Safety of long-acting beta-agonists - Perspective
Thu, 22 Dec 2005 00:00 - NeLM Headline News
A Perspective article in today's NEJM discusses the FDA warning on long-acting beta-agonists issued a few weeks ago. This noted an increased risk of severe asthma events associated with salmeterol in post-marketing safety studies, most notably the SMART study carried out in the US. The author briefly discusses the history of SMART and a previous UK study on the same issue, and covers some of their limitations. In particular, neither controlled for use of inhaled corticosteroids - he suggests that in the case of SMART this was inexplicable given the previous work. Overall, he concludes that the results of the two suggest an increased risk of severe asthma events in a small but significant subgroup of patients when treated with salmeterol; it is unfortunate that the data does not allow definitive conclusions on whether concurrent inhaled corticosteroids have any impact on this. Although no similar study has been done for formoterol, other data suggest a class effect. As these drugs do have an established beneficial effect, the dilemma is to reconcile the benefits and harms: until the manufacturers carry out studies to clarify the position, their safety will remain uncertain.

Acid-suppressing therapy may increase risk of Clostridium difficile-associated disease
Wed, 21 Dec 2005 00:00 - NeLM Headline News
A linked pair of case-control studies has found an increased risk of Cl. difficile-associated disease (CDAD) in patients treated with acid-suppressing drugs, especially proton-pump inhibitors. The studies used the UK GPRD, and the authors located all 1672 cases of CDAD recorded between 1994 and 2004 among all patients registered for at least 2 years in each practice. Each case was then matched with ten controls on the basis of GP practice and calendar time. For the second study, a subset of these cases was identified as ‘community-acquired’ as not having been in hospital in the previous year – these were then matched to appropriate non-hospitalised controls. All prescriptions of antibiotics and gastric-acid suppressing drugs written in the two years before the index date (date of CDAD diagnosis) were identified, and patients were classed as currently exposed if a prescription had been written within 90 days of the index date. From the data, the relative risk for community-acquired CDAD was estimated for exposure to current use of acid-suppressing drugs (proton-pump inhibitors - PPI - and histamine H2-receptor antagonists - H2RA), NSAID, aspirin, and antibiotics; adjustments were made for sex, co-morbidity, and co-prescriptions. Primary outcome was incidence of CDAD and risk associated with use of gastric acid–suppressive drugs. Of the 1672 cases identified, 1,233 (74%) had not been hospitalized in the prior year and were thus designated as community-acquired. There was an increase in GP diagnosis of CDAD over the ten years studied, from 1 case per 100,000 in 1994 to 22 per 100,000 in 2004: over this period, prescription of antibiotics had decreased and prescription of PPI had increased. Not surprisingly, there was a strong association between diagnosis of CDAD and use of antibiotics in the previous 90 days. Patients diagnosed tended to be elderly (mean age 71), female, and have significant co-morbidity. Analysis showed an increased risk of CDAD associated with current use of acid-suppressing drugs: the adjusted rate-ratios (RR) were 2.9 for PPI and 2.0 for H2RA (both statistically significant). Unexpectedly, there was also a smaller increased risk with NSAID (RR 1.3). The authors conclude that the use of acid-suppressing drugs, particularly PPI, is associated with an increased risk of CDAD. They also note the association between CDAD and use of NSAID, which they consider requires further investigation.

EMEA anticipates generic biotechnology drug licence applications in 2006
Wed, 21 Dec 2005 00:00 - NeLM Headline News
The latest management report from the EMEA contains a potentially interesting snippet of information on biotechnology drugs (biopharmaceuticals). They are anticipating up to eight licence applications for generic biotechnology drugs following the finalisation of guidelines for what are termed ‘biosimilar’ drugs during the first quarter of the year. The initial guidelines cover insulin, epoetin, somatropin, and granulocyte colony stimulating factor, and guidelines for interferons are being planned. [Comment: it’s likely that the approval process will be cautious initially, so we would not expect to see any bio-generics quickly; however if the process goes smoothly and based on existing timescales we could anticipate first launches in the middle of next year.]

Alzheimer's drugs 'are helping more people'
Tue, 20 Dec 2005 00:01 - Telegraph Health
Drugs to treat Alzheimer's disease may be more effective than previously thought but it is still not possible to tell which patients will benefit, says a new study.

Bandolier review of diabetes management in general practice
Mon, 19 Dec 2005 00:00 - NeLM Headline News
Bandolier has reviewed a cohort study from UK general practice which suggests that although many things are being done better, the impact has not been as one might expect. An anonymised primary care database of 74 practices in England and Wales that had continuous recording over the years 1994 to 2001 was searched for information about BMI, blood pressure, Hb A1c, and cholesterol in type 2 diabetics. The results were reported as follows: • There were about 500,000 patients in the 74 practices, 480,000 in 1994 and 525,000 in 2001. • The number of type 2 diabetics rose from about 8,000 in 1994 to 13,000 in 2001. • The prevalence of type 2 diabetes increased almost every year between 1994 and 2001 in both sexes, and at all ages. Overall the increase in prevalence was about 50%. • The proportion treated with diet only fell from 38% in 1994 to 33% in 2001, with small increases in the proportion treated with oral hypoglycaemic drugs only, and insulin. • Large changes in the types of oral agents used occurred over the period, with increases in metformin and short-acting sulphonylureas, and a large decrease in use of long-acting sulphonylurea. Other oral agents were used in under 5% of patients. • Monitoring improved significantly, with large increases in cholesterol and Hb A1c measurements, and small but significant increases in BMI and blood pressure measures. • Apart from cholesterol, where the proportion of patients achieving a target of less than 5 mmol/L rose, and small improvements in blood pressure targets achieved, the proportion of type 2 diabetics with BMI below 25 and Hb A1c below 7.5% or 6.5% fell. Please follow the link for graphs and tables of results.

Meta-analysis - dropout rates in placebo-controlled and active-control trials of antipsychotics
Mon, 19 Dec 2005 00:00 - NeLM Headline News
In this meta-analysis, the authors investigated whether high dropout rates in randomised clinical trials of antipsychotic drugs are due to a placebo-controlled design. Thirty-one double-blind, randomised, controlled clinical trials (n= 10, 058) involving risperidone, olanzapine, quetiapine, amisulpride, ziprasidone, and aripiprazole met the inclusion criteria (unselected patient population with a diagnosis of schizophrenia or schizoaffective disorder, change in psychopathologic symptoms as the primary end point, and trial duration of 12 weeks or less). They found the following from their analysis: • Weighted mean dropout rates in the active treatment arms were significantly higher in placebo-controlled trials (PCTs) than in active-control trials: 48.1% vs 28.3% for second-generation antipsychotics (OR 2.34; 95% CI 1.58-3.47) and 55.4% vs 37.2% for classical antipsychotics (OR 2.10; 1.29-3.40). • Within PCTs, attrition rates were significantly higher in the placebo arms than with second-generation antipsychotics (60.2% vs 48.1%; OR 1.63; 1.37-1.94). • Within the subset of trials in which both second-generation and classical antipsychotics were used, dropout rates were significantly higher with classical antipsychotics. The authors concluded that because ‘high dropout rates affect the generalisability of such studies, it is suggested that, in addition to the PCTs, studies with alternative designs need to be considered when evaluating an antipsychotic’s clinical profile’.

The NPC publish “A guide to good practice in the management of controlled drugs in primary care (England)”
Fri, 16 Dec 2005 00:00 - NeLM Headline News
The NPC has published “A guide to good practice in the management of controlled drugs in primary care (England)”. This version of the guide is the full First Edition and replaces the Preview version. It incorporates the changes affecting CDs that were announced on 14th November 2005. Each main section of the guide is separated, as appropriate, into two parts, which set out: 1. Current legal framework 2. Good practice - i.e. what is currently considered appropriate activity within the current legal framework.

Irish study finds primary care prescribing of antidepressive drugs to children has fallen
Fri, 16 Dec 2005 00:00 - NeLM Headline News
A pharmacoepidemiological study using data from an Irish primary care claims database found that over the period January 2001 to August 2004, prescribing of antidepressive drugs to children decreased. Use of SSRIs in children, however, was unchanged. The authors used data from the claims database of Irish General Medical Services, which provides means-tested free health services to about 30% of the Irish population (n=1.24 million). They identified all people who had been prescribed an antidepressive drug between the indicated dates and categorised them as child (age 0-15) or adult (age 16+). Analysis showed that in 2003, antidepressives were prescribed to 0.43% of children and 16.9% of adults, with a disparity towards females (odds ratio for girls 1.60 and for women 1.40). Type of antidepressive used was similar in adults and children, SSRIs being most commonly used. A majority of the children (58%) received only one prescription, whereas a majority of the adults (66.5%) received three months worth or more. Between January 2001 and August 2004, the overall trend in prescribing of these drugs for children showed a significant reduction. For SSRIs, however, there was no significant downward trend. Prescribing for adults showed an upward trend over the period. The authors conclude that there was a decrease in prescribing of antidepressive treatment to children over time overall, but that prescribing of SSRI did not change despite warnings from regulatory authorities. They note that a majority of children only received one month's treatment, although this may be of limited efficacy. They suggest that prescribers may need to receive regular reminders about potential safety problems and efficacy with antidepressants in children especially in the first few weeks of treatment. They note some limitations of their study - diagnostic data were not available, and social disadvantage is over-represented in the database.

Switching from tamoxifen to anastrozole after 2 years - a meta-analysis
Thu, 15 Dec 2005 00:00 - NeLM Headline News
AstraZeneca has presented data from a meta-analysis of three anastrozole studies at the San Antonio Breast Cancer Symposium, which indicated that women who switched from tamoxifen to Arimidex™ (anastrozole) after two years of a five-year treatment course were 29% less likely to die than those who remained on tamoxifen for the entire period. The three similarly designed trials were the Arimidex-Nolvadex (ARNO) 95 trial, the Italian Tamoxifen Arimidex (ITA) trial and the Austrian Breast & Colorectal Cancer Study Group (ABCSG) 8 trial. They involved over 4000 women who had undergone surgery and received tamoxifen for two years, followed by either continuation of tamoxifen or changing to anastrozole for the remaining 5 years. The women were monitored for an average of 2.5 years. The analysis found that in the anastrozole group: • The risk of dying was reduced by 29% (HR 0.71; 95% CI 0.52 - 0.98; p=0.0377) • The risk of the disease returning was reduced by 45% (HR 0.55; 95% CI 0.42 - 0.71; p<0.0001) • The risk of the disease spreading from the breast to other parts of the body was reduced by 39% (HR 0.61; 95% CI 0.45 - 0.83; p=0.0015) In addition, the meta-analysis showed that the safety profiles for anastrozole and tamoxifen were consistent with those previously observed. The authors concluded that “postmenopausal women currently receiving adjuvant tamoxifen should be switched to anastrozole upon completion of 2-3 years treatment”. However, NICE is due to deliver a verdict on the use of all three of these drugs in the post-surgery setting next November. Ref: Jonat W et al. Switching from adjuvant tamoxifen to anastrozole in postmenopausal women with hormone-responsive early breast cancer: a meta-analysis of the ARNO 95 trial, ABCSG Trial 8, and the ITA trial. Abstract No. 18. San Antonio Breast Cancer Symposium 2005.

Pfizer sponsors Celebrex® (celecoxib) safety study
Thu, 15 Dec 2005 00:00 - NeLM Headline News
According to a report by PharmaTimes, Pfizer is to sponsor a 20,000-patient study that it hopes will prove that Celebrex (celecoxib) is effective and no more likely to cause cardiovascular side effects than the older non-steroidal anti-inflammatory drugs ibuprofen and naproxen. The four-year trial called PRECISION, will start enrolling osteoarthritis patients with known coronary heart disease or who have multiple risk factors for heart disease early next year. Some patients with rheumatoid arthritis also will be included.

Unlicensed drugs seized in London raids
Wed, 14 Dec 2005 00:00 - NeLM Headline News
According to a press release from the MHRA, a quantity of unlicensed steroid creams, antibiotics, other drugs such as diazepam and the banned herbal products ‘M2’ and ‘Energy 2000’ were seized during an unannounced inspection of two retail outlets in London (Hackney and Southwark).

Reform report – ‘the NHS in 2010: reform or bust’
Wed, 14 Dec 2005 00:00 - NeLM Headline News
This report by the think-tank Reform warns that cost pressures on the health service will demand an extra £18.2 billion of funding yet only an extra £11.4 billion is likely to be available. Reform researchers looked at the cost pressures on the NHS over the next five years, including the consequences of extra staff, improved contracts, more expensive drugs and large building projects. The report said the NHS had two options - radical reform or cutting more jobs or delaying treatment - if the debts were not to get worse. Report co-author Henry de Zoete said: "What we are saying is that if the financial situation is not going to get worse, change is needed - "We are already seeing the signs with deficits being built up and recruitment freezes being introduced. There is a real risk it will get worse." The study welcomes the Government’s aim to create a reformed “patient-led” NHS based on patient choice and a variety of providers. It shows that the NHS will have more than enough resources to achieve that aim by the end of the decade. But it suggests that extra resources may be used to prop up existing providers rather than to develop new modern community-based services.

Scottish Medicines Consortium recommends restricted use of zonisamide (Zonegran) for partial seizures
Tue, 13 Dec 2005 00:00 - NeLM Headline News
The Scottish Medicines Consortium (SMC) has advised NHS Boards and Area Drug and Therapeutic Committees that Zonisamide (Zonegran™) is recommended for restricted use within NHS Scotland for the treatment of adult patients with partial seizures, with or without secondary generalisation. The SMC states that it should be initiated only by physicians who have appropriate experience in the treatment of epilepsy and should be used principally in patients who have not benefited from treatment with an older anti-convulsant drug such as carbamazepine or sodium valproate, or for whom these drugs are unsuitable because of contra-indications, interaction or poor tolerance.

Statin adverse effects on muscle resolve rapidly on drug withdrawal
Tue, 13 Dec 2005 00:00 - NeLM Headline News
A patient-record study indicates that statin-induced myopathy generally resolves after drug withdrawal, although some patients may have significant illness. The authors located 45 cases of confirmed statin-induced myopathy over 13 years from the University of Wisconsin Hospital and Clinics. They used patient records to determine the clinical course and long-term outcome for these patients. Mean duration of statin therapy before onset of symptoms was 6.3 months. After the drug was withdrawn, muscle pain resolved fairly slowly, over a mean period of 2.3 months. Most patients were managed on an out-patient basis, but 13% (6 patients) had to be hospitalised for management of rhabdomyolysis; two of these had reversible renal dysfunction and one with pre-existing renal insufficiency had to start dialysis. Patients who were hospitalised tended to develop myopathy more quickly and were more likely to be taking other drugs known to increase the risk. A significant proportion - 37 patients - were challenged with an alternative statin; of these, just over half (57%) reported recurrent muscle pain but the remainder tolerated the alternative without recurrent symptoms. The authors conclude that statin-associated muscle pain resolves fully on drug withdrawal, although a minority of patients may require hospitalisation. Around half of affected patients will experience similar symptoms with an alternative statin.

Do atypical antipsychotics increase VTE risk in elderly patients?
Tue, 13 Dec 2005 00:00 - NeLM Headline News
A retrospective cohort study suggests that atypical antipsychotic drugs may be associated with a small increase in risk of venous thromboembolism (VTE) in elderly patients. The study used data on US nursing home residents to identify 19,940 new users of antipsychotic agents and 112,078 nonusers. Hospitalization with VTE as primary discharge diagnosis was determined during a 6-month follow-up period using Medicare inpatient claims. Overall, the rate of hospitalisation for VTE was 0.91 per 100 person-years: 77.6% for venous thrombosis and 22.4% for pulmonary embolism. When antipsychotic users were compared with non-users, the risk of VTE was approximately doubled for atypical drugs including risperidone (adjusted hazard ratio [HR], 1.98; 95% confidence interval [CI], 1.40-2.78), olanzapine (adjusted HR, 1.87; 95% CI, 1.06-3.27), and clozapine and quetiapine fumarate (adjusted HR, 2.68; 95% CI, 1.15-6.28). There was no significant increase for phenothiazines or other conventional antipsychotics, however. Based on their results, the authors conclude that atypical antipsychotics appear to increase the rate of VTE in elderly patients. They note, however, that these events are rare overall and the increased risk should be balanced against the benefits the drugs may have in this population.

Prevalence and incidence of gastroduodenal ulcers during treatment with low dose aspirin
Tue, 13 Dec 2005 00:00 - NeLM Headline News
According to a report in ‘Alimentary Pharmacology and Therapeutics,’ gastroduodenal ulcers are found in one in 10 patients taking low-dose aspirin, and most are asymptomatic. These findings come from endoscopic examinations of 187 patients on aspirin 75– 325 mg daily, for at least 1 month. Those on gastroprotectant drugs or other NSAIDs were excluded. The primary variables were the proportion of patients with gastric and/or duodenal ulcers at baseline, and the proportion developing an ulcer within 3 months, having been ulcer-free at baseline. The following results were reported: • Ulcer prevalence was 11% [95% CI, 6.3–15.1%]. • Only 20% had dyspeptic symptoms, which was not significantly different from patients without ulcer. • Ulcer incidence at repeat endoscopy at 3 months in 113 patients with no ulcers at baseline was 7% (2.4–11.8%). • Helicobacter pylori infection increased the risk of a duodenal ulcer [odds ratio 18.5, 2.3–149.4], as did age > 70 years, for ulcers in stomach and duodenum combined (3.3, 1.3–8.7). • Smoking, higher aspirin doses, previous ulcer history and gender did not significantly affect risk. The authors advise that the risks and benefits need to be considered when starting patients on low dose aspirin.

Anti-epileptic drug withdrawal can be safe in patients without epileptic seizures
Mon, 12 Dec 2005 00:00 - NeLM Headline News
An observational study confirms that patients who are taking anti-epileptic drugs (AED) but do not have epilepsy can safely have the drugs withdrawn under appropriate conditions. The authors comment that there is a population of patients with seizures not due to epilepsy (non-epileptic seizures, NES), and that a significant proportion of these patients may be started on AED that are subsequently continued. These drugs may be continued for various reasons, however it is undesirable for patients to be taking these without good cause. The report describes the outcomes in a cohort of 78 patients with NES who satisfied a standard set of criteria for excluding epilepsy. They had AED withdrawn according to clear instructions, most on an out-patient basis, with prospective monitoring of safety and outcomes. A small number were admitted for drug withdrawal. The 78 patients included were taking between one and three AED. Of the total, 64 were successfully withdrawn as outpatients and the remainder had to be admitted. Five stopped suddenly and two were stopped abruptly by their GP. Two patients had to have the drug re-started, but both were subsequently withdrawn successfully. There were no serious adverse effects reported, and a majority of patients recorded a reduction in NES attacks. The authors conclude that with appropriate diagnosis, and good quality monitoring and follow-up, AED can be safely withdrawn in patients with NES.

Meta-analysis - do drugs acting via angiotensin really protect the kidney more than others?
Fri, 09 Dec 2005 00:00 - NeLM Headline News
A systematic review and meta-analysis found that the evidence available does not provide robust support for the widely held view that ACE-inhibitors (ACE-i) and angiotensin-receptor blockers (ARB) have specific protective effects against renal outcomes in the treatment of hypertension. The clinical trial evidence is consistent with the benefits of these drugs on renal outcomes being due to their blood-pressure lowering effects and any specific renoprotective effects are uncertain or unproven. The authors carried out a fairly comprehensive search (Medline, Embase, and the Cochrane Library) for randomised controlled trials investigating any antihypertensive drug and progression of renal disease in humans, published from 1960 to January 2005. They then searched the reference lists of all identified publications plus previous relevant meta-analyses and reviews. The search resulted in 127 eligible studies with 150 group comparisons; of these, 99 included only patients with diabetes, 36 only patients without diabetes, and 10 included both. The majority of comparisons (98/150, 65.3%) included fewer than 101 patients. The breakdown of drugs included in the 150 comparisons was ACE-i / ARB vs. placebo, 48 (n=16,588) ; ACE-i / ARB vs. other active intervention, 77 (n=43,439); ACE-i vs. ARB, 5 (n=594); other active intervention vs. placebo, 11 (n=6,390); other active intervention vs. other active intervention, 9 (n=6,503). The meta-analysis noted the following: • Studies comparing ACE inhibitors or ARBs with other antihypertensive drugs yielded a relative risk of 0•71 (95% CI 0•49–1•04) for doubling of creatinine and a small benefit on end-stage renal disease (relative risk 0•87, 0•75–0•99). • In patients with diabetic nephropathy, no benefit was seen in comparative trials of ACE inhibitors or ARBs on the doubling of creatinine (1•09, 0•55–2•15), end-stage renal disease (0•89, 0•74–1•07), glomerular filtration rate, or creatinine amounts. • Placebo-controlled trials of ACE inhibitors or ARBs showed greater benefits than comparative trials on all renal outcomes, but were accompanied by substantial reductions in blood pressure in favour of ACE inhibitors or ARBs. The researchers suggest from these findings that blood pressure control could account for the apparent renoprotective effect of ACE-i and ARB: Overall, they conclude, claims that ACE-i and ARB are renoprotective in diabetics "seem to derive from small placebo-controlled trials that provide uncertain evidence of the existence of any true advantage over and above blood pressure control." As a consequence, they conclude that "for renal outcomes, blood pressure lowering remains more important than the class of drug prescribed." The evidence for benefit in non-diabetic renal disease is better, but there is still uncertainty. There is therefore little justification for these drugs to be first-line choices for renoprotection in patients with diabetes, and uncertainty still exists over their value in other renal disorders. Treatment decisions for hypertension in renal disease should therefore be based on blood-pressure lowering effect, comparative tolerability, and cost. Further trials to determine whether these drugs do have a specific effect on renal outcomes will need to be designed to use active comparators and should be adequately powered to detect clinically important renal endpoints: such trials will need to be very much larger than those carried out so far.

BMJ Review: Treating obesity in individuals and populations
Fri, 09 Dec 2005 00:00 - NeLM Headline News
In this review, the author discusses the evidence behind interventions to treat or prevent obesity in adults, children, and communities; the strengths and weaknesses of current research; and recommends a direction for future treatment and research. The review is carried out under the following headings: • What has been studied? • Do any treatments work? • How good is the evidence? • Where do we go from here? • Conclusion The main summary points (taken directly from the article) are as follows: • A thorough search of the evidence for obesity treatment and prevention reveals that the research to date shows clearly what does not work but fails to establish what does • Research studies have largely concentrated on individually based treatments, which result in small amounts of weight loss and have little impact on the obesity epidemic in the population • Despite most experts agreeing that the obesity epidemic is due to environmental factors, the research has largely ignored this • It is time to be realistic with individuals about the effectiveness of lifestyle interventions and obesity drugs, and to focus on public health interventions rather than individual treatments, to halt the obesity epidemic

BMJ Updates: Antihypertensive drugs help prevent headaches
Fri, 09 Dec 2005 00:00 - NeLM Headline News
BMJ updates have summarised a study published in the journal Circulation. The summary below is taken directly from BMJ.com: Research question: Do blood pressure lowering drugs prevent headaches? Answer: Yes. Commonly used antihypertensive drugs reduce the prevalence of headache by a third compared with placebo. Why did the authors do the study? Doctors and patients have been debating for 50 years whether high blood pressure causes headache. Most doctors believe it doesn't, although there's limited evidence from clinical trials that treating hypertension can relieve headache, especially migraine. These authors wanted to clarify the picture by synthesising all high quality, unbiased data on the link between lowering blood pressure with drugs and headache What did they do? They did a systematic search for all double blind, randomised, placebo controlled trials of four classes of antihypertensive drug published between 1966 and 2001, then combined in a meta-analysis the 94 trials that reported data on headache. The four classes of drug were thiazides, beta-blockers, angiotensin converting enzyme inhibitors, and angiotensin II receptor antagonists. Calcium antagonists were excluded because they can cause headache through vasodilation. The 94 trials included 23 599 people in all who were treated, double blind, for 2-14 weeks. Trials of patients with heart failure or acute myocardial infarction were excluded, otherwise trials were included regardless of the diseases of the participants. What did they find? On average, active treatment lowered systolic and diastolic blood pressures by 9.4 and 5.5 mm Hg relative to placebo. People treated with an antihypertensive drug were a third less likely to report headache than control patients who took placebo (1416/17 641 (8%) v 818/6603 (12%); odds ratio 0.67, 95% CI 0.61 to 0.74; P < 0.001). The impact of treatment on the prevalence of headache was consistent across all four classes of drug, although there was a suggestion that beta-blockers were better at preventing headache than the other types of drug (odds ratio 0.47, 0.35 to 0.63). The authors estimate that one in 30 people who take these drugs get relief from headaches. There was a clear and direct relation between the reduction in diastolic blood pressure achieved by a trial, and the reduction in headache reported by its participants. Prevalence of headache went down by an extra 13% (relative to placebo) for every extra 5 mm Hg reduction in diastolic blood pressure achieved by a trial. The authors say their findings are unambiguous: blood pressure lowering drugs help prevent headache. What does it mean? It's likely that that these drugs relieve headache by lowering blood pressure, not by some other action. All four types of drug seem to work, and reducing blood pressure is one of the few pharmacological actions they have in common. If lowering blood pressure relieves headache, it follows intuitively that high blood pressure causes headache. Unfortunately, studies like this can never prove it, and a large body of observational evidence suggests otherwise. So the debate will go on, invigorated by this fresh ammunition. In the meantime, about one in 30 patients who take drugs that lower blood pressure will get welcome relief from headaches alongside the more conventional benefits to their cardiovascular risk.

Older people are wrongly excluded from drug trials
Fri, 09 Dec 2005 00:00 - NeLM Headline News
BMJ News reports on a conference on medication for older people at which speakers reported that age discrimination exists in many aspects of elderly people’s health care. One speaker (the President elect of the British Geriatrics Society) said, “The common imposition of upper age limits for clinical trials was an important form of discrimination. Frail older people show differences in their response to drugs. It is important that trials on drugs often used in older people are also performed in the [relevant] age group”. He added that when trials were performed in people older than 80 they mostly looked at the risks and not the benefits.

Febuxostat vs allopurinol in patients with hyperuricaemia and gout
Thu, 08 Dec 2005 00:00 - NeLM Headline News
Data comparing allopurinol and febuxostat, a novel nonpurine selective inhibitor of xanthine oxidase, have been published in the New England Journal of Medicine. The data come from a study in 762 patients with gout and serum urate concentrations of at least 8 mg/dL (480 micromol/L), randomised to febuxostat (80 mg or 120 mg) or allopurinol (300 mg) once daily for 52 weeks. Naproxen or colchicine was allowed during weeks 1 to 8 as prophylaxis against flare-ups. The primary end point was a serum urate concentration of less than 6mg/dL (360 micromol/L) at the last three monthly measurements. The secondary end points included reduction in the incidence of gout flares and in tophus area. The following results were reported: • The primary end point was achieved in 53% of patients on 80 mg febuxostat, 62% on 120 mg of febuxostat, and 21% on allopurinol (p < 0.001 for each febuxostat group vs allopurinol). • The overall incidence of gout flares during weeks 9 to 52 was similar in all groups: 64% on 80 mg, 70% on 120 mg and 64% on allopurinol (p = ns for both groups vs allopurinol). • The median reduction in tophus area was 83% in those on 80 mg, 66% on 120 mg and 50% on allopurinol (p = ns for both groups vs allopurinol). • The incidence of adverse events was similar in the three treatment groups and included abnormal LFTs, diarrhoea, headaches, joint-related signs and symptoms, and musculoskeletal and connective-tissue signs and symptoms. • 88 patients on 80 mg, 98 on 120 mg, and 66 on allopurinol discontinued the study (p = 0.003 for 120 mg vs allopurinol) • The most common adverse event leading to withdrawal was abnormal LFT, accounting for withdrawal of 5 subjects on 80 mg, 7 on 120 mg, and 1 on allopurinol (p = 0.04 for 120 mg vs allopurinol). Four subjects on 80 mg, 4 on 120 mg and 1 on allopurinol discontinued the study because of rashes. • Four (0.8%) of the 507 patients in the two febuxostat groups and none of the 253 patients in the allopurinol group died; all deaths were from causes that the investigators judged to be unrelated to the study drugs. The researchers conclude that febuxostat 80 mg or 120 mg, was more effective than allopurinol 300 mg in lowering serum urate, however similar reductions in gout flares and tophus area occurred in all treatment groups. An accompanying editorial makes the following comments about the study: • Although febuxostat was more effective than allopurinol in lowering serum urate levels, a large percentage of patients on this drug did not achieve the primary end point. Therefore, it needs to be ascertained whether higher doses that can be given safely, will achieve this outcome. • The reported toxicity of febuxostat and the high dropout rate emphasise the need for more information about the short- and long-term toxicity of febuxostat. There were large numbers of dropouts for reasons that are not clearly defined. In particular, more details are needed about the degree, duration, and reversibility of the elevation of LFTs. • It is important to determine whether patients with a creatinine clearance of less than 50 ml/min will have adverse events, as it is assumed that patients with renal insufficiency were excluded from this study because of the need to be randomised to the fixed dose of allopurinol. • The use of colchicine or naproxen for prophylaxis against acute gout for only 8 weeks after initiation of treatment with allopurinol or febuxostat is unorthodox, as prophylaxis with colchicine to prevent recurrent attacks is often needed for as long as 6 to 12 months. The editorial concludes “further studies will be needed to define better the long-term safety profile of febuxostat, especially when it is administered in patients with renal insufficiency, in those with other coexisting conditions, or in those receiving medications that may cause hepatotoxicity.”

Medical Letter reviews - mometasone (Asmanex) and ziconotide (Prialt)
Wed, 07 Dec 2005 00:00 - NeLM Headline News
The latest issue of the Medical Letter on Drugs and Therapeutics - the US equivalent of the Drug & Therapeutics Bulletin - includes reviews of the Asmanex (mometasone) Twisthaler for asthma and Prialt (ziconotide) for severe pain. It concludes that inhaled mometasone is effective in controlling asthma and improving pulmonary function, but it is not clear whether it offers any substantial advantages over other inhaled corticosteroids. While it can be used once daily, twice daily may be more effective. Intrathecal ziconotide is currently licensed in the US for intractable chronic pain - a licence application in the EU is in progress. This review briefly looks at the evidence for its use, and concludes that it may be effective in some patients but that serious psychiatric and CNS adverse effects may be a problem. It is expensive to buy (US cost $4,200 per 30 days at maximum dose) and should normally be used via an implanted infusion pump system (US cost for implantation estimated at around $20,000).

Department of Health announces NHS ahead of schedule to achieve efficiency savings
Wed, 07 Dec 2005 00:00 - NeLM Headline News
The Health Secretary has announced that efficiency savings across the NHS are being achieved ahead of schedule, with a saving of £1.7 billion having been achieved since March 2004 (£200million ahead of target). Following the Gershon Report “Releasing Resource to the Frontline”, the Department of Health had committed to annual efficiency gains of £6.5 billion by March 2008. According to the announcement, the savings of £1.7bn that have been achieved to date have been as a result of the following: • better management of patient admissions has reduced average hospital length • an increasing number of treatments are being done as day cases • improved proactive care of patients, particularly those with chronic conditions • reduced levels of staff sickness and reduced use of agency staff in 2004/05 • price reductions for branded and generic drugs effective in 2004 and early 2005 resulted in savings of £697 million, rising to an annual £975 million by March 2006 • recently renegotiated national procurement contracts for NHS supplies and services are already providing annualised savings of £90 million.

FDA approves Hylenex (recombinant human hyaluronidase)
Tue, 06 Dec 2005 00:00 - NeLM Headline News
According to BioSpace, the FDA has approved Halozyme's Hylenex recombinant (hyaluronidase human injection) for use as an adjuvant agent to increase the absorption and dispersion of other injected drugs. Data supporting the application came from a double-blind trial in which Hylenex was compared to a saline control in 100 human volunteers. These volunteers were injected intradermally with Hylenex in one forearm and saline control in the other forearm, and evaluated for allergic responses and injection site side effects. The data showed injection site discomfort (e.g., stinging, burning, other discomfort) of 28% in the saline arm and 3% in the Hylenex arm.

Epoetin, darbepoetin US prescribing information update - red cell aplasia and severe anaemia
Mon, 05 Dec 2005 00:00 - NeLM Headline News
The FDA and the manufacturers involved have issued updated US prescribing information for epoetin-alfa (Epogen and Procrit) and darbepoetin, giving further information on the occurrence of pure red cell aplasia and severe anaemia, with or without other cytopenias, associated with neutralising antibodies to the drugs. The updated prescribing information includes recommendations for evaluation and treatment of patients suspected of being affected. The warning and updated prescribing information can be found via the FDA website (see links above).

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