PharmaCIT

Case report: erythropoietins affecting HbA1c in a diabetic not on dialysis

2009-09-27T22:36:00.000+01:00

In this case report, they authors describe an interaction between two erythropoietins and haemoglobin A1c (HbA1c) levels in a diabetic patient not on dialysis.

Some evidence suggests that treatment with erythropoietins can reduce HbA1c levels in patients on haemodialysis, however this has not previously been reported in non-dialysed patients. They authors describe a case in which this effect occurred in a diabetic patient not on dialysis and resulted in a prolonged period of under-treatment of his diabetes.

The patient was a male aged 64 with long-standing insulin-treated type 2 diabetes and chronic renal failure, amongst other problems. He presented with severe anaemia (Hb 4.4gm/100ml) and was treated with epoetin. His HbA1c level subsequently fell, and his insulin dose reduced in consequence. His most recent stable pre-admission insulin dose was 156 units daily with no hypoglycaemic episodes. Subsequent management involved home-based darbepoetin: his HbA1c level was consistently in the range 4.4 to 5.8 and his daily insulin dose was reduced to 22 units daily: this was despite raised blood glucose levels and no hypoglycaemic episodes. After 31 months, he started haemodialysis and the darbepoetin stopped: after three months, his HbA1c rose to 8.8%.

The authors conclude that in this case, treatment with erythropoietin resulted in a falsely reduced HbA1c level, and that the patient’s insulin dose would have been managed differently without this. The effect was seen with both epoetin and darbepoetin, and can thus be considered a class effect. Healthcare professionals treating diabetic patients should be aware of agents that can affect HbA1c levels, and that in patients receiving erythropoietins diabetes should be controlled on the basis of blood glucose levels and hypo- or hyper-glycaemic episodes rather than on HbA1c alone.

Pharmacotherapy 2009; 29: 468-72 (link to abstract); from Medscape, 8th July 2009 (free registration required)

Validation study for the QRISK cardiovascular risk assessment tool

2009-09-27T22:21:00.001+01:00

An independent validation study of the QRISK score found that it was better at identifying cardiovascular risk in a UK population than the established scoring system in current use and based on the Framingham equations.

The authors note some of the problems with risk prediction models, commenting that many of those published are of poor methodological quality. An essential step often missed is independent external validation, and in this paper they describe an independent validation study on the QRISK cardiovascular risk scoring tool that has been developed using UK data. QRISK has been validated by its original authors, revised following criticism, and re-validated by its original authors.

The study population came from the THIN database, which comprises anonymised patient data from UK GP practices running one of the standard GP software packages in use. Exclusion criteria were pre-existing cardiovascular disease, invalid data, age under 35 years, or over 75 years, were missing Townsend scores, had a diagnosis of pre-existing diabetes, or were prescribed statins at baseline. The authors then calculated the QRISK score for each patient in the cohort, using age-sex reference values for missing risk-factor data.

Predictive performance of QRISK was assessed against observed cardiovascular risk by examining measures of calibration and discrimination. Calibration measures how closely predicted 10 year cardiovascular disease risk agrees with observed 10 year cardiovascular disease risk; discrimination is the ability of the risk prediction model to differentiate between patients who experience a cardiovascular disease event during the study and those who do not. QRISK performance was then compared with scores using the Anderson Framingham equation described in current UK guidelines.

There were data on 1,787,169 patients in the THIN database. After exclusions, 1,072,800 patients were eligible for analysis: median follow-up for this cohort was 4.9 years (range 0 to 12 years), and 36,483 patients were followed for at least 10 years. One of the three main risk factors (total : HDL serum cholesterol ratio, systolic blood pressure, and BMI) was missing for almost two-thirds of patients (63%) and all were missing for 9%: standard values were used for these patients. Overall 10-year observed risk of a cardiovascular event in men aged 35-74 years was 9.87% (95% CI, 9.71% to 10.03%) and in women was 6.55% (95% CI, 6.43% to 6.68%). Observed 10-year risk was significantly higher for patients with all risk factors recorded (19.9% for men, 12.8% for women) compared to those with at least one risk factor missing (5.0% and 3.4% respectively).

In comparison to the Anderson Framingham equation, QRISK gives a more accurate estimate of predicted 10-year cardiovascular risk for both men and women. QRISK tended to under-predict risk (by 13% for men, 10% for women), whereas Anderson Framingham tended to over-predict risk (32% for men and 10% for women).

The authors conclude that the QRISK cardiovascular risk equation offers an improvement over the Anderson Framingham equation in terms of identifying a high risk population for cardiovascular disease in the United Kingdom. While QRISK underestimates 10 year cardiovascular disease risk, the magnitude of under-prediction is smaller than the over-prediction with Anderson Framingham. QRISK also identified a group of high risk patients who will go on to experience more cardiovascular events over the next 10 years than a similar high risk group identified by Framingham. The authors note potential weaknesses of their study, and discuss other cardiovascular risk scoring systems; they also note areas for future research.

BMJ 2009; 339: b2584 (link to abstract, full text freely available at time of posting)

Famotidine reduces peptic ulcer risk in patients receiving low-dose aspirin

2009-09-27T22:20:00.000+01:00

A controlled trial found that over the short-term, famotidine, a histamine-H2 receptor blocker, was effective in reducing new gastric and duodenal ulceration in patients taking low-dose aspirin.

The incidence of upper-gastrointestinal complications associated with low-dose aspirin has increased along with its wider use, however there is debate over the most effective prophylaxis because effective drugs and clinical trials are few. Proton-pump inhibitors (PPI) are widely used, but may be costly and recent studies suggest a possible adverse interaction between PPI and clopidogrel – often co-prescribed with aspirin. The authors of this study aimed to determine whether a histamine-H2 blocker, famotidine, was effective in reducing peptic ulceration and erosive oesophagitis in patients taking low-does aspirin.

Participants were adult patients of the cardiovascular, cerebrovascular, and diabetes clinics of one UK hospital, who were eligible for low-dose aspirin treatment that was likely to last at least 12 weeks (the intended study duration). Other anti-platelet treatment was not a criterion for exclusion.

Potential study patients had a baseline endoscopy and those with active serious upper gastro-intestinal disease excluded: those eligible were randomised to receive famotidine 20mg twice daily or matching placebo. They had a further endoscopy at 12 weeks after randomisation, and the primary outcome was development of new peptic ulcers or erosive oesophagitis at this point.

The study was stopped early before the planned full recruitment (700 patients) because interim analysis indicated overwhelming evidence of benefit. At this point, 14,515 had been assessed for eligibility and 404 randomised (famotidine n=204, placebo n=200). The main reason for exclusion was ineligibility (n=9,085). There were 90 withdrawals (famotidine n=37, placebo n=53), the most common reasons being withdrawal of consent (n=29) and loss to follow-up (n=17).

In the intention to treat analysis, peptic ulcers and erosive oesophagitis were less frequent in the famotidine group compared to the placebo group: any endpoint component developed in 5.4% vs. 32.5%, with an odds ratio (OR) of 0.12 (95% CI, 0.06 to 0.23; p<0.0001).

In terms of individual components, gastric ulcers were found in 3.4% vs. 15.0% (OR, 0.20; 95% CI, 0.09 to 0.47; p=0.0002), duodenal ulcers in 0.5% vs. 8.5% (OR 0.05%; 95% CI, 0.01 to 0.40; p=0.0045), and erosive oesophagitis in 4.4% vs. 19.0% (OR, 0.20; 95% CI, 0.09 to 0.42; p<0.0001). There were 24 reported adverse events (famotidine n=9, placebo n=15), none of which were considered to be related to the study treatment. There was no indication of any interaction with clopidogrel, nor were patients taking famotidine more likely to have a cardiac event.

The authors conclude that famotidine is effective in prevention of peptic ulcers and erosive oesophagitis in patients taking low-dose aspirin. It may therefore offer an alternative option to PPI in such patients.

An accompanying Comment discusses the study, including the observation that famotidine was more effective in patients with H. pylori infection.

Lancet, published early online 6 July 2009; doi:10.1016/S0140-6736(09)61246-0 (link to abstract); Lancet, published early online 6 July 2009; doi:10.1016/S0140-6736(09)61245-9 (Comment, link to full text; subscription required for access)

Early RAS-blockade in type 1 diabetes slows retinal damage, but not kidney damage

2009-09-27T22:07:00.000+01:00

Early renin-angiotensin system (RAS) blockade in patients with type 1 diabetes slows the progression of retinopathy, but does not affect nephropathy according to a long-term controlled trial.

Diabetic nephropathy is responsible for a significant proportion of cases of end-stage renal disease, and there is evidence that once it is clinically detectable by the presence of albuminuria, drugs that block the RAS are effective in slowing its progression. Despite the lack of trial evidence for value in patients without overt nephropathy, it has therefore been accepted that RAS blockade at all stages will be beneficial in reducing diabetic nephropathy. This trial aimed to test that concept over the longer term using a hard clinical outcome measure: it was partly-industry sponsored, but designed, carried out, analysed, and written-up without industry input.

Participants were patients with type 1 diabetes, normotensive, and with normal albuminuria. Exclusion criteria included glomerular filtration rate (GFR) of less than 90ml/min (80ml/min for strict vegans) and urinary albumin excretion greater than 20microgm/min; a two-week placebo run-in period was used to exclude those poorly compliant with treatment (<85% of doses taken). Eligible patients were randomised to treatment with enalapril 10mg, losartan 50mg, or placebo daily for a study duration of five years. Drug doses were doubled during the study on the basis of trial data published after it started. Primary outcome measured actual kidney damage over the study period by determining change in the fraction of glomerular volume occupied by mesangium in kidney-biopsy specimens. Secondary renal outcomes included incidence of microalbuminuria and GFR. Retinopathy progress was assessed in those for whom lack of baseline (within one year of randomisation) retinopathy could be confirmed: the measure for this outcome was a progression on a retinopathy severity scale of two steps or more.

A total of 1,065 patients was screened for eligibility - most (n=707) declined to participate and 73 were ineligible, leaving 285 randomised participants. Of these, 256 were available for the renal outcome (29 had no exit biopsy, mostly due to withdrawal of consent/loss to follow-up), and 223 for the retinal outcome (32 no baseline photograph; 30 no final photograph, mostly due to withdrawal/loss).

There was no significant difference between the groups in the primary outcome: change in mesangial fractional volume per glomerulus over the 5-year period was 0.016 units in the placebo group compared to 0.005 units in the enalapril group (P=0.38) and 0.026 units in the losartan group (P=0.26). Albumin excretion rate increased significantly from baseline only in the losartan group, and the 5-year cumulative incidence of microalbuminuria was 6% in the placebo group, 4% in the enalapril group, and 17% in the losartan group (P=0.01 by the log-rank test vs. placebo). GFR declined at a similar rate in all three groups (6.6 to 8.9 ml/min).

Both enalapril and losartan reduced the rate of retinopathy progression compared to placebo: rates over five years were 25%, 21%, and 38% respectively, for odds ratios vs. placebo of 0.35 (95% CI, 0.14 to 0.85) and 0.30 95(% CI, 0.12 to 0.73) respectively. These differences were independent of differences in blood pressure.

There were three serious adverse events related to biopsy, all of which resolved, and three deaths unrelated to the study drugs or procedures. Chronic cough occurred in 12 patients receiving enalapril, 6 receiving losartan, and 4 on placebo.

The authors conclude that early RAS blockade in patients with type 1 diabetes did not affect the progression of diabetic nephropathy. It did, however, significantly slow diabetic retinopathy. They comment that the effect of losartan on albumin excretion was unexpected and is not currently confirmed by other studies, nevertheless, they suggest that urinary albumin should be carefully monitored when angiotensin-receptor blockers are prescribed to similar patients. They comment that this study is not comparable to earlier work, and suggest that the inclusion criteria may have selected for patients at lower intrinsic risk of nephropathy.

An accompanying editorial comments on the study and its implications.

NEJM 2009; 361: 40-51 (link to abstract); NEJM 2009; 361: 83-5 (Editorial, link to extract)

HTA report: Research assesses the use of glucose monitoring for type 1 and type 2 diabetes

2009-09-27T22:03:00.002+01:00

The National Institute for Health Research Health Technology Assessment (NIHR HTA) programme has published two new studies focusing on self-monitoring of blood glucose (SMBG) levels in the management of both type 1 and type 2 diabetes.

The first study, (the Diabetes Glycaemic Education and Monitoring [DiGEM] tested whether self-monitoring of blood glucose alone, or with training in incorporating the findings into self-care, compared with standardised usual care improved glycaemic control in non-insulin treated patients with type 2 diabetes. The DiGEM trial has previously been published in the BMJ (see previous NeLM news report link below). The trial involved 453 participants recruited from 48 general practises in Oxford and South Yorkshire and found that the routine use of SMBG, with or without additional training, was associated with higher costs and lower quality of life in patients with well controlled non-insulin treated type 2 diabetes.

The second study assessed the effectiveness and acceptability to patients of two minimally invasive continuous glucose monitoring devices (Glucowatch® and the MiniMed® Continuous Glucose Monitoring System) to help improve diabetes control. The study randomised 404 participants into four groups: group one wore the Glucowatch a minimum of four times per month and a maximum of four times per week for the first three months; group two had the MiniMed Continuous Glucose Monitoring System fitted three times over the first three months of the study; group three received standard treatment with three nurse feedback sessions during the first three months; and group four received standard treatment only.

The results found no significant difference between any of the groups and indicated no advantage in having the additional information provided by a continuous glucose monitoring device. The study found that continuous glucose monitors do not lead to improved clinical outcomes in individuals with poorly controlled, insulin-requiring diabetes.

Health Technology Assessment 2009; Vol. 13: No. 28 (MITRE study);
Health Technology Assessment 2009; Vol. 13: No. 15 (DiGEM study)
NIHR HTA media release

Meta-analysis: statins for primary prevention of cardiovascular disease in those with risk factors

2009-09-27T22:01:00.003+01:00

A meta-analysis of controlled trial data found that in a range of people with cardiovascular risk factors but no overt cardiovascular disease, statin treatment reduced overall mortality and risk of major cardiovascular and cerebrovascular events. Absolute risk reductions, however, were fairly small.

Statin treatment for secondary prevention of cardiovascular disease is well accepted, however its use for primary prevention is still debated as this would have significant public health implications. In particular, the effects in women, older people, and those with diabetes are unclear. The authors of this meta-analysis aimed to use published clinical trial data to determine the effects of statins as primary prevention including assessment in the three subgroups mentioned. They carried out an extensive literature search to locate randomised controlled trials that compared statins with control in people with cardiovascular risk factors but no established cardiovascular disease. Eligibility criteria included follow-up for at least one year, mortality or cardiovascular disease as primary outcomes, at least 80% of participants without established cardiovascular disease or complete separate reporting of this subgroup. Primary end point of the meta-analysis was all cause mortality; secondary end points included composite major coronary events and composite major cerebrovascular events.

The initial search located 1,230 reports: 1,188 were excluded on the basis of title or abstract. Of the remaining 42 studies retrieved for full assessment, 32 were excluded to leave 10 eligible studies for analysis. These included 70,388 people, of whom 23,681 (34%) were women and 16,078 (23%) had diabetes. Specific data on the subgroups of interest were available for six of the studies, for one (ALLHAT) in the published paper and for five others from the original investigators. About 6% of the included participants were actually secondary prevention patients that could not be excluded from analysis, which was therefore also carried out excluding the three studies involved. Treatment allocation was evenly balanced (statin n=35,138, control n= 35,250); mean age was 63 years, and mean follow-up was 4.1 years.

Statin treatment was associated with a reduction in overall mortality: over the 4.1 years, this was 5.7% in the control group compared to 5.1% in the statin group for a relative risk reduction (RRR) of 12% (odds ratio 0.88; 95% CI, 0.81 to 0.96) and an absolute risk reduction (ARR) of 0.6% (NNT over 4.1 years 167).

There was also a reduction in major cardiovascular events: 5.4% in the control group vs. 4.1% in the statin group for a RRR of 30% (OR 0.70, 95% CI, 0.61 to 0.81) and an ARR of 1.3% (NNT over 4.1 years 77).
Similarly, cerebrovascular events were reduced: 2.3% vs. 1.9%, RRR 19% (OR 0.81; 95% CI, 0.71 to 0.93), ARR 0.4% (NNT over 4.1 years 250). There was no association between statin use and risk of cancer over the study period (OR, 0.97; 95% CI, 0.89 to 1.05).

Analysis by the defined subgroups showed no evidence of heterogeneity between the groups, and analysis without the studies that included secondary prevention patients did not change the results significantly.

The authors conclude that primary prevention with statins in patients with cardiovascular risk factors has similar relative effects on cardiovascular risk as secondary prevention, and that these are not significantly different in women, older people, and patients with diabetes. They comment that the absolute treatment benefit is low, however, and the current data do not allow identification of those patients who would most benefit. Correct identification of these people remains a challenge, however current risk scoring systems, as well as current data, indicate that older men (>65 years) with risk factors, or older women with diabetes and risk factors are the highest risk groups and would be most likely to benefit from long-term statin use.

BMJ 2009; 338: b2376 (link to abstract, fulltext freely available at time of posting)

Drug in development: taspoglutide in type 2 diabetes

2009-09-27T22:01:00.000+01:00

Taspoglutide, an anti-diabetic drug in late stage development as a prolonged-release injection, was effective in maintaining blood glucose control over the short term in patients with type 2 diabetes when given once weekly or fortnightly.

A number of drugs that target glucagon-like peptide-1 (GLP-1) system have been recently launched or are in development. Two different drug types acting on this system are currently being used researched – the ‘gliptin’ class drugs inhibit the enzyme that degrades endogenous GLP-1 (dipeptidyl peptidase-4, DPP-4), and the GLP-1 analogues that act as agonists resistant to degradation to DPP-4. Taspoglutide is a GLP-4 analogue that has been shown to have anti-diabetic effects: this study tested a prolonged-release formulation suitable for once-weekly dosing. Participants were adults with type 2 diabetes not adequately controlled on metformin 1.5gm daily. They were randomised to receive taspoglutide 5mg, 10mg, or 20mg weekly, or 10mg or 20mg every two weeks, or matching placebo (in addition to their existing dose of metformin). Study duration was eight weeks with an additional four weeks follow-up, and the primary outcome was glycaemic control assessed as haemoglobin A1c (HbA1c) change from baseline one week after eight consecutive weeks of treatment.

A total of 306 patients was randomised to treatment from 572 screened. After nine weeks, HbA1c levels were significantly lower in all the taspoglutide groups compared to placebo. Baseline value was 7.9% (SD ± 0.7%): at assessment, values compared to baseline were -1.0 ± 0.1% (5 mg once weekly), –1.2 ± 0.1% (10 mg once weekly), –1.2 ± 0.1% (20 mg once weekly), –0.9 ± 0.1% (10 mg fortnightly), and –1.0 ± 0.1% (20 mg fortnightly) vs. –0.2 ± 0.1% with placebo. Weight loss, a secondary outcome, was significantly greater than placebo in the 10mg and 20mg weekly groups, and in the 20mg fortnightly group.
Based on their results, the authors conclude that in patients with type 2 diabetes inadequately controlled on metformin, adding taspoglutide to therapy significantly improves glycaemic control. It also improved weight loss in a dose-dependent fashion, and was generally well tolerated.

[Editor’s note: taspoglutide is currently in phase 3 clinical trials – if these are successful, it might be expected to be marketed in around 3 to 4 years time.]

Diabetes Care 2009; 32: 1237-43 (link to abstract)

Insulin glargine: three observational studies raise a possible link with cancer

2009-09-27T21:50:00.000+01:00

Three observational studies conducted in Sweden, Germany and Scotland, all suggesting a possible link between the use of insulin glargine (Lantus) and an increased risk of cancer compared to human insulin, have been published in Diabetologia. A fourth study from the UK found that insulin analogues were not associated with any increased risk of cancer above that of human insulin.

All of these studies, alongside a statement from the European Association for the Study of Diabetes (EASD), an expert commentary (webcast) and information for patients, are available to access freely at the link below.

In brief, the studies were as follows:

German cohort study:

The aim of this study was to investigate the risk of malignant neoplasms and mortality in patients treated with either human insulin or with one of three insulin analogues. Data were provided from the largest statutory German health insurance fund between Jan 1998 and June 2005 on 127,031 adults receiving first-time insulin therapy for diabetes (mean follow-up of 1.63 years). A positive association between cancer incidence and insulin dose was found for all insulin types; when adjusted for dose, a dose-dependant increase in cancer risk was found for treatment with insulin glargine compared with human insulin: HR 1.09 (95% CI 1.00 to 1.19) for daily dose of 10 IU; 1.19 (1.10 to 1.30) for 30 IU; and 1.31 (1.20 to 1.42) for 50 IU. The risks associated with the other insulin analogues studied (lispro and aspart) were not statistically significantly higher than that associated with human insulin. The press release notes that compared with people using similar doses of human insulin, out of every 100 people who used Lantus insulin over an average of about one-and-a-half years, one additional person was diagnosed with cancer.

Swedish study:

This was conducted upon request by the EASD. A total of 114,841 individuals who were aged 35-84 years at the end of 2005 and who had at least one prescription for insulin dispensed between July and Dec 2005 were included in this analysis; the outcome of interest was the occurrence of a first diagnosis of a primary malignancy, occurring between Jan 2006 and Dec 2007. Individuals using insulin glargine monotherapy were found to have an increased risk of breast cancer (RR of 1.99; 95% CI 1.31-3.03) compared to users of other types of insulin (grouped together); no statistically significant results were obtained for other individual cancer types studied or for the category ‘all malignancies’.

Scottish study:

Using a nationwide diabetes clinical database, a fixed cohort based on insulin exposure during a 4 month period in 2003 (n=36254, in whom 715 cases of cancer occurred) and a cohort of new insulin users across the period (n=12852 in whom 381 cancers occurred) were defined. Records from these cohorts were linked to cancer registry data. Although the subset of patients using insulin glargine alone (n=447) had a higher incidence of all cancers than those using other insulins only (n=32295) (HR 1.55, 95% CI 1.01–2.37, p=0.045), other findings presented taking into account overall use (i.e. use in combination with other insulins) lead the authors to conclude that ‘insulin glargine use was not associated with an increased risk of all cancers or site-specific cancers in Scotland over a 4 year time frame’.

UK study

This retrospective cohort study involved a total of 62,809 patients treated in UK general practices participating in The Health Information Network (THIN). They were divided into groups according to whether they received monotherapy with metformin, combination therapy with metformin and a sulfonylurea, or insulin. The risk of progression to any solid tumour for those on basal human insulin alone was not statistically significantly different compared to those on insulin glargine alone (HR 1.24; 95% CI 0.90 1.70), although in general those on insulin of any kind were more likely to develop solid cancers than those on metformin (combination with metformin appeared to abolish most of this excess risk).

The EASD have communicated their findings to the EMEA and are in contact with sanofi-aventis with regards to further analyses. While further research is awaited to either confirm or refute these initial findings, the EASD as advising patients not to stop using Lantus insulin on the basis of the current research findings. However the patient information produced by the EASD notes that people with diabetes do have the option of using long acting human insulin or a mixture of long- and short-acting human insulin twice a day as alternatives if they wish, and that they may wish to consider this option if they already have cancer or, for women, if there is a family history of breast cancer. They stress however that patients should not make any changes to their insulin treatment without consulting their own doctor, and should on no account stop using their insulin.

Sanofi-aventis has issued the following statement to NeLM:
“Sanofi-aventis is aware of the data published in Diabetologia from four retrospective studies conducted within patient registries investigating the possible link between the use of insulin and the risks of cancer. The authors of these studies recognise that the results of these data are inconclusive, and that no conclusion can be drawn regarding a possible causal relationship between insulin glargine (Lantus®) use and the occurrence of malignancy. Of note, the UK study found no link between insulin glargine and cancer.

Clinical studies, which represent the gold standard of evidence, do not indicate an association between insulin glargine and cancer. This includes data from clinical studies covering over 70 000 patients as well as data from post marketing surveillance which confirm the strong safety profile of Lantus. Over 24 million patients-years of exposure to Lantus equally confirm its benefits.

Patient safety is the primary concern of sanofi-aventis. The Group will continue to vigorously monitor the safety of Lantus® in close collaboration with regulatory agencies and scientific experts.
Sanofi-Aventis considers the benefit risk ratio of Lantus to be unchanged and we see no need to change therapeutic strategy with regards to its use. The EASD and the ADA advise that patients do not stop taking Lantus insulin on the basis of the findings reported in Diabetologia.”

In a press release, the European Medicines Agency (EMEA) has stated that it is looking into four recently published registry studies investigating a possible link between insulin analogues, in particular insulin glargine, and the risk of cancer. The studies were published on the Diabetologia website on 26th June 2009 (see NeLM report). The Agency has concluded in the interim that “on the basis of the currently available data, a relationship between insulin glargine and cancer cannot be confirmed nor excluded. However, the concerns raised by the four studies require further in-depth evaluation.” The Agency’s Committee for Medicinal Products for Human Use (CHMP) will perform a detailed assessment of the studies and any other relevant information. Sanofi-Aventis, the Marketing Authorisation Holder for Lantus® and Optisulin®, has been asked to comment on this potential safety concern. The Agency has advised that patients on insulin glargine continue their treatment as normal, and reiterated that at this time, there is no recommendation that patients should change their current treatment. In case of any concerns, patients should consult their doctor. Further information will be provided once the CHMP has concluded its review.

The published papers, an EASD media report and advice for patients are available from Diabetalogia;
the EMEA media release is here

Comment: hazards of dual renin-angiotensin blockade in chronic kidney disease

2009-09-27T19:06:00.003+01:00

Dual renin-angiotensin system (RAS) blockade using ACE-inhibitor plus angiotensin-receptor blocker (ARB) has uncertain benefits and significant potential harms in chronic kidney disease (CKD), according to the authors of a Comment article in Archives of Internal Medicine. In consequence, they recommend that the combination should not be used for the average CKD patient in the community.

The authors briefly note the epidemiology of CKD and discuss the physiological rational behind dual RAS blockade in these patients. They note that its use appears to be increasing in primary care, but comment that the mechanism behind its use is still speculative. They then discuss the evidence for use, particularly the landmark COOPERATE trial that randomised patients with non-diabetic kidney disease to losartan, trandolapril, or both. While 11% of the combination group reached the study endpoint (doubled serum creatinine or ESRD) after three years, 23% of those on the individual drugs alone did so. Although the results appear impressive, a number of questions have subsequently arisen over the study that cast doubt on their robustness.

A further problem with COOPERATE and other trials of combined RAS blockade is that the patients involved mostly had primary glomerulonephropathic diseases, however in most patients with kidney failure it is consequent on diabetes or hypertension.

A meta-analysis recently examined the question: this excluded COOPERATE due to concerns over statistical reporting, however it still found a potential benefit for dual blockade. The authors of the comment note that in two of the large studies included, patients in the combination groups had lower blood pressure than those in the monotherapy groups, raising doubts over whether the effect was purely due to better blood pressure control. They also comment on issues raised by the authors of the meta-analysis – there is no robust evidence on appropriate dose escalation and limited evidence on adverse effects with the combination.

More recently, a large (n>25,000) relevant study has reported. The ON-TARGET trial compared dula blockade with monotherapy in patients with vascular risk factors. Renal outcomes were secondary (to all-cause mortality), however both primary and secondary outcomes were found to occur with combination treatment compared to monotherapy. While there are still some concerns over the results of this study, the authors suggest that it should still raise caution over use of dual RAS blockade.

They conclude that while there is no doubt over the benefits of ACE-inhibitor or ARB monotherapy in the treatment of CKD, they question the notion that dual blockade is superior. Although there is some physiological rationale, the harms may outweigh the benefits and until more efficacy and safety data are available they suggest that it should not be used by the general practitioner.

Arch Intern Med 2009; 169: 1015-8 (link to extract)

Pre-launch trial data: liraglutide appears better than exenatide in type 2 diabetes

2009-09-27T19:06:00.000+01:00

Patients with type-2 diabetes treated with liraglutide had better glycaemic control over 26 weeks than those treated with exenatide in an open-label trial published in the Lancet.

Liraglutide and exenatide are glucagon-like peptide-1 (GLP-1) receptor agonists. GLP-1 is released by intestinal cells: it stimulates insulin secretion by the pancreas, slows intestinal motility, and promotes satiety. As these characteristics are potentially helpful in the treatment of type-2 diabetes, drugs that act via this pathway are of significant clinical interest. Exenatide is a GLP-1 agonist of animal origin that is currently in clinical use whereas liraglutide is an analogue of human GLP-1 in late stage development. This trial compared liraglutide with exenatide in patients with type-2 diabetes poorly controlled on maximal oral antidiabetic therapy.

Participants were adults with confirmed type-2 diabetes who were poorly controlled (glycated haemoglobin [HbA1c] level 7% to 11%) on maximal doses metformin, sulphonylurea, or both, for 3 months or more. Exclusion criteria included severe obesity (BMI 45 kg/m2 and above), previous long-term insulin treatment, and previous exposure to study drugs. They were randomised to liraglutide 1.8mg daily or exenatide 10microgm twice daily, both by s/c injection, reached after two weeks and four weeks respectively of dose escalation. Background oral antidiabetic therapy was continued, with up to 50% dose reduction of a sulphonylurea allowed if hypoglycaemia occurred. Study duration was 26 weeks from randomisation, and the primary outcome was change in HbA1c level from baseline to study end. Safety outcomes included hypoglycaemic episodes grouped as minor (could be self-treated) or major (third-party assistance needed to treat).

Of 663 patients screened, 464 were randomised, 233 to liraglutide and 231 to exenatide: 202 and 187 respectively completed the study, with nausea being the commonest reason for withdrawal. Three additional patients received study drugs without randomisation and were included in the safety but not efficacy analyses. Mean baseline HbA1c was 8.2% overall and over the course of the study it fell further in patients receiving liraglutide (by 1.2%) than in those receiving exenatide (by 0.79%) for an estimated treatment difference of −0.33% (95% CI −0.47 to −0.18; p<0.0001). p="0.0015)." p="0.0131).">

Lancet, published early online 8 June 2009; doi:10.1016/S0140-6736(09)60659-0 (link to abstract); Lancet, published early online 8 June 2009; doi:10.1016/S0140-6736(09)60942-9 (Comment; link to full text, access to subscribers only)

Antidiabetic therapy may affect risk of pancreatic cancer

2009-09-27T19:05:00.000+01:00

A case-control study from a large US cancer centre suggests that treatment of diabetes may affect risk of pancreatic cancer, metformin reducing it and insulin and sulphonylureas increasing it.

Patients with type 2 diabetes seem to be at increased risk of several cancers, and there is evidence that it may have a role in pancreatic cancer. Other studies have suggested that metformin reduces and insulin and sulphonylureas increase risk of any cancer, but have not examined the risk of pancreatic cancer specifically. The authors of this paper used data from an existing case-control study that is ongoing at their institution (University of Texas M. D. Anderson Cancer Centre) to study the potential association. This study started in 2004 and aimed to define environmental and genetic factors that contribute to the development of pancreatic cancer.

Cases were consecutively recruited from patients with newly diagnosed and confirmed pancreatic ductal adenocarcinoma seen at the Centre. Controls were recruited from healthy individuals accompanying patients being treated at non-gastrointestinal centres within the institute: they were spouses and non-related relatives and friends of patients with cancers other than gastrointestinal or smoking-related. They were matched by age (+/- 5yr), sex, and race. Neither cases nor controls had a previous cancer history except for non-melanoma skin cancer. Diagnosis of diabetes, and frequencies of use of insulin, insulin secretagogues, metformin, and other antidiabetic medications among diabetic patients were compared between cases and controls. The risk of pancreatic cancer was then estimated using unconditional logistic regression analysis.

There were 973 cases (259 diabetic) and 863 controls (109 diabetic); the two groups were generally comparable except that cases included more black people and people aged over 70. After adjustment for potential confounding factors, diabetics who had taken metformin had a significantly lower risk of pancreatic cancer compared with those who had not (odds ratio[OR], 0.38; 95% CI, 0.22 to 0.69; P = 0.001). The association remained present when analysis was restricted to those with a duration of diabetes >2 years, and those who had never used insulin (OR 0.44; 95% CI, 0.22 to 0.87; and OR, 0.41; 95% CI, 0.19 to 0.87 respectively). Diabetics who had taken metformin also had a lower risk than non-diabetics (OR, 0.38; 95% CI, 0.21 to 0.67; P = .001), however the difference between non-diabetics and diabetics who had taken insulin secretagogues was not significant.

Diabetics who had used insulin or taken insulin secretagogues had a significantly higher risk of pancreatic cancer than diabetics who had not (OR, 4.99; 95% CI, 2.59 to 9.61; P<0.001; and OR, 2.52; 95% CI, 1.32 to 4.84; P=0.005, respectively).

The authors conclude that in this study population, patients with type 2 diabetes who had used metformin, especially for >5 years, had a significantly reduced risk of pancreatic cancer compared to never users. Additionally, although the numbers were smaller and therefore the confidence intervals wider, there was also an indication that use of insulin or insulin secretagogues was associated with an increased risk. They caution that although the overall study had a large sample size, statistical power was limited for diabetic subjects only: as a result, they consider that the observations need to be confirmed in larger studies.

An accompanying editorial discusses the study.

Gastroenterology 2009; 137: 482–8 (link to abstract, full text available free at time of posting); Gastroenterology 2009; 137: 412-5 (link to full text, available free at time of posting); from Medscape for 18th August 2009 (free registration required)

Glitazones appear to increase fracture risk in men and women, pioglitazone possibly more so

2009-09-27T19:02:00.000+01:00

A prospective cohort study in patients with type 2 diabetes found that treatment with a thiazolidinedione (glitazone) increased fracture risk in both men and women; pioglitazone appeared to be associated with a greater risk than rosiglitazone.

Observational studies and analysis of clinical trial data indicate that treatment with a glitazone increase the risk of bone fractures in women, however the evidence is still uncertain especially in relation to effects on risk in men. The authors of this study used healthcare data on a large population to study the association between bone fractures and treatment with a glitazone or a sulphonylurea. Their study population was derived from all residents of British Columbia at any time between January 1998 and December 2007 who were registered for healthcare services in the Province. Using prescription data, they identified all users of either a glitazone or a sulphonylurea between January 1996 and December 2007: sulphonylureas were chosen as the comparator because they were, like glitazones, more likely to be used second line. They then obtained data on peripheral and all fractures, and estimated adjusted hazard ratios for fracture in the two user groups.

After general exclusions, the source population was about 4.2 million people; of these, 127,581 began treatment with one of the study drugs during the relevant period, and 84,339 were eligible after exclusion (mainly because of treatment with a drug from the other study group). Average age of the study cohort was 59 years, and 43% were women.

There were 2,214 fractures in the study patients, most (76%) peripheral. Average time to fracture was 1.71, 1.66, and 1.44 patient-years in the sulfonylurea, rosiglitazone, and pioglitazone cohorts respectively.

Compared to those treated with sulphonylureas, patients receiving a glitazone had an increased risk of peripheral fracture (adjusted hazard ratio [HR], 1.28; 95% CI, 1.10 to 1.48) across the group. When the glitazones were examined separately in comparison to sulphonylureas, the risk with rosiglitazone for women was not significant (HR, 1.17; 95% CI, 0.91 to 1.50) whereas that for pioglitazone was (HR, 1.77; 95% CI, 1.32 to 2.38).

Overall fracture risk for men was not significantly different in the glitazone group (HR, 1.20; 95% CI, 0.96 to 1.50), however analysis by individual drug found no significant risk with rosiglitazone (HR, 1.00; 95% CI, 0.75 to 1.34) but a significant increase for pioglitazone (HR, 1.61; 95% CI, 1.18 to 2.20).

The authors conclude that their analysis further supports the association of glitazones with increased risk of fractures in women, and indicates a possible association between pioglitazone use and increased risk in men. They caution, however, that the 95% CI in the subgroup analysis overlap and the association should thus be regarded as a basis for further research rather than a definitive result. Overall, they conclude that glitazone treatment increases fracture risk in both men and women compared to sulphonylureas, and that the effect may be stronger with pioglitazone than with rosiglitazone. Further research is needed to gain greater certainty.

Arch Intern Med 2009; 169: 1395-402 (link to abstract)

Another study shows benefits of healthy lifestyle

2009-09-27T18:59:00.004+01:00

Results from part of a major European study of the effects of diet and lifestyle on chronic illness confirm the benefits of a range of healthy behaviours, showing significant reductions in risks of cancer and cardiovascular disease.

European Prospective Investigation into Cancer and Nutrition (EPIC) is a large (n>500,000, recruited between 1994 and 1998) ongoing study involving ten European countries; it is designed to investigate the relationships between diet, nutritional status, lifestyle and environmental factors and the incidence of cancer and other chronic diseases. This report is from EPIC-Potsdam, which covers the German participants in the study. The authors examined the effects of four potential factors: never smoking, having a body mass index (BMI) lower than 30, performing 3.5 h/wk or more of physical activity, and adhering to healthy dietary principles (high intake of fruits, vegetables, and whole-grain bread and low meat consumption). The 4 factors (healthy, 1 point; unhealthy, 0 points) were summed to form an index that ranged from 0 to 4. Outcomes included confirmed incident type 2 diabetes mellitus, myocardial infarction, stroke, and cancer; mean follow-up was 7.8 years.

There were 27,548 participants originally recruited, of whom 23,153 (8965 men and 14 188 women) were included in the analyses: main reason for exclusion was self-report of diabetes, cardiovascular disease or cancer at baseline (n=3,130). Mean age at baseline was 49.3 years; few had no healthy factors (score 0, 4%) and 9% had all four. Over the follow-up period reported, 2,006 developed an outcome event: despite the small number of individuals with a zero score, enough adverse events occurred in this group to allow reliable evaluation.

After adjustment for confounding factors, the hazard ratio for developing a chronic disease decreased progressively as the number of healthy factors increased. Participants with all 4 factors at baseline had a 78% (95% CI, 72% to 83%) lower risk of developing a chronic disease: compared to those with zero scores, reductions in risk for the specific diseases were diabetes, 93% (95% CI, 88% to 95%), myocardial infarction 81% (95% CI, 47% to 93%), stroke 50% (95% CI, –18% to 79%), and cancer 36% (95% CI, 5% to 57%). Those with intermediate scores had lower risks, with some combinations being more protective than others (e.g. never smoking plus BMI <30: HR 0.28; 95% CI, 0.23 to 0.34).

Overall, the authors conclude that their results confirm the benefits of a healthy lifestyle, and note that adoption of a few healthy behaviours can result in significant reductions in morbidity. They therefore reinforce current recommendations for lifestyles: adherence to all four could produce enormous reductions in the onset of chronic diseases such as diabetes, cardiovascular disease, and cancer.

An accompanying Comment discusses the study.

Arch Intern Med 2009; 169: 1355-62 (link to abstract); Arch Intern Med 2009; 169: 1362-3 (Comment, link to abstract)
Further information on EPIC is available from the study website

Meta-analysis: effects of intensive glucose control on cardiovascular outcomes in type 2 diabetes

2009-09-27T18:59:00.003+01:00

Intensive blood glucose control in patients with type 2 diabetes decreases the risk of some cardiovascular disease (CVD), but does not decrease the risk of death in the medium term and increases the risk for severe hypoglycaemia, according to this systematic review and meta-analysis: recent studies with stringent control suggest an increased risk for cardiovascular death.

Type 2 diabetes is a major risk factor for CVD. Intensive control of blood glucose reduces microvascular complications in people with type 2 diabetes, but its effect on clinical CVD is uncertain. Earlier trials suggested benefits, however later studies found no effect or adverse effects. There were fewer than expected events in later studies, so the authors of this paper carried out a meta-analysis of the available trials to clarify the effects of intensive control on CVD as a whole and on a range of individual clinical outcomes.

They searched the literature using Medline, and experts contacts and reference lists only. Eligible studies were large (>500 participants), randomised controlled trials comparing intensive blood glucose control with conventional treatment in patients with type 2 diabetes, that had clinical CVD as a primary endpoint. From these, they extracted data on all-cause mortality, and CVD mortality, along with coronary heart disease (CHD), congestive heart failure (CHF), and stroke events. Additionally, they recorded single endpoints for fatal and non-fatal myocardial infarction (MI) and strokes, and peripheral artery disease. The main safety outcome was severe hypoglycaemic events. Individual patient data were not obtained.

The initial literature search identified 341 reports, of which 304 were excluded on the basis of title and abstract. From the remaining 37 reports, 5 papers were eligible for analysis (23 duplicate reports, 5 not type 2 diabetes, 2 n<500, and 2 did not include groups of interest). The five eligible studies included 27,802 participants (range 753 to 11,140) and had durations of between 3.4 and 10.7 years. The two earlier studies (UKPD 33 and 34) recruited newly diagnosed patients whereas participants in more recent studies (ADVANCE, ACCORD and VADT) had established diabetes (average duration from 7.9 to 11.5 years).

Analysis of the summary results found that intensive control was associated with a 10% reduction in risk of CVD compared to conventional control (relative risk [RR], 0.90; 95% CI, 0.83 to 0.98). The risk difference (RD, per 1000 patients over 5 years of treatment) for CVD was -15 (95% CI, –24 to –5), and intensively treated patients also had a reduced risk of CHD (RR, 0.89; 95% CI, 0.81 to 0.96; RD, –11; 95% CI, –17 to –5).

Intensive control was associated with a 16% overall reduction in risk of non-fatal MI, however the absolute reduction (i.e. RD) was 9 events per 1000 patients over 5 years of treatment. There were no significant effects on fatal MI, or on fatal or non-fatal stroke, or peripheral artery disease.

Intensive control was not associated with a reduced risk of cardiovascular death (RR, 0.97; 95% CI, 0.76 to 1.24; RD, –3; 95% CI, –14 to 7), nor was it associated with reduced all-cause mortality (RR, 0.98; 95% CI, 0.84 to 1.15; RD, –4; 95% CI, –17 to 10).

Overall, intensive treatment was associated with a doubled risk of severe hypoglycaemia (RR, 2.03; 95% CI, 1.46 to 2.81; RD, 39; 95% CI, 7 to 71), absolute increase of 39 events per 1000 patients over 5 years). Most of this increase came from the three later studies, in which the absolute increase was 54 events per 1000 patients over 5 years.

The authors conclude that in patients with type 2 diabetes, intensive blood glucose control reduces the risk for some CVD, such as non-fatal MI, but does not (over the period studied) reduce cardiovascular or all-cause death. It does, however, double the risk of severe hypoglycaemia. They note that the earlier trials suggested a reduction in cardiovascular death, however the later studies, which had more stringent blood glucose control, suggested an increase. There were significant differences between the trials in the treatments used in both active and control groups, and in the patients recruited. Limitations include use of summary rather than individual patient data, and the short duration of the more recent studies.

Ann Intern Med, published early online 21 July 2009; 151(6) (link to abstract)

Perspective: aggressive blood pressure lowering is of uncertain benefit

2009-09-27T18:59:00.002+01:00

A short ‘News and Perspectives’ piece in JAMA discusses a recently released Cochrane Review that found no evidence to support aggressive blood pressure lowering.

The Review aimed to determine whether aggressive blood pressure targets (≤ 135/85 mmHg) improved clinical outcomes (mortality and serious morbidity) any more than standard targets (≤ 140-160/ 90-100 mmHg). Its authors found no trials comparing systolic targets and seven trials (n=22,089) comparing diastolic targets; primary outcomes for the review were total mortality; total serious adverse events; total cardiovascular events; myocardial infarction, stroke, congestive heart failure and end stage renal disease.

The analysis found that although BP was lower in groups treated to more aggressive targets, there was no significant benefit in any of the outcome measures studied. Because only one trial reported serious adverse effects and withdrawals, the net health effects of aggressive targets could not be assessed. Subgroup analysis in patients with diabetes and patients with chronic renal disease also found no significant benefit: as guidelines are recommending lower targets still for these patients, the authors are currently conducting systematic reviews in these specific patients.

The JAMA article notes that two major guidelines on hypertension treatment are currently under review (European and US), and quotes members of the respective review committees on the new evidence. It also notes that two clinical trials in progress may help to answer some of the questions raised by the review.

JAMA 2009; 302: 1047-8 (link to extract);
Cochrane Review: Cochrane Database Syst Rev. 2009;3:CD004349 (link to abstract)
11Sept2009

Mediterranean-style diet better than low-fat diet in early type 2 diabetes

2009-09-27T18:59:00.001+01:00

In patients with newly diagnosed type 2 diabetes, a low-carbohydrate Mediterranean-style diet improved glycaemic control and reduced the need for drug treatment compared to a high-carbohydrate, low fat diet.

US guidance on initial therapy of type-2 diabetes recommends starting therapy with pharmacotherapy in addition to dietary measures: either low fat, high carbohydrate, or low carbohydrate calorie-restricted diets are recommended, however there have been no direct comparisons of the two types of diet. This study investigated the medium-term efficacy and safety of a low-carbohydrate Mediterranean-style diet containing a high-proportion of unsaturated fat, compared with a standard low-fat, high carbohydrate diet.

Participants were patients newly diagnosed with type 2 diabetes at the diabetic clinic of one Italian university hospital. Eligibility criteria included BMI >25kg/m2, haemoglobin A1c (HbA1c) <11%, minimal physical activity level (<1 hour/week), and stable weight for at least six months. They were randomised to either a low-fat diet (based on American Heart Association guidelines) in which no more than 30% of energy was from fat, or a Mediterranean-style diet with no more than 50% energy from carbohydrates and at least 30% from fat (mainly as olive oil). Both were calorie-controlled (women 1,500 daily, men 1,800 daily). All patients received guidance on increasing their energy levels. Primary outcome was time to initiation of hypoglycaemic drug therapy according to a specified protocol, and planned follow-up was for four years: those who assessed study outcomes were blind to group allocation. Power calculations based on a pilot study indicated a study size of 87 patients per group.

Of 283 patients assessed for eligibility, 215 were randomised to the study (108 to the Mediterranean diet and 107 to the low fat diet); only 20 patients (10 in each group) were lost to follow-up. Average age at baseline was about 52, average BMI just under 30kg/m2, and average HbA1c 7.75% (Mediterranean diet) and 7.71% (low-fat diet). On intention to treat analysis at four years, those in the Mediterranean diet group were significantly less likely to require drug treatment: 44% vs. 70% (absolute difference, –26.0 percentage points; 95% CI, –31.1 to –20.1 percentage points; hazard ratio [HR], 0.63; 95% CI, 0.51 to 0.86).

More patients in the Mediterranean diet group lost weight (absolute difference -2kg; 95% CI -3.0 to -0.9kg): after adjustment for weight loss, the difference in likelihood of requiring drug treatment remained significant (HR 0.70; 95% CI, 0.59 to 0.90; P < 0.001). Reported energy intake and physical activity levels were similar in the two groups. Adverse events were similar in both groups, and one patient died in each group (of causes unrelated to the study).

The authors conclude that in patients with newly diagnosed type 2 diabetes, a Mediterranean-style diet delayed the need for hypoglycaemic drug therapy compared with a high-carbohydrate low fat diet. It was also associated with greater weight loss and some improvements in cardiac risk factors. They note that the study was inevitably only single blind, and that participants received intensive encouragement to continue with the recommended treatment. Nevertheless, they suggest that their study results reinforce the potential benefits of lifestyle intervention in type 2 diabetes.

Ann Intern Med 2009; 151: 306-14 (link to abstract)

Meta-analysis: Aspirin for cardiovascular primary prevention in patients with and without diabetes

2009-09-27T18:58:00.000+01:00

According to a report published early online in Diabetes Care, the relative benefit of aspirin for primary prevention of cardiovascular events is similar in patients with and without diabetes.

This finding comes from a systematic review and meta-analysis, which set out to estimate the efficacy of aspirin for the primary prevention of cardiovascular events among patients with diabetes, and to estimate the extent to which the effect of aspirin differs in patients with and without diabetes.

Nine RCTs of aspirin for primary prevention of cardiovascular events with moderate to high methodological quality were identified. The ratios of relative risks of the benefit of aspirin among patients with diabetes compared to patients without diabetes for the following outcomes were reported:

Mortality: 1.12 (95% CI, 0.92 to 1.35)
Myocardial infarction: 1.19 (0.82 to 1.17)
Ischaemic stroke: 0.70 (0.25 to 1.97)

The researchers conclude “while there are insufficient data among patients with diabetes to conclusively show a benefit of aspirin therapy for the primary prevention of cardiovascular events, our data suggest, but do not confirm, that the relative benefit of aspirin is similar in patients with and without diabetes. Additional evidence from RCTs and individual-patient-data meta-analyses may help to further clarify this issue.”

Diabetes Care, published early online 9 September 2009; doi: 10.2337/dc09-1297 (link to abstract)
11 September 2009

Top Searched Men's Health Topics

2009-09-27T18:45:00.002+01:00

Statistics show that men are more likely to turn to the Internet for information on health topics rather than call a nurse or doctor for advice. Men generally don't like discussing their health issues due to embarrassment.

To help drive awareness to common problems, I decided to find out what the top searched men's health topics are on AOL Search. As you can see from the list below, prostate cancer, urinary tract infections and insomnia are among the top three. Men are also searching for everything from ulcerative colitis to prostatitis to hair loss. They also want to learn more about vasectomies and indigestion.

Is there a health topic that you go online to learn more about? If you think you are experiencing any of these health issues you should see your doctor, but you can also learn more by searching for men's health on AOL Search or going to AOL Health for information.

Top Searched Men's Health Topics on AOL Search:
1. Prostate Cancer
2. Urinary Tract Infection
3. Insomnia
4. Hair Loss
5. Vasectomy
6. Ulcerative Colitis
7. Diabetes
8. Impotence
9. Prostatitis
10. Indigestion

More Sponsored Links For: prostate cancer treatment, insomnia cures, hair loss treatment.

Source:
HOT SEARCHES

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

2007-10-16T18:46:00.001+01:00

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

2007-10-16T18:46:00.000+01:00

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.

2007-10-16T18:26:00.002+01:00

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.

2007-10-16T18:26:00.001+01:00

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.

2007-10-16T18:26:00.000+01:00

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.

2007-10-16T18:18:00.000+01:00

A recent meta-analysis of 42 clinical trialsconcluded that rosiglitazone was associated with an approximately43% increased risk for myocardial infarction and an approximately64% increased risk for cardiovascular death. The sensitivityof these conclusions to several methodological choices was notassessed. The meta-analysis was not based on a comprehensivesearch for all studies that might yield evidence about rosiglitazone’scardiovascular effects. Studies were combined on the basis ofa lack of statistical heterogeneity, despite substantial variabilityin study design and outcome assessment. The meta-analytic approachthat was used required the exclusion of studies with zero eventsin the treatment and control groups. Alternative meta-analyticapproaches that use continuity corrections show lower odds ratiosthat are not statistically significant. The authors of this commentary conclude that therisk for myocardial infarction and death from cardiovasculardisease 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 thosein the original analysis: short follow-up; low event rates; absenceof patient-level data about time to event; variable and probablyincomplete outcome ascertainment; and inability to reliablyassess total mortality rate or composite outcomes, such as deathor myocardial infarction. Neither analysis is a comprehensivesystematic summary of all available evidence about the potentialcardiovascular risks of rosiglitazone. Only prospective clinical trialsdesigned for the specific purpose of establishing the cardiovascularbenefit or risk of rosiglitazone will resolve the controversyabout its safety. They conclude that the available evidence does notjustify 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.

2007-10-16T18:02:00.004+01:00

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

2007-10-16T18:02:00.003+01:00

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

Data were collected from Womenin the Pregnancy Exposures and Preeclampsia Prevention Study(1997–2001) who had reported their regular multivitaminuse 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 witha reduced risk of preterm births (<> (OR) = 0.29, 95% CI: 0.13 to 0.64) and spontaneouspreterm births (<>

There was a trend towards a lower risk of SGA (<> 0.64: 0.40 to 1.03).
There wasno effect of multivitamin use on risk of preterm births (34 to <> weeks) or SGA (5^th to <>
Sensitivityanalysis for unmeasured confounding by folate intake supportedthese findings.

The authors of the study suggest from these preliminary findings that “periconceptionalvitamin use is associated with lower rates of severepreterm births and extreme SGA.” However they stress that these data should be considered cautiouslyuntil 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.

2007-10-16T18:02:00.002+01:00

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

2007-10-16T18:02:00.001+01:00

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

2007-10-16T18:02:00.000+01:00

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

2007-10-16T17:46:00.000+01:00

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.

2007-10-16T17:19:00.001+01:00

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?

2007-10-16T17:19:00.000+01:00

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

2007-10-16T16:29:00.000+01:00

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.

2007-10-16T16:12:00.004+01:00

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

2007-10-16T16:12:00.003+01:00

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

2007-10-16T16:12:00.002+01:00

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

2007-10-16T16:12:00.001+01:00

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)

2007-10-16T16:12:00.000+01:00

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.

2007-10-16T15:43:00.002+01:00

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.

2007-10-16T15:43:00.001+01:00

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?

2007-10-16T15:43:00.000+01:00

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

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

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

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

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

2007-05-21T09:01:00.003+01:00

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.

2007-05-21T09:01:00.001+01:00

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

2007-05-21T09:01:00.000+01:00

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

2007-05-18T19:20:00.000+01:00

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

2007-05-17T09:26:00.004+01:00

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

2007-05-17T09:26:00.003+01:00

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

2007-05-17T09:26:00.002+01:00

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.

2007-05-17T09:26:00.001+01:00

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.

2007-05-17T09:26:00.000+01:00

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

2007-05-16T10:20:00.001+01:00

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?

2007-05-16T10:20:00.000+01:00

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?

2007-05-16T09:43:00.000+01:00

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.

2007-05-15T08:37:00.001+01:00

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.

2007-05-15T08:37:00.000+01:00

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?

2007-05-14T16:07:00.000+01:00

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.

2007-05-14T15:51:00.011+01:00

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.

2007-05-14T15:51:00.010+01:00

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

2007-05-14T15:51:00.009+01:00

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

2007-05-14T15:51:00.008+01:00

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.

2007-05-14T15:51:00.007+01:00

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.

2007-05-14T15:51:00.006+01:00

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.

2007-05-14T15:51:00.005+01:00

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

2007-05-14T15:51:00.004+01:00

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.

2007-05-14T15:51:00.003+01:00

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?

2007-05-14T15:51:00.002+01:00

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?

2007-05-14T15:51:00.001+01:00

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

2007-05-14T15:26:00.000+01:00

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

2007-05-14T15:10:00.005+01:00

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

2007-05-14T15:10:00.004+01:00

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?

2007-05-14T15:10:00.003+01:00

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.

2007-05-14T15:10:00.002+01:00

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

2007-05-14T15:10:00.001+01:00

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?

2007-05-14T15:10:00.000+01:00

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

2007-05-03T08:46:00.000+01:00

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

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

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

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

2007-04-30T17:59:00.000+01:00

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

2007-04-30T17:42:00.002+01:00

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

2007-04-30T17:42:00.001+01:00

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)

Review: Assessment and management of severe asthma in adults in hospital

2007-04-30T17:42:00.000+01:00

Review: Assessment and management of severe asthma in adults in hospital

The fifth instalment of a series of review articles on acute asthma exacerbations has been published in Thorax. This review covers the assessment and management of severe asthma in adults in hospital, under the following headings:

History

Clinical examination

Assessment (lung function tests, oxygen assessment and other tests)

Management (oxygen, NIPPV, inhaled bronchodilators, intravenous bronchodilators, systemic corticosteroids, inhaled corticosteroids)

Response to treatment

ICU transfer

Ward admission

Discharge arrangements

Assessment sheets and treatment protocols

The authors note the following key points:

The management of asthma in the emergency department can be improved through the use of simple assessment and treatment protocols.

Assessment of asthma severity should be based primarily on the measurement of FEV1, expressed as the percentage of normal predicted values.

For most patients, initial treatment with high-flow oxygen, nebulised beta-agonists and oral corticosteroids is sufficient.

Currently available evidence does not support the routine use of intravenous theophylline or intravenous beta-agonist treatment in acute asthma; magnesium is the preferred intravenous bronchodilator in life-threatening asthma.

Patients with any feature of a severe attack persisting after initial treatment should be admitted; patient circumstances should also be considered.

For patients who are discharged, long-term management should be reviewed and medical follow-up arranged.

Thorax 2007; 62: 447-58 (link to abstract)

Anti-secretory agents - especially PPI - and nitrates reduce NSAID-associated GI bleeding

2007-04-25T19:22:00.000+01:00

Anti-secretory agents - especially PPI - and nitrates reduce NSAID-associated GI bleeding

A large epidemiological study suggests that anti-secretory drugs reduce the risk of gastro-intestinal bleeding in patients taking NSAID, as do nitrates, however proton-pump inhibitors (PPI are much the most effective. The authors note that gastro-intestinal bleeding is a major risk with NSAID therapy, a problem for which various strategies are suggested. Use of COX-2 selective agents has been recommended, however drug withdrawals and reported cardiovascular problems with this group has reduced their popularity. Misoprostol has proven benefit, but is poorly tolerated by many people. Anti-secretory agents are widely used, but the evidence for their protective effects is weaker, and some experimental work suggests that organic nitrates may have clinically useful benefit.

This study was carried out to determine which agents were effective in reducing the risk of upper GI peptic ulcer bleeds associated with nonselective NSAIDs, aspirin and other antiplatelet agents, and anticoagulants. It was a case-control study, with prospective case determination and retrospective data collection, carried out during 2001 to 2004 and using data collected from Spanish hospital associated with a gastroenterology network. Cases were adults hospitalised with confirmed upper GI peptic ulcer bleeding: each case was matched with two controls by age, hospital and admission month, admitted or seen in outpatients for any condition not related to NSAID use, any GI bleeding, and cardiovascular or joint diseases. Cases and controls were classified as having a history of ulcer, dyspepsia, or neither. Current relevant drug use included NSAID, aspirin or other antiplatelet drugs, anticoagulants, PPI, histamine-2 receptor antagonists, and any nitrate.

A total of 2,777 patients were matched with 5,532 controls. Unsurprisingly, use of NSAID (including aspirin) was associated with increased risk of peptic ulcer bleeding, as was use of antiplatelet agents and anticoagulants. PPI, histamine-2 blockers, and nitrates all reduced the risk of peptic ulcer bleeding, with relative risks compare to non-use of 0.33, 0.65, and 0.52 respectively. Use of PPI was associated with greatest risk reductions for NSAID and antiplatelet drugs, however no agent reduced the risk with oral anticoagulants. There was no difference between omeprazole and other PPI.

Based on their analysis, the authors conclude that all three drug groups - PPI, histamine-2 blockers, and nitrates - reduce the risk of peptic ulcer bleeding in patients taking NSAID and antiplatelet drugs. PPI, however, gave the most marked and consistent reduction in risk. None of the drugs studied reduce the risk associated with oral anticoagulants.

Am J Gastroenterol 2007;102:507-15 (link to abstract); from Reuters Health for 25th April 2007, via Medscape (free registration required)

Follow-up, and continuity of care important in ensuring medication adherence

2007-04-24T18:13:00.000+01:00

Follow-up, and continuity of care important in ensuring medication adherence

Patients who stop taking statins are more likely to re-start if they have good follow-up and they see the same doctor who originally prescribed for them, according to a study published today. The authors note that adherence to prescribed statins is relatively poor, with many patients stopping them within a year of initiation. They therefore attempted to determine some of the factors that result in patients re-starting treatment using a case-crossover study design.

Data on new users of a statin were obtained from healthcare databases in British Columbia, Canada, Medication dispensing for these individuals was then followed to determine those who became non-adherent, defined as 90 days from finishing one supply to having a new one dispensed. These individuals were then followed to determine what factors prompted re-starting statin use.

Between January 1997 and June 2004, a total of 253,951 patients were started on a statin. After exclusions (mainly those started on cerivastatin), there were 239,911 studied. Of these, over half had (129,167, 53.8%) had a period of non-adherence that lasted for at least 90 days. About half of these (48%) restarted within a year of stopping, and 60% within two years. The factor most strongly associated with re-starting was, perhaps not surprisingly, incident MI - the odds ratio for re-starting after MI was 12.2 (95% CI, 8.9-16.9) - although the number of actual events was small. Numerically, the most frequent factor was visiting any doctor (OR, 2.9; 95% CI, 2.8-3.0), and visiting the doctor who started the statin was the second-strongest factor (OR 6.1; 95% CI, 5.9-6.3). Having a cholesterol test and hospital admission for any other cardiovascular condition were also factors.

The authors conclude that patients frequently interrupt statin use, with long periods of non-adherence. The most important factor in re-starting use is visiting the doctor who originally started the therapy, especially when the visit is combined with a cholesterol test. The message therefore, is that regular follow-up and continuity of care are major factors likely to improve long-term adherence to statins.

Arch Intern Med 2007; 167: 847-52 (link to abstract)

Dietary sodium reduction seems to reduce cardiovascular events long term

2007-04-23T16:03:00.000+01:00

Dietary sodium reduction seems to reduce cardiovascular events long term

According to the findings of this long term follow up study, sodium reduction, previously shown to lower blood pressure, may also reduce long term risk of cardiovascular events. The study followed up participants in two randomised lifestyle intervention trials - the trials of hypertension prevention I (TOHP I) and II (TOHP II) - for subsequent cardiovascular outcomes. The original trials found small but significant direct effects of sodium reduction on reducing blood pressure in adults with high normal blood pressure. TOHP I involved 10 clinic sites between 1987-90 and TOHP II involved 9 sites between 1990-5.

In this study, the authors determined the long term effects, over a period of 10-15 years, of sodium reduction on cardiovascular disease and mortality. Data was collected on all events occurring since the end of the original trials. A co-ordinating centre conducted the follow-up centrally by mail and phone. Questionnaires (seeking detailed information on cardiovascular and other health outcomes) were posted in January 2000, followed by phone calls as needed. Additional questionnaires were sent to responders at two year intervals through early 2005. The primary outcome measure used in the study was cardiovascular disease, a composite of myocardial infarction, stroke, coronary artery bypass graft (CABG), percutaneous transluminal coronary angioplasty (PTCA), or death with a cardiovascular cause. In the original studies, 744 participants in TOHP I and 2382 in TOHP II were randomised to a sodium reduction intervention or control.

The results found:

Follow-up information on cardiovascular outcomes or death was obtained for 2415 participants (77%).
200 participants reported a cardiovascular event. Risk of a cardiovascular event was 25% lower among those in the intervention group (relative risk 0.75, 95% confidence interval 0.57 to 0.99, P=0.04), adjusted for trial, clinic, age, race, and sex
The risk was 30% lower after further adjustment for baseline sodium excretion and weight (0.70, 0.53 to 0.94), with similar results in each trial.
In secondary analyses, it was found 67 of the total 3126 participants died; 35 in the intervention groups and 42 in the comparison groups. After adjustment for baseline characteristics, including weight and sodium excretion, there was a 20% lower mortality among those in the sodium reduction intervention (0.80, 0.51 to 1.26, P=0.34 – not significant).

The authors note limitations of their study, including the lack of direct measurement of blood pressure, weight, and sodium intake during follow-up. They also note the less than complete rate of follow up, although add that the rates were high (77% for morbidity and 100% for mortality).

[Editor's note: to add perspective, the relative reduction in cardiovascular events is similar to that associated with statins - but with no significant adverse effects. Applied across the whole population, the absolute risk reduction would be small, nevertheless because of the numbers involved the reduction in cardiovascular events would be large. A modelling paper published last October looked at this issue and gives an indication of the potential differences between interventions in populations and interventions in at-risk individuals.]

Br Med J, published early online 20 April 2007; doi:10.1136/bmj.39147.604896.55 (link to abstract)

Delivering Diabetes care in Africa

2007-04-23T14:12:00.000+01:00

Delivering diabetes care in Africa

Diabetes is a difficult disease to treat even with the best drugs and support, and in most parts of Africa the problems are enormous. Even regular supplies of insulin are often difficult to maintain. The range of tablets is limited, and self-monitoring equipment absent. Specialist doctors are few, as are nurse educators, chiropodists, and dieticians. Glycosylated haemoglobin (HbAlc) – ‘the gold standard’ test for overall glycaemic control – is usually too difficult and expensive to provide, and specialist services for complications are well beyond health budget capabilities, (e.g. laser photocoagulation, dialysis, and

Unsurprisingly, most people with diabetes in the African continent rely on rudimentary services from local doctors or nurses, or, if they are fortunate, may be able to access a Diabetic Clinic - usually only available at major teaching centres. Even at these hospitals, the services offered are severely hampered by the shortages described above.

There have, however, been recent attempts to improve Diabetes care delivery in some parts of Africa by a variety of partnership projects, eg. The London-based Tropical Health and Education Trust (THET) has been supporting devolved care of diabetes, and other non-communicable diseases, in the Gondar area of Ethiopia. In South Africa, the Liverpool School of Tropical Medicine has been linking with Hlabisa Hospital in Kwazulu Natal to promote nurse-led protocol-based diabetes care at both central and primary health clinic (PHC) levels.

In a recent issue of the British Medical Journal, Kaushik Ramaiya reports on a larger and more ambitious diabetes care delivery system from Tanzania. External support has been provided mostly by Novo Nordisk’s World Partnership Programme, but the Tanzanian Ministry of Health has also given help. Diabetes clinics have been established in all major hospitals in the country, as well as on the offshore islands of Zanzibar and Pemba. The Tanzanian Diabetes Association has also played a major part in the reorganisation, including the establishment of healthcare worker training programmes.

Ramaiya points out that current predictions suggest that within the next 20 v-ears non-communicable disease mortality will exceed infective deaths. The setting up of appropriate and efficient diabetes care delivery systems now will help to combat this growing problem.

Ref:
African Health: Medicine Review – Delivering Diabetes care in Africa. Medical Education Resource Africa MERA, May 2005, p.25.
Ramaiya K. Tanzania and Diabetes – a model for developing countries?
British Med J 2005; 330: 679.

Asthma (3)

2007-04-19T17:12:00.001+01:00

Asthma - Epidemiology

Asthma is usually diagnosed in childhood. The risk factors for asthma include:

a personal or family history of asthma or atopy;
triggers (see Asthma Pathophysiology);
premature birth or low birth weight;
viral respiratory infection in early childhood;
maternal smoking;
being male, for asthma in prepubertal children; and
being female, for persistence of asthma into adulthood.

There is a reduced occurrence of asthma in people who were breast-fed as babies. Current research suggests that the prevalence of childhood asthma has been increasing. According to the Centers for Disease Control and Prevention 's National Health Interview Surveys, some 9% of US children below 18 years of age had asthma in 2001, compared with just 3.6% in 1980. The World Health Organization (WHO) reports that some 8% of the Swiss population suffers from asthma today, compared with just 2% some 25–30 years ago. Although asthma is more common in affluent countries, it is by no means a problem restricted to the affluent; the WHO estimate that there are between 15 and 20 million asthmatics in India. In the U.S., urban residents, Hispanics, and African Americans are affected more than the population as a whole. Globally, asthma is responsible for around 180,000 deaths annually.

On the island Tristan da Cunha , 50% of the population are asthmatics due to heredity transmission of a mutation in the gen CC16.

Socioeconomic factors

The incidence of asthma is higher among low-income populations, which in the western world are disproportionately minority, and more likely to live near industrial areas. Additionally, asthma has been strongly associated with the presence of cockroaches in living quarters, which is more likely in such neighbourhoods.

The quality of asthma treatment varies along racial lines, likely because many low-income people cannot afford health insurance and because there is still a correlation between class and race. For example, black Americans are less likely to receive outpatient treatment for asthma despite having a higher prevalence of the disease. They are much more likely to have emergency room visits or hospitalization for asthma, and are three times as likely to die from an asthma attack compared to whites. The prevalence of "severe persistent" asthma is also greater in low-income communities compared with communities with better access to treatment.

Asthma and athletics

Asthma appears to be more prevalent in athletes than in the general population. One survey of participants in the 1996 Summer Olympic Games showed that 15% had been diagnosed with asthma, and that 10% were on asthma medication. These statistics have been questioned on at least two bases. Persons with mild asthma may be more likely to be diagnosed with the condition than others because even subtle symptoms may interfere with their performance and lead to pursuit of a diagnosis. It has also been suggested that some professional athletes who do not suffer from asthma claim to do so in order to obtain special permits to use certain performance-enhancing drugs.

There appears to be a relatively high incidence of asthma in sports such as cycling, mountain biking, and long-distance running , and a relatively lower incidence in weightlifting and diving. It is unclear how much of these disparities are from the effects of training in the sport, and from self-selection of sports that may appear to minimize the triggering of asthma.

In addition, there exists a variant of asthma called exercise-induced asthma that shares many features with allergic asthma. It may occur either independently, or concurrent with the latter. Exercise studies may be helpful in diagnosing and assessing this condition.

Thank you.

Asthma (2)

2007-04-19T17:12:00.000+01:00

Asthma

Asthma is a disease of the respiratory system in which the airways constrict, become inflamed, and are lined with excessive amounts of mucus, often in response to one or more "triggers," such as exposure to an environmental stimulant (or allergen ), cold air, exercise , or emotional stress. In children, the most common triggers are viral illnesses such as those that cause the common cold. This airway narrowing causes symptoms such as wheezing, shortness of breath , chest tightness, and coughing, which respond to bronchodilators. Between episodes, most patients feel fine.

Asthma - Diagnosis

In most cases, a physician can diagnose asthma on the basis of typical findings in a patient's clinical history and examination. Asthma is strongly suspected if a patient suffers from eczema or other allergic conditions—suggesting a general atopic constitution —or has a family history of asthma. While measurement of airway function is possible for adults, most new cases are diagnosed in children who are unable to perform such tests. Diagnosis in children is based on a careful compilation and analysis of the patient's medical history and subsequent improvement with an inhaled bronchodilator medication. In adults, diagnosis can be made with a peak flow meter (which tests airway restriction), looking at both the diurnal variation and any reversibility following inhaled bronchodilator medication .

Testing peak flow at rest (or baseline) and after exercise can be helpful, especially in young asthmatics who may experience only exercise-induced asthma. If the diagnosis is in doubt, a more formal lung function test may be conducted. Once a diagnosis of asthma is made, a patient can use peak flow meter testing to monitor the severity of the disease.

Differential diagnosis

Before diagnosing someone as asthmatic, alternative possibilities should be considered. A physician taking a history should check whether the patient is using any known bronchoconstrictors (substances that cause narrowing of the airways, e.g., certain anti-inflammatory agents or beta-blockers).

Chronic obstructive pulmonary disease , which closely resembles asthma, is correlated with more exposure to cigarette smoke, an older patient, less symptom reversibility after bronchodilator administration (as measured by spirometry ), and decreased likelihood of family history of atopy.

Pulmonary aspiration , whether direct due to dysphagia (swallowing disorder) or indirect (due to acid reflux), can show similar symptoms to asthma. However, with aspiration, fevers might also indicate aspiration pneumonia . Direct aspiration (dysphagia) can be diagnosed by performing a Modified Barium Swallow test and treated with feeding therapy by a qualified speech therapist . If the aspiration is indirect (from acid reflux) then treatment directed at this is indicated.

Only a minority of asthma sufferers have an identifiable allergy trigger. The majority of these triggers can often be identified from the history; for instance, asthmatics with hay fever or pollen allergy will have seasonal symptoms, those with allergies to pets may experience an abatement of symptoms when away from home, and those with occupational asthma may improve during leave from work. Occasionally, allergy tests are warranted and, if positive, may help in identifying avoidable symptom triggers.

After pulmonary function has been measured, radiological tests, such as a chest X-ray or CT scan , may be required to exclude the possibility of other lung diseases. In some people, asthma may be triggered by gastroesophageal reflux disease , which can be treated with suitable antacids . Very occasionally, specialized tests after inhalation of methacholine - or, even less commonly, histamine — may be performed.

Asthma is categorized by the NIH Heart Lung and Blood Institute as falling into one of four categories: mild intermittent, mild persistent, moderate persistent and severe persistent. The diagnosis of "severe persistent asthma" occurs when symptoms are continual with frequent exacerbations and frequent nighttime symptoms, result in limited physical activity and when lung function as measured by PEV or FEV1 tests is less than 60% predicted with PEF variability greater than 30%.

Asthma - Pathophysiology

Bronchoconstriction

During an asthma episode, inflamed airways react to environmental triggers such as smoke, dust, or pollen. The airways narrow and produce excess mucus , making it difficult to breathe.

In essence, asthma is the result of an abnormal immune response in the bronchial airways. The airways of asthmatics are " hypersensitive " to certain triggers, also known as stimuli. In response to exposure to these triggers, the bronchi (large airways) contract into spasm (an "asthma attack"). Inflammation soon follows, leading to a further narrowing of the airways and excessive mucus production, which leads to coughing and other breathing difficulties.

There are seven categories of stimuli:

allergens , typically inhaled, which include waste from common household insects, such as the house dust mite and cockroach , grass pollen , mould spores and pet epithelial cells;
medications , including aspirin and ß-adrenergic antagonists (beta blockers);
air pollution , such as ozone , nitrogen dioxide , and sulfur dioxide , which is thought to be one of the major reasons for the high prevalence of asthma in urban areas;
various industrial compounds and other chemicals, notably sulfites; chlorinated swimming pools generate chloramines —monochloramine (NH 2 Cl), dichloramine (NHCl 2) and trichloramine (NCl 3)—in the air around them, which are known to induce asthma.
early childhood infections, especially viral respiratory infections. However, persons of any age can have asthma triggered by colds and other respiratory infections even though their normal stimuli might be from another category (e.g. pollen) and absent at the time of infection.
exercise, the effects of which differ somewhat from those of the other triggers; and
emotional stress, which is poorly understood as a trigger.

Bronchial inflammation

The mechanisms behind allergic asthma—i.e., asthma resulting from an immune response to inhaled allergens —are the best understood of the causal factors. In both asthmatics and non-asthmatics, inhaled allergens that find their way to the inner airways are ingested by a type of cell known as antigen presenting cells, or APCs. APCs then "present" pieces of the allergen to other immune system cells. In most people, these other immune cells ( T H 0 cells ) "check" and usually ignore the allergen molecules. In asthmatics, however, these cells transform into a different type of cell (T H 2), for reasons that are not well understood. The resultant T H 2 cells activate an important arm of the immune system, known as the humoral immune system . The humoral immune system produces antibodies against the inhaled allergen. Later, when an asthmatic inhales the same allergen, these antibodies "recognize" it and activate a humoral response . Inflammation results: chemicals are produced that cause the airways to constrict and release more mucus, and the cell-mediated arm of the immune system is activated. The inflammatory response is responsible for the clinical manifestations of an asthma attack. The following section describes this complex series of events in more detail.

Pathogenesis

The fundamental problem in asthma appears to be immunological : young children in the early stages of asthma show signs of excessive inflammation in their airways. Epidemiological findings give clues as to the pathogenesis : the incidence of asthma seems to be increasing worldwide, and asthma is now very much more common in affluent countries.

In 1968 Andor Szentivanyi first described The Beta Adrenergic Theory of Asthma; in which blockage of the Beta-2 receptors of pulmonary smooth muscle cells causes asthma. Szentivanyi's Beta Adrenergic Theory is a citation classic [10] and has been cited more times than any other article in the history of the Journal of Allergy.

In 1995 Szentivanyi and colleagues demonstrated that IgE blocks Beta2 receptors. Since overproduction of IgE is central to all atopic diseases, this was a watershed moment in the world of Allergy.

The Beta-Adrenergic Theory has been cited in the scholarship of such noted investigtors as Richard Lockey (former President of The American Academy of Allergy, Asthma, and Immunology), Charles Reed (Chief of Allergy at Mayo Medical School), and Craig Venter (Human Genome Project).

One theory of pathogenesis is that asthma is a disease of hygiene. In nature, babies are exposed to bacteria and other antigens soon after birth, "switching on" the T H 1 lymphocyte cells of the immune system that deal with bacterial infection. If this stimulus is insufficient—as it may be in modern, clean environments—then T H 2 cells predominate, and asthma and other allergic diseases may develop. This " hygiene hypothesis " may explain the increase in asthma in affluent populations. The T H 2 lymphocytes and eosinophil cells that protect us against parasites and other infectious agents are the same cells responsible for the allergic reaction. In the developed world, these parasites are now rarely encountered, but the immune response remains and is wrongly triggered in some individuals by certain allergens.

Another theory is based on the correlation of air pollution and the incidence of asthma. Although it is well known that substantial exposures to certain industrial chemicals can cause acute asthmatic episodes, it has not been proven that air pollution is responsible for the development of asthma. In Western Europe , most atmospheric pollutants have fallen significantly over the last 40 years, while the prevalence of asthma has risen.

Finally, it has been postulated that some forms of asthma may be related to infection, in particular by Chlamydia pneumoniae . This issue remains controversial, as the relationship is not borne out by meta-analysis of the research. The correlation seems to be not with the onset, but rather with accelerated loss of lung function in adults with new onset of non-atopic asthma. One possible explanation is that some asthmatics may have altered immune response that facilitates long-term chlamydia pneumonia infection.] The response to targeting with macrolide antibiotics has been investigated, but the temporary benefit reported in some studies may reflect just their anti-inflammatory activities rather than their antimicrobic action.

Asthma and Sleep Apnea

It is recognized with increasing frequency, that patients who have both obstructive sleep apnea (OSA) and bronchial asthma, often improve tremendously when the sleep apnea is diagnosed and treated. Individuals who have OSA have repetitive episodes of upper airway closure during sleep. Upper airway clossure results in low arterial oxygen levels and CO 2 retention, both of which stimulate the respiratory center. The patient makes increasingly stronger efforts to breathe, which only worsens the upper airway collapse ("like sucking a thick milkshake through a straw"). When the patient starts arousing and the pharyngeal muscles recover their tone, the airway suddenly opens up, airflow is suddenly restored (manifested as a loud "heroic" gasping breath), during which contents of the oropharynx may be aspirated. If gastro-esophageal reflux disease is present, the patient may have repetitive episodes of acid aspiration, which results in airway inflammation and "irritant-induced" asthma.

Treatment, Epidemiology.

To be continued . . .

Asthma

2007-04-19T16:54:00.002+01:00

Asthma

Asthma

The Asthma disorder is a chronic or recurring inflammatory condition in which the airways develop increased responsiveness to various stimuli, characterized by bronchial hyper-responsiveness, inflammation, increased mucus production, and intermittent airway obstruction. The symptoms of asthma, which can range from mild to life threatening, can usually be controlled with a combination of drugs and lifestyle changes.

Public attention in the developed world has recently focused on asthma because of its rapidly increasing prevalence, affecting up to one in four urban children. Susceptibility to asthma can be explained in part by genetic factors, but no clear pattern of inheritance has been found. Asthma is a complex disease that is influenced by multiple genetic, developmental, and environmental factors, which interact to produce the overall condition.

Asthma - Symptoms

In some individuals, asthma is characterized by chronic respiratory impairment. In others it is an intermittent illness marked by episodic symptoms that may result from a number of triggering events, including upper respiratory infection, airborne allergens, and exercise.

An acute exacerbation of asthma is referred to as an asthma attack. The clinical hallmarks of an attack are shortness of breath ( dyspnea ) and wheezing. Although the latter is "often regarded as the sine qua non of asthma," some victims present primarily with coughing, and in the late stages of an attack, air motion may be so impaired that no wheezing may be heard. When present the cough may sometimes produce clear sputum. The onset may be sudden, with a sense of constriction in the chest, breathing becomes difficult, and wheezing occurs (primarily upon expiration, but can be in both respiratory phases).

Signs of an asthmatic episode are wheezing, rapid breathing ( tachypnea ), prolonged expiration, a rapid heart rate ( tachycardia ), rhonchous lung sounds ( audible through a stethoscope ), and over-inflation of the chest. During a serious asthma attack, the accessory muscles of respiration (sternocleidomastoid and scalene muscles of the neck) may be used, shown as in-drawing of tissues between the ribs and above the sternum and clavicles , and the presence of a paradoxical pulse (a pulse that is weaker during inhalation and stronger during exhalation). During very severe attacks, an asthma sufferer can turn blue from lack of oxygen, and can experience chest pain or even loss of consciousness. Severe asthma attacks may lead to respiratory arrest and death. Despite the severity of symptoms during an asthmatic episode, between attacks an asthmatic may show few signs of the disease.

Diagnosis, Pathophysiology, Treatment, Epidemiology.

To be continued. . .

Omeprazole before endoscopy beneficial in patients with gastrointestinal bleeding

2007-04-19T16:54:00.001+01:00

Omeprazole before endoscopy beneficial in patients with gastrointestinal bleeding

A study published in the New England Journal of Medicine has evaluated the effect of pre-emptive infusion of omeprazole before endoscopy on the need for endoscopic therapy.

Over a 17-month period, consecutive patients admitted with upper GI bleeding were stabilised and then randomised to omeprazole 80-mg IV bolus followed by 8mg/hour infusion (n= 319) or matching placebo (n= 319) before endoscopy the next morning.

The following findings were reported:

Need for endoscopic treatment was lower in the omeprazole compared with placebo group (60 of 314 patients included in analysis [19.1%] vs. 90 of 317 patients [28.4%], p = 0.007).
There were no significant differences between the omeprazole and placebo group in:
mean amount of blood transfused (1.54 and 1.88 units)
number of patients who had recurrent bleeding (11 and 8),
number who underwent emergency surgery (3 and 4),
number who died within 30 days (8 and 7)
Hospital stay was < p =" 0.005).">
On endoscopy, fewer patients on omeprazole had actively bleeding ulcers (12 of 187, vs. 28 of 190 in the placebo group; p = 0.01) and more omeprazole-treated patients had ulcers with clean bases (120 vs. 90, p = 0.001).

The study concluded “infusion of high-dose omeprazole before endoscopy accelerated the resolution of signs of bleeding in ulcers and reduced the need for endoscopic therapy.”

N Engl J Med 2007; 356: 1631-40 (link to abstract)

HRT and the incidence of ovarian and breast cancer

2007-04-19T16:54:00.000+01:00

HRT and the incidence of ovarian and breast cancer

Two major epidemiological studies published today look at the possible increased risk of ovarian and breast cancers associated with hormone replacement therapy (HRT). They have, inevitably, generated significant media interest.

A study published early online by the Lancet found that current use of HRT for prolonged periods is associated with a 20% increase in risk of ovarian cancer. The authors used data from the Million Women Study, a large prospective cohort study of UK women aged 50 and over that is investigating a range of factors that affect women's health. Data collected at recruitment includes whether the woman is using HRT, confirmed by subsequent questionnaire three years later if possible. Each participant is followed-up for death, emigration, or cancer registration, so that relevant events are reported to the study investigators.

This analysis aimed to determine whether use of HRT affected risk of ovarian cancer; it involved women from the cohort who were post-menopausal, had no history of cancer or bilateral oophorectomy, and for whom data on use of HRT was available. They were followed for averages of 5.3 years for incident ovarian cancer and 6.9 years for death. Primary outcome of the analysis was relative risk for ovarian cancer, adjusted for a range of relevant factors.

A total of 1.3 million women were recruited into the Million Women Study cohort. Of these, 948, 576 were included in the analysis. When they last reported data to the study, 50% reported current or past use of HRT - 30% were current users and 20% past users: the two groups were fairly similar with only past use of oral contraceptives and hysterectomy being major differences between them (both higher in HRT users). Mean duration of use was 7.7 years.

There were 2,273 ovarian cancers in total and 1,591 deaths from ovarian cancer. Women who were current users of HRT had a statistically significant increase in risk both of ovarian cancer (relative risk 1.20, 95% CI 1.09 to 1.32; p=0.0002) and death from ovarian cancer (RR 1.23, 95% CI 1.09 to 1.32; p=0.0002). Risk increased with duration of use, however past users were not at significantly increased risk. Crude incidence rate in the study population as a whole was 2.2 per 1,000 women; in never-users it was 2.2 per 1,000, and in users 2.6 per 1000 (rates for death from ovarian cancer 1.3, 1.3, and 1.6 per 1,000 respectively). From these figures, assuming that the differences are due to HRT the authors calculate that over a five year period there would be about one extra case of ovarian cancer for every 2,500 users (and one extra death per 3,300 users).

The authors conclude that women who use HRT are at greater risk of ovarian cancer and of death due to it. The risk increases with duration of use: mean duration of use in the study population was 7.7 years and this was associated with a 20% increase in risk. It is related to current use, not past use, and falls back to baseline level soon after use is stopped. An accompanying Comment discusses the paper and its implications; the author discusses some potential mechanisms for the effect, and notes the difference between pre-menopausal use of the same hormones as oral contraceptives, which is protective, and the data on HRT. He notes that although the absolute increase in risk is small, the large number of women who used HRT until recently meant that the toll in terms of cancers and mortality was significant.

The second paper reports that the rate of breast cancer in the US fell appreciably in 2003 compared to the rate in 2002; while a number of explanations are possible, the decrease seems to be related to reporting of results from the Women's Health Initiative in 2002 that was followed by a decrease in HRT use among post-menopausal women in the US.
The authors use data from a program (SEER) run by the US National Cancer Institute: this collects data from nine cancer registries reporting on 9% of the total US population. Data from the registries were adjusted for reporting delays and standardised to the US female population in 2000. Annual incidence rates were plotted and compared to determine trends.

The results show a sharp fall in incidence of 6.7% in 2003 compared to 2002; the incidence stabilised in 2004 with little further decrease. Analysis showed that the decrease actually started in mid-2002 and had begun to level off by mid-2003, and comparison between 2001 and 2004 showed an overall decrease of 8.6% (95% CI 6.8 to 10.4%). The decrease was age-specific and occurred only in women aged over 50; there was no significant change in incidence in younger women. It was also primarily in oestrogen-receptor positive tumours. Examination of trends since 1975 showed a steady increase in women aged over 50 from the late 1970's onwards, with rates rising by about 0.5% per year during most of the 1990's. Rates in women under 50 were substantially the same over the whole of this period.

The authors discuss a number of possible reasons for the changed incidence, but conclude that reductions in HRT use are the most likely. There is evidence that stopping HRT may cause clinically occult oestrogen-receptor positive breast cancers to stop growing or even regress soon after withdrawal, and evidence of studies involving hormonal manipulation therapies (e.g. tamoxifen) supports this. HRT prescriptions in the US declined sharply during 2002 and 2003 and stabilised at a lower level in 2004, from around 60 million to 21 million prescriptions per year.

The MHRA has issued a statement on the two papers. The new evidence is being reviewed by experts, but is unlikely to result in major changes in current advice: this is that HRT is effective for short-term relief of menopausal symptoms but should be used in the lowest effective dose and the minimum duration.

Ovarian cancer study: Lancet, published early online 19 April 2007; DOI:10.1016/S0140-6736(07)60534-0 (link to abstract) and Lancet, published early online 19 April 2007; DOI:10.1016/S0140-6736(07)60535-2 (Comment; link to full text, may be available to subscribers only);
breast cancer study: New Engl J Med 2007; 356: 1670-4 (link to abstract, full text available free at time of posting)
The MHRA statement is available here
BBC News report;
there is full information on the Million Women Study on its website

Moderate-dose methylprednisolone effective for severe adult respiratory distress syndrome?

2007-04-19T16:20:00.001+01:00

Moderate-dose methylprednisolone effective for severe adult respiratory distress syndrome?

According to the results of a randomised controlled trial (RCT) reported in the journal ‘Chest’, the use of early, moderate-dose, prolonged methylprednisolone therapy successfully down-regulates systemic inflammation, reduces organ dysfunction and improves outcome of patients with severe adult respiratory distress syndrome (ARDS).
The trial involved 91 patients in the ICUs of five hospitals in the US, who had severe early ARDS (within the first 72 hours); 66% had sepsis. Participants were randomised to receive methylprednisolone infusion (n=63) or placebo (n=28) for up to 28 days. Methylprednisolone was administered as a loading dose of 1 mg/kg followed by an infusion of 1 mg/kg/d from day 1 to day 14, 0.5 mg/kg/d from day 15 to day 21, 0.25 mg/kg/d from day 22 to day 25, and 0.125 mg/kg/d from day 26 to day 28. If the patient was extubated between days 1 and 14, the patient was advanced to day 15 of drug therapy and tapered according to schedule. Once enteral intake was resumed, the methylprednisolone was converted to a single oral dose. The study’s primary endpoint was a 1-point reduction in lung injury score (LIS) or successful extubation by day 7, and the results were analysed according to the intention-to-treat principle.

The main results were as follows:

At Day 7, 69.8% of those receiving active treatment achieved a 1-point reduction in LIS compared to 35.7% in the placebo group (p = 0.002)

At Day 7, 53.9% of those receiving active treatment were breathing without assistance versus 25.0% of the placebo group (p = 0.01).

Active treatment was also associated with improvements in various secondary endpoints including a reduction in the duration of mechanical ventilation (5 days versus 9.5 days; p = 0.002), ICU stay (7 days versus 14.5 days; p = 0.007), ICU mortality (20.6% versus 42.9%; p = 0.03) and a reduced rate of infections (p = 0.0002).

The authors conclude that “the findings of this study provide evidence that glucocorticoid treatment-induced down-regulation of systemic inflammation in ARDS is associated with a significant improvement in pulmonary and extrapulmonary organ dysfunction and a reduction in duration of mechanical ventilation and ICU length of stay. ….A larger trial is necessary to confirm the mortality findings of this study. In a future trial, we recommend adding stratification by shock at study entry, and strict implementation and monitoring of a ventilator and weaning protocol”.

Chest 2007;131:954-963 (link to abstract)