Tuesday, October 16, 2007

New US guidance: HbA1c targets for glycaemic control in type 2 diabetes.

The American College of Physicians has issued updated guidance on the use of haemoglobin-A1c (HbA1c) levels in monitoring glycaemic control of patients with type 2 diabetes.

It is accepted that good glycaemic control is necessary in diabetes and if achieved will significantly reduce the likelihood of adverse complications. HbA1c is widely used as a means of monitoring diabetic control, and this paper is intended to summarise the evidence base for monitoring and for suitable HbA1c levels in particular. As there are already many guidelines available on this topic, the College considered that it was appropriate to provide a rigorous review of suitable existing guidelines rather than produce a new guideline from first principles.
A comprehensive search strategy was used to locate guidelines that included discussion of diabetic control. Eligibility was restricted to English language because of the difficulties in translating non-English documents, and only most recent updates were used. Eligible guidelines were assessed using the Appraisal of Guidelines, Research and Evaluation in Europe (AGREE) collaboration method to get an assessment of guideline quality. Recommendations on glycaemic control were extracted from high quality guidelines and used to synthesise overall recommendations.

Nine sets of guidelines were accepted as being of sufficient quality and included specific recommendations on control. Based on these, the authors recommend the following (taken directly from the article summary with Anglicisation of spellings):

  • Statement 1: To prevent microvascular complications of diabetes, the goal for glycaemic control should be as low as is feasible without undue risk for adverse events or an unacceptable burden on patients. Treatment goals should be based on a discussion of the benefits and harms of specific levels of glycaemic control with the patient. A haemoglobin A1c level less than 7% based on individualized assessment is a reasonable goal for many but not all patients.
  • Statement 2: The goal for haemoglobin A1c level should be based on individualized assessment of risk for complications from diabetes, comorbidity, life expectancy, and patient preferences.
  • Statement 3: We recommend further research to assess the optimal level of glycaemic control, particularly in the presence of comorbid conditions.
The authors comment that there are still challenges in understanding the benefits and harms of particular levels of control, especially in complex patients, and further research would be valuable. Attention should also be paid to control of blood pressure and lipid levels.

Ann Intern Med 2007; 147: 417-22

Adding insulin to oral agents in poorly controlled type 2 diabetes - trial evidence to guide practice

Interim results from a controlled trial in patients with type 2 diabetes and poor glycaemic control showed that adding one of three simple insulin regimens to maximally tolerated oral antidiabetic drugs benefited some patients; regimens giving greater control also caused more adverse events.

The 4-T (Treating to Target in Type 2 Diabetes) study aims to clarify the use of insulin in patients with type 2 diabetes poorly controlled despite maximum tolerated doses of oral antidiabetic drugs. While the addition of insulin is widely practised in such patients, there is little evidence from large clinical trials to guide such use: the first year of the three-year 4-T study, reported here, compared three simple insulin regimes - more complex regimens are being compared in the remaining two years. Patients were adults with type 2 diabetes not previously treated with insulin, and had poor glycaemic control (glycated haemoglobin, HbA1c, 7-10%) with maximally tolerated doses of sulphonylurea plus metformin, or individual drugs if the other was not tolerated. They were randomised to open-label treatment with one of three regimens: basal insulin (insulin detemir at bedtime), prandial insulin (insulin aspart immediately before meals), or biphasic insulin (NovoMix 30 twice daily). Primary outcome was glycaemic control as HbA1c at one year; secondary outcomes included weight gain and hypoglycaemia as well as other measures of control.

A total of 936 patients were screened for inclusion, and 708 were randomised; 235 to biphasic, 239 to prandial, and 234 to basal insulin. The most common reason for exclusion was a baseline HbA1c outside the range 7-10%. Withdrawals were not statistically different across the three groups (5.5%, 7.1%, and 4.3% respectively). Maximum fall in HbA1c levels was achieved by week 24 in all groups, however at week 52 the biphasic and prandial groups had significantly lower mean levels than the basal group (7.3% and 7.2% vs. 7.6% respectively, p<0.001 for both comparisons): most differences were in patients with poorest baseline control - there was less difference between the three regimens in patients with a baseline HbA1c of <8.5%. Patients in the prandial group were most likely to reach HbA1c of 6.5%, however even in this group only a quarter did so (prandial 25%, biphasic 17.0%, basal 8.1%). Patients in the prandial group were most likely to have hypoglycaemic events and also gained the most weight (basal least for both).

The authors conclude that adding a single insulin to maximal oral therapy in these patients achieved target glycaemic control, measured as HbA1c level, in only a minority of patients. Biphasic and prandial insulin gave better control but at the cost of more hypoglycaemic events and more weight gain. They conclude that the results support basal insulin therapy for a first line option, as it has lowest levels of adverse effects, and is simple and convenient for patients; however many will need rapid intensification of therapy. The final phase of the study is examining more complex regimens in this patient group.

According to an accompanying editorial, “the 4-T study provides a clear indication that prandial and biphasic insulin formulations are suboptimal choices for insulin initiation and probably expose patients to an unnecessarily high risk of hypoglycemia without clinically important benefit.” Results are awaited from the second phase of the study to define the best next step for patients who do not reach their glucose target whilst on basal insulin alone, since they are most likely to benefit from additional prandial insulin.

For now, the author suggests that the recommendations for starting insulin therapy need not change as a result of this study: for patients with a HbA1c > 7% on maximal doses of two oral agents, the best approach is to continue metformin and add a basal insulin; sulfonylureas are not synergistic with insulin and should generally be stopped. He adds that choice of strategies for insulin initiation is probably less important than taking steps to start insulin in patients who need it. Furthermore, he stresses that though it is important to focus on glucose levels, clinicians should be aggressive with BP management since hypertension contributes at least as much as glucose to overall cardiovascular risk. In addition, aspirin, lipid-lowering therapies, smoking cessation, exercise and weight-loss programmes should be initiated when appropriate. He concludes that “achieving these integrated goals saves lives, whatever insulin formulation is chosen.”

New Engl J Med, published early online 21 September 2007; doi: 10.1056/NEJMoa075392 (link to abstract); New Engl J Med, published early online 21 September 2007; doi: 10.1056/NEJMe078196

Ten minute consultation: Ramadan, fasting and Diabetes.

This ‘ten minute consultation,’ part of a series of occasional articles in the BMJ on common problems in primary care, looks at issues to cover and subsequent management, when a patient with type 2 diabetes mellitus turns up for advice on how he might fast safely during Ramadan. The main advisory points are as follows:

  • If blood glucose is well controlled by diet alone, advise him that fasting is safe
  • Encourage him to eat foods high in dietary fibre and have a low glycaemic index at the pre-dawn (Suhur) and sunset (Iftar) meals to promote glycaemic control and discourage foods with a high glycaemic index until about half an hour after taking drugs to minimise sharp rises in blood sugar at sunset.
  • Self monitoring of blood glucose is essential for safe fasting in patients taking antidiabetic drugs, particularly before and after the pre-dawn and sunset meals.
  • To minimise the risk of hypoglycaemia in patients on oral therapy, those on a long acting sulphonylurea should be switched to a short acting preparation or metformin, or both. If a single daily dose is used, take this with the sunset meal, if two or three doses are taken daily, take half the normal evening dose before dawn and the normal morning (and any midday) dose after sunset.
  • To minimise the risk of hypoglycaemia in patients on insulin, those on a once daily regimen should be switched to a twice daily regimen whilst those on a twice daily regimen should use half of the evening dose before dawn and the normal morning dose after sunset. If basal bolus insulin is used, reduce the long acting component to two thirds of normal, split into two equal doses taken during the sunset and pre-dawn meals; take the rapid acting component as before, but omit the middle dose.
  • Emphasise the need to carry glucose tablets at all times to treat hypoglycaemia and explain the importance and legitimacy of breaking the fast in emergency situations.
  • Arrange for a review one week into Ramadan or earlier if concerns arise.

BMJ 2007; 335: 613-4

Statins safe and effective in patients with very low LDL cholesterol.

Statins used in patients with extremely low LDL cholesterol levels are safe and may lead to improved survival, according to the results of a new study. This survival benefit, was observed across multiple subgroups, including patients with LDL cholesterol levels <40mg/dl>

The study investigated the safety and clinical outcomes associated with statin therapy in patients with very low LDL levels, such as <60 style=""> More than 6000 consecutive patients were identified from a tertiary-care medical centre or affiliated community clinic. Statin therapy was defined as a prescription during the 150 days after the low LDL value (<60mg/dl) style="">

During a median follow-up of two years, there were 510 deaths. After controlling for the propensity to receive a statin, statin therapy was associated with a significant 35% reduction in the risk of death. The lower mortality was observed across various subgroups, including a 42% reduction in total mortality among those treated with a statin at baseline, a 49% reduction among those with LDL cholesterol levels <40 style="">

In terms of potential side effects, statin therapy was not associated with an increase in any adverse events. No cases of rhabdomyolysis were reported, nor was there a risk of developing liver enzyme elevations. There was also no increase in the risk of malignancy or renal insufficiency.

Circulation 30 July 2007; 116:613-618
Heartwire News Service per Medscape News 3 August 2007(registration required)

Cochrane review: anticoagulants better than antiplatelets for stroke prevention in AF patients.

According to a Cochrane review,adjusted-dose warfarin and related oral anticoagulants are superior to antiplatelets in the prevention of stroke and major vascular events in patients with non-valvular atrial fibrillation (AF).

The authors of the review note that non-valvular AF ‘carries an increased risk of stroke mediated by embolism of stasis-precipitated thrombi originating in the left atrial appendage’. Although both oral anticoagulants and antiplatelets have proven effective for stroke prevention in most patients at high risk for vascular events, they sought to separately characterise their relative effects in primary stroke prevention, i.e. in those patients without a history of stroke or transient ischaemic attack (TIA).

The authors carried out a comprehensive search of the literature and located eight relevant RCTs (n=9,598) comparing long-term (more than four weeks) adjusted-dose oral anticoagulant treatment to antiplatelet therapy in patients with chronic non-valvular AF and no history of stroke or TIA. The trials included were: ACTIVE W; AFASAK 1; AFASAK II; ATHENS; NASPEAF; PATAF; SPAF IIa and SPAF IIb. All trials used warfarin as the oral anticoagulant except NASPEAF (acenocumarol) and PATAF (several oral anticoagulants including warfarin). Aspirin was the antiplatelet agent tested (75-325mg/day), except ACTIVE W (combination of aspirin plus clopidogrel) and NASPEAF (triflusal).

Oral anticoagulants were associated with lower risk of all stroke (odds ratio (OR) 0.68, 95% CI 0.54 to 0.85; p="0.0007"), ischaemic stroke (OR 0.53, 95% CI 0.41 to 0.68; p ≤ 0.00001) and systemic emboli (OR 0.48, 95% CI 0.25 to 0.90).Assuming an estimated annualised rate of stroke of 4% per year on antiplatelet therapy for primary prevention, about 13 strokes (ischaemic and haemorrhagic) and 19 ischaemic strokes (fatal and non-fatal) per year would be prevented for every 1000 AF patients given oral anticoagulants instead of antiplatelet therapy.

No statistically significant differences were observed between the two treatments in terms of disabling or fatal strokes (OR 0.71, 95% CI 0.59 to 1.04), myocardial infarction (OR 0.69, 95% CI 0.47 to 1.01), vascular death (OR 0.93, 95% CI 0.75 to 1.15) or all cause mortality (OR 0.99, 95% CI 0.83 to 1.18). Intracranial haemorrhages (OR 1.98, 95% CI 1.20 to 3.28; p="0.008") were increased by oral anticoagulant therapy.

Cochrane Database of Systematic Reviews 2007, issue 3 Link to abstract
Ann Int Med (NeLM)

Reassessment of the cardiovascular risks of Rosiglitazone.

A recent meta-analysis of 42 clinical trials concluded that rosiglitazone was associated with an approximately 43% increased risk for myocardial infarction and an approximately 64% increased risk for cardiovascular death. The sensitivity of these conclusions to several methodological choices was not assessed. The meta-analysis was not based on a comprehensive search for all studies that might yield evidence about rosiglitazone’s cardiovascular effects. Studies were combined on the basis of a lack of statistical heterogeneity, despite substantial variability in study design and outcome assessment. The meta-analytic approach that was used required the exclusion of studies with zero events in the treatment and control groups. Alternative meta-analytic approaches that use continuity corrections show lower odds ratios that are not statistically significant. The authors of this commentary conclude that the risk for myocardial infarction and death from cardiovascular disease for diabetic patients taking rosiglitazone is uncertain - neither increased nor decreased risk is established.

The authors state that their analysis is restricted by the same limitations as those in the original analysis: short follow-up; low event rates; absence of patient-level data about time to event; variable and probably incomplete outcome ascertainment; and inability to reliably assess total mortality rate or composite outcomes, such as death or myocardial infarction. Neither analysis is a comprehensive systematic summary of all available evidence about the potential cardiovascular risks of rosiglitazone. Only prospective clinical trials designed for the specific purpose of establishing the cardiovascular benefit or risk of rosiglitazone will resolve the controversy about its safety. They conclude that the available evidence does not justify the recommendations for action of the original study.

Ann Intern Med 7 Aug 2007 – Early online(to be published 16 October 2007)

Cochrane review: corticosteroids to reduce relapse following asthma exacerbation.

The Cochrane Collaboration has produced a systematic review on the benefit of corticosteroids for the treatment of asthmatic patients discharged from an acute care setting (i.e. usually the emergency department) after assessment and treatment of an acute asthmatic exacerbation. Researchers evaluated six randomized controlled trials involving 374 people comparing two types of corticosteroids (oral or intramuscular) with placebo for outpatient treatment of asthmatic exacerbations in adults or children. One study used IM corticosteroids, five used oral corticosteroids.

The following results were reported:

· Significantly fewer patients in the corticosteroid group relapsed to receive additional care in the first week (Relative risk (RR) 0.38; 95% confidence interval (CI) 0.2 to 0.74). This favourable effect was maintained over the first 21 days (RR 0.47; 95% CI 0.25 to 0.89) and there were fewer subsequent hospitalizations (RR 0.35; 95% CI 0.13 to 0.95).

· Patients receiving corticosteroids had less need for beta2-agonists (mean difference (MD) -3.3 activations/day; 95% CI -5.6 to -1.0).

· Changes in pulmonary function tests (SMD 0.045; 95% CI -0.47 to 0.56) and side effects (SMD 0.03; 95% CI -0.38 to 0.44) in the first 7 to 10 days, while rarely reported, showed no significant differences between the treatment groups. Statistically significant heterogeneity was identified for the side effect results; all other outcomes were homogeneous.

· From these results, as few as ten patients need to be treated to prevent relapse to additional care after an exacerbation of asthma.

The authors conclude that “a short course of corticosteroids following assessment for an asthma exacerbation significantly reduces the number of relapses to additional care, hospitalizations and use of short-acting beta2-agonist without an apparent increase in side effects. Intramuscular and oral corticosteroids are both effective”.

Cochrane Database of Systematic Reviews 2007 Issue 3

Periconceptional multivitamin use and risk of preterm or small-for-gestational-age births

This study examined the relationship between periconceptional multivitamin use and the risk of small-for-gestational-age (SGA: <>th to <> preterm ( <>

Data were collected from Women in the Pregnancy Exposures and Preeclampsia Prevention Study (1997–2001) who had reported their regular multivitamin use in the past 6 months (n = 1823) at enrolment. The following findings were reported:

  • 47% of women regularly used periconceptional multivitamins
  • Periconceptional multivitamin use was associated with a reduced risk of preterm births (<> (OR) = 0.29, 95% CI: 0.13 to 0.64) and spontaneous preterm births (<>
  • There was a trend towards a lower risk of SGA (<> 0.64: 0.40 to 1.03).
  • There was no effect of multivitamin use on risk of preterm births (34 to <> weeks) or SGA (5th to <>
  • Sensitivity analysis for unmeasured confounding by folate intake supported these findings.

The authors of the study suggest from these preliminary findings that “periconceptional vitamin use is associated with lower rates of severe preterm births and extreme SGA.” However they stress that these data should be considered cautiously until they have been replicated as there were several important limitations of their data such as the self-reported nature of vitamin use, and unmeasured factors relating to lifestyle, nutrition, access to health care, and maternal genetic variation.

Am J Epidemiol 2007;166:296-303 - Abstract

Review – new antithrombotics in cardiology.

In this article, the authors review new antithrombotic agents, with emphasis on those that have been or are likely to be introduced into clinical practice in cardiology. They also briefly review the limitations and advantages of unfractionated heparin (UFH) and low molecular weight heparin (LMWH) as ‘it is these limitations that provide opportunities for new parenteral anticoagulants’. The following agents are discussed:

  • Thrombin inhibitors – hirudin, bivalirudin, argatroban, ximelagatran, dabigatran, odiparcil
  • Factor Xa inhibitors – fondaparinux, idraparinux, rivaroxaban, razaxaban, otamixaban
  • Factor IXa inhibitors
  • Role of new anticoagulants by indication – acute coronary syndrome, prevention of arterial thromboembolism in AF, active ischaemic stroke
The authors note that “improvements of new over established anticoagulants are likely to relate to properties other than their inhibition of a specific activated clotting factor. These properties include freedom from non-haemorrhagic side effects, more favourable pharmacokinetics, a predictable dose response that obviates the need for coagulation monitoring, and more appropriate dose selection for the indication of interest”.

Circulation 2007; 116: 552-60 (link to full text, free at time of posting)

Effect of antibiotic prescribing on antibiotic resistance in children in primary care

A prospective cohort study has assessed the effect of antibiotic prescribing for acute respiratory infection on the prevalence of antibiotic resistance in individual children in primary care. The study involved general practices in Oxfordshire and 119 children, of whom 71 received a beta-lactam antibiotic, (amoxicillin 70, cephradine 1) at presentation and 48 received no antibiotic. The main outcome measures were antibiotic resistance as assessed by the geometric mean minimum inhibitory concentration (MIC) for ampicillin and presence of the ICEHin1056 resistance element in up to four isolates of Haemophilus species recovered from throat swabs at recruitment, 2 and 12 weeks.

The following findings were reported:

  • In children who did not receive an antibiotic, the MIC for ampicillin was the same (2.7 microg/ml) at both follow-up points, with no significant change from the initial level of 4.1 microg/ml.
  • In children who received an antibiotic, the MIC increased about fourfold to 9.2 microg/ml at the two week follow-up (ratio to no antibiotic group 3.5, p = 0.005); at the 12 week follow-up, it fell back to 5.7 microg/ml (ratio to no antibiotic group 2.1, p = 0.06).
  • The ratio of MIC at 12 weeks vs initial visit was 2.33 in children on an antibiotic and 0.71 in those not on them (p = 0.05).
  • Prescribing amoxicillin doubled the risk of isolation of the ICEHin1056 resistance element in Haemophilus isolates (67% vs 36%; relative risk 1.9, 95% CI, 1.2 to 2.9) two weeks later; this increase was transient and ampicillin resistance fell close to baseline by week 12. This element was recovered from most children from whom Haemophilus species were isolated (83%, 95% CI, 76% to 89%) at some point in the study, irrespective of whether they received an antibiotic.
Based on these findings, the authors suggest that in the few cases where it is appropriate to repeat the prescription of an antibiotic in under 3 months, it may be sensible to choose one that has activity against beta lactamase producing strains, rather than give a further course of amoxicillin. They add that from a population perspective, the issue of concern is the high (35%) equilibrium level of recovery of resistant Haemophilus species to which the children receiving antibiotics returned after 12 weeks and the endemic carriage of the ICEHin1056 resistance element by nasopharyngeal Haemophilus species. Therefore any reduction in community resistance is likely to need a substantial and sustained reduction in community prescribing; one option that deserves further investigation is to reduce the duration of each course of antibiotics prescribed in the community, another more radical option is to stop prescribing antibiotics to any child with respiratory infection in the community except in well defined and exceptional circumstances, though it does run the risk of some children with bacterial disease being treated later in the course of their illness.

The study concluded that prescribing amoxicillin to a child in general practice doubles the risk of recovering a beta lactamase encoding resistance element from that child's throat two weeks later; this risk falls back to the level seen before treatment within 12 weeks. The researchers note that though the short term effect of amoxicillin is transitory in the individual child, it is sufficient to sustain a high level of antibiotic resistance in the population. They add that “the ICEHin1056 resistance element is endemic in UK children, but reversal of this will require further substantial and sustained changes in antibiotic prescribing in the community.”

BMJ, published early online 26 July 2007; doi:10.1136/bmj.39274.647465.BE (link to abstract)

Role of statins for the primary prevention of cardiovascular disease in patients with type 2 diabetes

The authors of this American article review and evaluate the major statin trials that included a significant number of patients with diabetes without pre-existing coronary heart disease (CHD). They also discuss the role statins should play in primary prevention. The following primary prevention trials are discussed in the article:

  • Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT-LLT)
  • Heart Protection Study (HPS)
  • Anglo–Scandinavian Cardiac Outcomes Trial–Blood Pressure Lowering Arm (ASCOT-BPLA)
  • Collaborative atorvastatin diabetes study (CARDS)
  • The atorvastatin study for prevention of coronary heart disease endpoints in non-insulin-dependent diabetes mellitus (ASPEN)
Guidelines from the American Diabetes Association (ADA) recommend statin therapy in the majority of patients with diabetes. The authors note that the first 4 studies above (which included a significant number of patients with diabetes and no history of CHD) have had an impact on treatment guidelines. However, they also add that these studies had various methodological flaws and some non-significant results. ASPEN was the most recent trial published since the ADA guidelines were issued. This trial found that in patients with diabetes at lower CHD risk, atorvastatin 10 mg was not superior to placebo in reducing time to the first major CV event or procedure.

The authors conclude, “Current ADA recommendations may be too aggressive as available evidence suggests that the decision to initiate pharmacotherapy with a statin in patients with type 2 diabetes mellitus who do not have pre-existing CHD should be individualised rather than based solely on the diagnosis of type 2 diabetes mellitus.”

Am J Health-Syst Pharmacy 2007; 64: 1603-10

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)

Monday, May 21, 2007

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).

Friday, May 18, 2007

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)

Thursday, May 17, 2007

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

Wednesday, May 16, 2007

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)