400mg for patients receiving cyclical therapy. IM use is not recommended - it is no safer and has significant local toxicity at the injection site.

Overall, the authors conclude that intravenous iron is a misunderstood and under-used tool in the treatment of iron-deficiency anaemia; this is due at least in part to misinformation and misinterpretation of the data on serious adverse events. If the high-molecular-weight dextran form is excluded, it is associated with no substantially increased risk.

Lancet 2007; 369: 1502-4 (Comment; link to full text, available to subscribers only)

Talc pleurodesis - safe with the right product

Talc pleurodesis - safe with the right product

Pleurodesis using a talc preparation produced specifically for the purpose is safe, and has a low incidence of severe adverse effects according to a prospective cohort study published in today's Lancet. Talc pleurodesis has been used for decades in the treatment of a range of pleural diseases; it is effective, cheap, and widely available. It has generally been considered to be safe, however reports of severe adverse effects including acute respiratory distress syndrome (ARDS) have raised questions over this. The authors of this study note that the incidence of severe adverse effects in case series has not been consistent, with no relationship to the underlying diseases being treated. As there is evidence that the incidence of adverse effects may relate to the particle size of the talc used, they carried out a prospective cohort study of patients treated with a commercially produced talc intended for pleurodesis and graded to include predominantly large particles (Steritalc). This product has a mean particle size of 24.5 microns and only 11% of particles are <5 microns.

The cohort included patients from 13 European and one South African hospitals. All underwent thorascopy and pleurodesis for malignant pleural effusions with 4 grams of insufflated talc given using a standardised technique. Other treatment and procedures were at the doctor's choice according to clinical need and local practice; all patients had a chest X-ray at baseline and within 24 hours of the procedure. The primary endpoint of the study was occurrence of ARDS; the authors estimated a maximum frequency of 1% for this based on previous reviews, and thus aimed to include at least 300 patients to show that the risk was no more than this.

An eventual total of 558 patients was eventually recruited into the study; their mean age was 64.4 (range 30 to 96), and the most frequent underlying condition was non-small cell lung cancer (41%). No patient developed ARDS. Eleven patients died within 30 days of the procedure, mostly due to consequences or progression of their underlying disease. One developed respiratory failure due to other causes and there were six other serious adverse events, however there were no serious pulmonary complications within the first 48 hours after the procedure. The authors conclude that large particle talc is safe for pleurodesis in patients with malignant pleural effusion, and is not associated with ARDS.

They discuss their results, noting that reports of ARDS have come from the US and Brazil, whereas reviews from Europe and Israel have not found any cases. Evidence suggests that talc preparations containing a high proportion of small particles are more likely to cause adverse effects. In view of this, the authors considered that a comparative study of small-particle and large particle talc would be unethical, hence their choice of a prospective cohort study. Based on their data, they consider that ARDS would develop after pleurodesis with large-particle talc in no more than 6 patients per thousand.

An accompanying Comment discusses the study.

Lancet 2007; 369: 1535-9 (link to abstract); Lancet 2007; 369: 1494-6 (Comment; link to full text, available to subscribers only)

Beta-blockers in hypertension and cardiovascular disease.

Beta-blockers in hypertension and cardiovascular disease.

The author of this review provides practical pointers on the use of beta-blockers for the non-specialist clinician under the following headings:

• Are beta-blockers less protective in hypertensive patients?
• Do beta-blockers have any role in cardiovascular disease?
• Is treatment outcome affected by type of beta-blocker used or age profile of patient?
• Which beta-blocker should we use?
• How should beta-blockers be used?

The main summary points (taken directly from the article) are as follows:

• Beta-blockers reduce mortality after a myocardial infarction and improve prognosis in patients with systolic heart failure
• They reduce adverse outcomes in perioperative management of high risk patients
• In younger hypertensive patients (aged under 60 years), beta-blockers are equivalent to other antihypertensive agents
• Beta-blockers may improve prognosis and favourably retard disease progression in coronary artery disease
• Atenolol may be less useful than other beta-blockers, and other antihypertensive drugs, in reducing cardiovascular disease in hypertensive patients

Br Med J 2007; 334: 946-9 (link to extract)

DTB review: Which statin, what dose?

DTB review: Which statin, what dose?

The authors of this DTB (Drug Therapy Bulletin) review discuss the relative merits of different statins in addressing cardiovascular risk under the following headings:

• Overview of effectiveness of statins
• Different statins at standard doses
• High versus standard doses of statins
• Unwanted effects
• Contraindications and precautions
• What do national guidelines say?
• Who needs high-dose therapy?
• Cost-effectiveness
• Should patients be switched?

The authors reiterate the advice that generic simvastatin is currently the most cost-effective statin and should be regarded as the first-line option for most patients. They make the following suggestions for the other statins (directly from source):

• Pravastatin: For patients in whom drug interactions are a problem, the interactions may be less likely if pravastatin is used instead. However, the weaker lipid-lowering effects of pravastatin make it a less attractive first choice.
• Atorvastatin: should be reserved for second-line treatment or for patients intolerant to simvastatin. Many patients currently taking atorvastatin could be switched to simvastatin, to gain similar benefits at lower cost.
• Rosuvastatin/fluvastatin: There are very limited clinical trial data for fluvastatin or rosuvastatin; these are much more expensive than simvastatin, and we can see no reason for using them in routine management.

Drug Therap Bull May 2007 Vol. 45 (5)