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)

Sitagliptin plus metformin better than either alone?

Sitagliptin plus metformin better than either alone?

A controlled trial found that the combination of sitagliptin plus metformin had a greater effect on glycated haemoglobin (HbA1c) than either singly. The authors of the study note that metformin and sitagliptin lower blood glucose by potentially complementary mechanisms, and that use in combination may therefore have greater activity than either alone.

The trial had five treatment arms plus a placebo arm, and involved patients with type 2 diabetes not controlled by diet and lifestyle measures and HbA1c >7.5%; current oral hypoglycaemic drug treatment was not a reason for exclusion. Preliminary treatment included a trial of diet and lifestyle measures for those not taking oral hypoglycaemic therapy and with HbA1c >11% , a washout of any previous therapy if appropriate, and a single-blind run in period. Patients were then randomised to sitagliptin 100mg daily, metformin 1gm or 2gm daily, or sitagliptin 100mg daily plus either 1gm or 2gm metformin daily, or placebo. Study duration was 24 weeks and the primary endpoint was change in HbA1c from baseline to 24 weeks. Analysis was based on all patients treated (i.e. receiving at least one dose of study medication). Those with HbA1c >11% after a trial of diet and lifestyle measures were allocated to open label treatment with the higher dose combination.

A total of 1,091 patients met the eligibility criteria for the double blind portion of the study; 775 (71%) completed the 24 weeks, and 1,056 (96.8%) were included in the analysis. All active treatments produced statistically significant reductions in HbA1c from baseline to week 24 compared to placebo. Reductions for the monotherapy groups were 0.83% for sitagliptin alone, 0.99% for metformin 1gm and 1.3% for metformin 2gm. Reductions for the combination groups were 1.57% for the combination with metformin 1gm and 2.07% for that with metformin 2gm: the differences between monotherapies and the combinations were also statistically significant. Results for secondary outcomes showed a similar spread. Adverse effects were similar across the groups, and there was a low incidence of hypoglycaemia (and no instance of severe hypoglycaemia). The authors conclude that metformin and sitagliptin have additive effects on diabetic control as measured HbA1c, with no decrease in tolerance.

Diabetes Care, published early online 7 ay 2007; DOI: 10.2337/dc07-0627 (link to abstract).

Systematic review: aspirin for prevention of cardiovascular disease

Systematic review: aspirin for prevention of cardiovascular disease

A systematic review published in the Journal of the American Medical Association looks at the evidence for aspirin in the prevention of cardiovascular disease. The authors note that more than 50 million US adults [about 1 in 6 of the total population] take aspirin daily for prevention of cardiovascular disease, however there is still controversy over the most appropriate dose for long-term use. Doses most commonly used in the US are 81mg or 325mg daily; outside the US, 75mg and 300mg daily are also common. In an attempt to clarify the issue, they have reviewed the literature to investigate the mechanism of action of aspirin, and any relationships among aspirin dosage, efficacy, and safety.

The review included data from clinical trials using various doses of aspirin for cardiovascular disease, ranging from 81mg/day to 325 mg/day. Most were for secondary prevention. Pharmacodynamic studies indicate that doses around 30mg daily are sufficient to inhibit platelet thromboxane production. Clinical trials indicate that 75 to 81mg daily is effective, and that higher doses do not increase efficacy but are associated with a higher incidence of adverse effects - mainly gastro-intestinal.

The authors conclude that long-term aspirin therapy at doses greater than 75 to 81 mg/day does not enhance the prevention of cardiovascular events but does increase the risk of gastrointestinal bleeding. They therefore conclude that currently available evidence does not support the routine, long-term use of aspirin dosages greater than 75 to 81mg/day for cardiovascular disease prevention.

JAMA 2007; 297: 2018-24 (link to abstract).

Lancet review: Inflammatory Bowel Disease

Lancet review: Inflammatory Bowel Disease

Two articles in the Lancet provide a review on inflammatory bowel disease (IBD; Crohn's disease and ulcerative colitis).

The first article looks at the cause and immunology behind IBD and includes a discussion around how environmental factors (e.g. cigarette smoking, sanitation), infectious microbes, ethnic origin, genetic susceptibility, and a dysregulated immune system can lead to mucosal inflammation.

The authors of the second article critically review the evidence for established treatments (5-aminosalicylic acid compounds, corticosteroids, immunomodulators, calcineurin inhibitors) and emerging new therapies - including biological therapies directed at cytokines (e.g., infliximab, adalimumab, certolizumab pegol) and receptors involved in T-cell activation (e.g., visilizumab, abatacept), amongst other agents (such as natalizumab, MLN-02, alicaforsen, interleukin 10, antibiotics, prebiotics, probiotics). The second article is set out under the following headings:

• Ulcerative colitis
• Crohn's disease
• Extraintestinal manifestations of inflammatory bowel disease
• Emerging therapies for inflammatory bowel disease
• Safety and monitoring of medical treatments for inflammatory bowel disease
• Neoplastic complications of inflammatory bowel disease

Cause and immunobiology review: Lancet 2007; 369: 1627-40; clinical aspects and treatment: Lancet 2007; 369: 1641-57 (links to abstracts).

Depression during pregnancy

Depression during pregnancy

The authors of this article present a case relating to a 34 year old woman who was admitted as a psychiatric inpatient for the treatment of depression following the birth of her second child. The woman had a history of depression and had tried to commit suicide 2 months after the birth of her baby. The authors go on to highlight the main issues involved in managing pregnant women with depression under the following headings:

• How common is depression during pregnancy?
• Who is at risk?
• How does pregnancy affect depression?
• How does depression affect the outcome of pregnancy?
• How is depression treated in pregnancy?
• What advice should be given about family planning?
• As pregnancy progresses

The main summary points (taken directly from the article) are provided below:

• Rates of depression are higher during pregnancy than at any other point during a woman's life
• About half of "postnatal" depression starts during pregnancy
• Two thirds of women with a history of recurrent depression will relapse during pregnancy if they discontinue their medications after conception
• Depression during pregnancy is associated with poorer obstetric outcomes, particularly preterm delivery
• Women who are depressed during pregnancy are more likely to smoke and drink alcohol and less likely to attend for antenatal obstetric care than women who are not depressed
• The treatment of depression during pregnancy must be considered individually for each woman, with the possibility of relapse and poorer obstetric outcomes balanced against the possible risks associated with taking antidepressant medication

Br Med J 2007; 334: 1003-5 (link to extract).

Aspirin for prevention of bowel cancer?

Aspirin for prevention of bowel cancer?

Analysis of data from two long-term controlled trials of aspirin indicates that taking regular aspirin may reduce the risk of colorectal cancer, however this was shown only for doses of 300mg daily and over.

Several controlled trials have shown that aspirin and other NSAID may reduce colorectal adenomas, potential precursor lesions to carcinomas, however these have generally had relatively short follow-up and have not been able to show whether the progression from adenoma to cancer has been interrupted. Analysis of data up to ten years in the Women's Health Study did not show any effect. The authors therefore used long-term follow-up data from two large studies of aspirin as prophylaxis for vascular events to determine whether these demonstrated any reduction in colorectal cancer in the aspirin compared to the control groups. They also carried out a systematic literature review for observational studies on the association between aspirin or other NSAID use and colorectal cancer.

The British Doctor's Aspirin Study, published in 1988, investigated whether aspirin reduced the risk of death from stroke, MI, or other vascular conditions. It involved 5,139 male British doctors who were randomised to treatment with aspirin (normally 500mg daily, n=4,377) or no specific treatment (n=762). Study duration was five or six years, and all participants were flagged in national registers to collect all cancers and deaths in the group up to 2001 or emigration from the UK. The UK-TIA study investigated whether aspirin reduced the risk of recurrent stroke after a minor stroke or transient ischaemic attack (TIA). It recruited 2,449 participants who were randomised to aspirin 300mg or 1200mg daily (n=1,632) or placebo (n=817). Median follow-up for cancers and deaths was 23 years for both studies. Primary outcome for this study was colorectal cancer.

There were 216 colorectal cancers in the total study population (aspirin n=5,061, placebo n=2,527). Of these, 87 occurred in the placebo group (3.4%) and 129 in the combined aspirin groups. The difference was significant, with a hazard ratio of 0.74 (95% CI 0.56 to 0.97, p=0.02) overall. When just those who received aspirin for five years or more were included, the difference became greater (HR 063, 95% CI 0.47 to 0.85, p=0.002). The effect was seen only after at least ten years from randomisation and was dependent on duration of treatment and compliance. There were no significant effects on other cancers.

Analysis of data from observational studies indicated an association between regular use of NSAID and aspirin, and a reduction in risk of colorectal cancer. The effect for aspirin was only consistent in those taking 300mg daily or more. Based on their results, the authors conclude that use of aspirin at least 300mg daily for at least five years is associated with a reduction in risk of colorectal cancer. There is, however, a latency of about ten years, and this is consistent with the results of observational studies. Long-term follow-up of trials using lower doses of aspirin is important to clarify whether such doses have any benefit.

An accompanying Comment discusses the study. The author comments on the discrepancy between the results of this analysis and those of other studies. He suggests that a likely cause would be the different doses used, as there is substantial animal and laboratory evidence that higher doses are needed than those used for anti-platelet effects. He notes that the study has limitations, however concludes that in combination with other evidence it helps to confirm that aspirin at relevant doses can prevent colorectal cancer. More work is needed to identify those patients for whom the risks would outweigh the benefits, and to identify the mechanism so that other strategies for prevention can be developed.

Lancet 2007; 369: 1603-13 (link to abstract); Lancet 2007; 369: 1577-8 (Comment; link to full text, available to subscribers only).

Review: update on irritable bowel syndrome.

Review: update on irritable bowel syndrome.

This clinical review in the Lancet gives an overview of current knowledge about the management of irritable bowel syndrome, one of the commonest reasons for medical consultation. A difficulty for many doctors is that the syndrome is poorly understood, however the author of the review considers that successful management is possible with some time and effort: this can significantly improve the patient's quality of life. There are internationally agreed diagnostic criteria for irritable bowel syndrome, the Rome-III criteria, and under these, the condition affects around 5 to 10% of the population in both developing and developed countries.

The author describes the typical presentation, noting that many sufferers also have functional dyspepsia and other non-gastrointestinal somatic symptoms. Because of this, a holistic approach is valuable to avoid fragmentation of care. There are alarm symptoms that suggest the need to consider an alternative diagnosis, and in these cases further investigations will be required. Irritable bowel disease tends to be a long-term condition, with many patients being high users of healthcare services; it does not, however, lead to more serious disease.

Management involves primarily reassurance, explanation, and lifestyle advice; dietary modification may be helpful in some cases - the most common culprits are wheat and dairy products. Psychological therapy may be appropriate for patients reporting stress as an important factor and hypnosis has been beneficial in trials. Drug treatment is often sought, by both patient and doctor, however there are few drugs with proven benefits. Antispasmodics may be useful when pain predominates, loperamide reduces bowel frequency (but not pain) when diarrhoea is predominant, and tricyclic antidepressives may help some patients. There is, however, an unmet need for more effective medications in this condition.

Lancet 2007; 369: 1586-8 (link to full text, available to subscribers only)

Press reports of association between valproate use during pregnancy and children with lower IQ

Press reports of association between valproate use during pregnancy and children with lower IQ

There have been several reports in the press that women who take valproate during pregnancy are at a greater risk of having children with a lower IQ (The Guardian and NetDoctor, 4th May 2007).

These reports are based on research presented at the American Academy of Neurology's annual meeting. Investigators looked at IQ results of 187 children born to mothers who had taken carbamazepine, lamotrigine, phenytoin, or valproate during pregnancy. A total of 24% of the children of mothers who took valproate had an IQ low enough to be defined as mentally retarded, compared to 12% for carbamazepine, 9% for lamotrigine, and 12% for phenytoin. The average IQ scores were 84, 93, 96 and 93, respectively. No further details of the study, including potential confounders and details of the use of other medications, were presented in the articles.

The lead researcher commented that "valproate should not be used as the drug of first choice for women of child bearing potential, and when used, its dosage should be limited if possible." A representative of the British Epilepsy Association, Ms Burns, agreed that women with epilepsy should be counselled before embarking on a pregnancy, but said that "we believe there should be a balance struck between the potential effects of seizures on the developing brain of foetuses and the effects of valproate. While this is very concerning, it has to be said that valproate is a highly effective anti-epileptic drug…..what we don't want is to scare people to stop people taking this drug suddenly because that can result in seizures and, potentially, deaths."

[Editor's comment: this report appears to relate to an ongoing prospective study called NEAD (Neurodevelopmental Effects of Antiepileptic Drugs), having the same lead researcher. Data from this study was also presented at another conference in December 2006 - this only included 166 children, of whom 28 were born to mothers taking valproate.]

The Guardian's report is available here; and the NetDoctor report here;
there is information from the December 2006 presentation on Medscape (free registration required)
and there is a NEAD website giving much more information about the study

COX-2-selective NSAID plus PPI safe in patients at high risk of GI bleeding?

COX-2-selective NSAID plus PPI safe in patients at high risk of GI bleeding?

A controlled trial has found that combining a proton-pump inhibitor (PPI) with a COX-2 inhibitor is more effective in reducing the risk of gastro-intestinal (GI) bleeding in high-risk patients than use of the COX-2 inhibitor alone.

Patients taking NSAID are at increased risk of GI bleeding, and those with a past history of ulcer bleeding are at highest risk. Guidelines suggest use of a COX-2 inhibitor or NSAID plus PPI in patients at higher risk based on trial evidence, however there is limited evidence on the safest option for the highest risk patients. This trial aimed to determine whether a COX-2 inhibitor plus a PPI was better than the COX-2 inhibitor alone for reducing the risk of recurrent bleeding in patients who had previous NSAID-induced bleeding and continued to need an anti-inflammatory analgesic. It included patients with upper GI bleeding who were taking a non-selective NSAID for arthritis. They were taken off the NSAID, treated for H. pylori infection if appropriate, and given a PPI for eight weeks to promote ulcer healing. Eligible patients were those for whom this regimen successfully treated any H. pylori infection and healed their ulcer, and who continued to require NSAID therapy. They were randomised to receive celecoxib 200mg twice daily plus either esomeprazole or placebo daily. Study duration was twelve months, and patients were followed-up at two-month intervals and at 13 months; primary outcome was recurrent ulcer bleeding during treatment and up to a month from the end of treatment.

Of 441 patients screened, 273 were randomised and eligible for the intention-to-treat analysis - 137 to combined treatment and 136 to control (celecoxib alone). Median follow-up was 13 months and treatment compliance was good in both groups (>90%). Combination treatment was more effective than the control: there were no primary endpoint events in the combination group vs. 12 (8.9%) in the control group (95% CI for the difference 4.1 to 13.7, p=0.0004). The authors conclude that the combination of a COX-2 inhibitor plus a PPI is effective in patients at very high risk of NSAID-induced GI bleeding and should thus be used in such patients. They suggest that organisations producing guidelines in this area should review their recommendations accordingly.

An accompanying Comment article discusses the study: the authors note that the risk reduction is consistent with that seen in other similar studies. They caution, however, that all risk factors need to be considered and that the cardiovascular effects of the COX-2 inhibitors need to be taken into account. For patients with cardiovascular risks, NSAID selection is complex and careful individual assessment will be required.

Lancet 2007; 369: 1621-6 (link to abstract); Lancet 2007; 369: 1580-1 (Comment; link to full text, available to subscribers only)

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

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)

International Diabetes Federation (IDF): Consensus statement on Type 2 diabetes prevention

International Diabetes Federation (IDF): Consensus statement on Type 2 diabetes prevention

The International Diabetes Federation (IDF) has issued a consensus statement on the prevention of type 2 diabetes in both the developed and the developing world. The consensus statement advises that prevention of Type 2 diabetes is based on controlling modifiable risk factors and can be divided into two target groups:

• People at high risk of developing Type 2 diabetes
• The entire population

In planning national measures for the prevention of Type 2 diabetes, it is recommended that both groups should be targeted simultaneously with lifestyle modification the primary goal through a stepwise approach. For identifying people at high risk, the IDF recommends the use of opportunistic screening by health-care personnel including those working in general practice, nurses and pharmacists.

The IDF recommends that lifestyle modification should be the first choice to prevent or delay diabetes. With respect to drugs, the following is recommended (directly from source):

• The IDF recommends that when lifestyle intervention alone has not achieved the desired weight loss, and/or improved glucose tolerance goals, as set by the health-care provider, metformin in the dose of 250–850 mg b.i.d. (depending on tolerance) should be considered as a diabetes prevention strategy (particularly in those aged less than 60 years with a BMI > 30 kg/m2 (greater than 27 kg/m2 in certain ethnic populations) and a FPG > 6.1 mmol/l or 110 mg/dl who do not have any contraindications).
• Acarbose is also worthy of consideration for those who can tolerate it.
• PPAR gamma agonists such as rosiglitazone have shown promising results, but concerns must remain about side-effects including weight gain and congestive heart failure as well as durability, and so we do not recommend them for routine use at present.
• A further option for the obese might be orlistat.
• Similarly, newer agents such as rimonabant show some promise, but long-term safety and specific diabetes preventive efficacy data are lacking and are not currently recommended for diabetes prevention in those at increased risk. The IDF working group awaits with interest the results of ongoing studies into newer therapies.

The announcement from the IDF is here; and the Consensus has been published in Diabetic Medicine 2007: 24; 451-63 (link to abstract, full text available free at time of posting)

Waking up from the DREAM of preventing diabetes with drugs

Waking up from the DREAM of preventing diabetes with drugs

The authors of this “Analysis” article discuss the research investigating whether drugs can reduce an individual’s risk of developing diabetes. In particular, they note that the recent DREAM trial found rosiglitazone decreased the risk of diabetes in people at risk and this has led to the promotion of rosiglitazone for the prevention of diabetes. However, they argue that strategies such as this “will bring harms and additional costs while the benefits for patients remain questionable.”

The following topics are discussed in the article:

• Preventing diabetes
• Effectiveness of drugs
• Use of a composite end point
• Are patients better off taking pills to prevent diabetes?
• Downsides of taking pills to prevent diabetes
• Benefits of diabetes prevention with glitazones

The authors conclude, “Because of the risk of harming people with no or minimal symptoms, the threshold for use of drugs in otherwise healthy people must be set high. To get the required data for rosiglitazone requires large and long randomised controlled trials measuring its effect on outcomes important to patients and use of healthcare resources. Clinical use of glitazones to prevent diabetes is, at present, impossible to justify because of unproved benefit on patient important outcomes or lasting effect on serum glucose, increased burden of disease labelling, serious adverse effects, increased economic burden, and the availability of effective and less costly lifestyle measures”.

The main summary points (taken directly from the article) are provided below:

• Lifestyle changes and certain drugs are effective in preventing the diagnosis of diabetes
• No trial has shown that prevention with drugs improves outcomes important to patients
• Lifestyle changes are equally effective, much safer, and cheaper
• Clinical use of glitazones for prevention cannot be justified

Br Med J 2007; 334: 882-4 (link to extract);
BBC News report ( Anti-diabetes pills 'unjustified')

Chromium supplements don't seem to have any benefit in type 2 diabetes

Chromium supplements don't seem to have any benefit in type 2 diabetes

A controlled trial found no benefits from adding chromium, in the form of chromium yeast, to standard therapy in patients with type 2 diabetes. Chromium is known to be an important trace mineral with a role in glucose metabolism, and as a result it is widely touted as supplement with potential benefits for people with diabetes. Previous controlled trials have been equivocal, and systematic results have concluded that the effects of chromium on diabetic control are inconclusive. One form of chromium that was widely used, chromium picolinate, has been banned due to concerns over its toxicity: this study aimed to determine whether an alternative form, chromium-enriched brewers yeast, had any benefits. Patients enrolled were from one area in the Netherlands and had type 2 diabetes moderately-well controlled on oral hypoglycaemic agents. They were randomised to treatment with a supplement containing chromium yeast equivalent to 400micrograms daily or placebo; study duration was six months, and the primary outcome was change in levels of haemoglobin A1c (HbA1c).

A total of 57 patients was randomised, of whom one did not complete the study. In the remainder, there was no difference between the active and placebo groups in the primary outcome, or in any of the secondary outcomes measured. One patient in each group reported adverse effects: nausea with chromium yeast and 'non-specific stomach problems' with the placebo. The authors conclude that chromium supplementation using chromium yeast had no effect on glycaemic control in their population of moderately well controlled Western patients with type 2 diabetes. They note that patients were not selected on the basis of chromium deficiency, as there is currently no consensus on what this might be; they also note that treatment duration was only six months. On the basis of current evidence, however, they suggest that there is no reason to recommend chromium therapy in Western patients treated with oral hypoglycaemic agents or insulin.

Diabetes Care 2007; 30: 1092-6 (link to abstract)