• Foot and mouth disease update
• Homoeopathic medicines
• New product for preventing traveller's thrombosis
• UK names for BP monitors
• Most benzodiazepines not linked to hip fractures
• Continuing education of pharmacists and GPs improves prescribing
• Mycobacterial antigens associated with improvement in dermatitis
• Chief pharmacist to present the Pharmaceutical Care Awards 2000
• Accessing evidence on clinical effectiveness
• Clopidogrel reduces cardiovascular incidents by one-fifth
• Study confirms beta-blockers post-MI
• Use beta-blockers for patients with severe heart failure
• DTB recommends simvastatin use first
• Lifestyle measures and vitamin supplements
• Self-monitoring of cholesterol levels improves compliance
• Endothelin antagonist safe and effective in heart failure

Foot and mouth disease update

Confusion reigns over how to control the further spread of foot and mouth disease. Based on the conclusions of a European Commission scientific committee on animal health and animal welfare, a call was made this week for limited vaccination to be used to control the UK outbreak. However, as The Journal went to press, the Ministry of Agriculture, Fisheries and Food (MAFF) was standing by its policy that vaccination was not appropriate at this stage.

The EC scientific committee concluded in 1999 that: “Having reviewed the scientific and technological progress made in the field of FMD diagnosis and vaccine production [it] considers that emergency vaccination can be a useful tool in the control of FMD outbreaks with a risk or tendency towards uncontrolled spread.” However, this conclusion is only advisory and member countries are under no legal obligation to follow the recommendations.

A spokeswoman for MAFF told The Journal on March 20 that there was no question that vaccination should be used at this stage and it would only be used as a last resort. European policy was that it was not acceptable to use vaccine in the current situation, she said.

Nevertheless, a report in the Guardian on March 19 based on the EC scientific committee's findings suggested that the disease is too infectious for the current policy of slaughtering to control the outbreak. It describes the use of an emergency vaccination plan which was effective in controlling outbreaks of the disease in Albania and in Macedonia in 1996 where it was eliminated in 12 and three weeks, respectively. “A decision to use emergency vaccination is very likely to be approved without delay by the European Commission since the current outbreak meets almost all the criteria outlined in their 1999 policy guidelines,” the report states. According to a spokeswoman for MAFF this was “clearly incorrect”.

The Guardian's report suggests that vaccination could be used either to create an immune barrier to prevent spread of infection or to dampen down infection within infected areas. In order for Britain to return to a foot and mouth disease free status, all vaccinated animals would have to be slaughtered. Disease-free status would only be gained three months after the last vaccinated animal had been destroyed. However, this form of slaughter could take place in an orderly manner, the report notes.

There is also disagreement over how long vaccines take to work. A spokesman for the British Veterinary Association said that it takes a minimum of a week to get a response from the the vaccine and the response varies between species. The MAFF spokeswoman said it took three weeks for the vaccine to work. The BVA spokesman also said, based on the information he currently had access to, that the cons of vaccination outweigh the pros and he supported the current MAFF position.

Burying animals was difficult simply in terms of logistics, the MAFF spokeswoman said. However, the development of a landfill site in Cumbria was planned. Burying carcasses was potentially dangerous for the water table, she said but it was not a specific threat from foot and mouth disease, rather it was the danger posed by large numbers of decomposing animals. Keeping carcasses on farms for a number of days before burning was not a risk in terms of disease control. Once an animal had died, the virus also died quickly as the pH in the animal's body dropped, she said.

Thorough use of disinfectant is needed to prevent disease spread. However, although removal of clods of earth from shoes and wheels was required, there was no need to remove every grain of dirt because disinfectant would penetrate any remaining in the treads, the spokeswoman said. JM Loveridge, supplier of formaldehyde (one of the disinfectants recommended by MAFF) says that there has been no dramatic change in demand for formaldehyde over the past month. The company was not aware of any stock problems with the product.

Useful websites:
MAFF: www.maff.gov.uk
EC report.

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Homoeopathic medicines

Demand for the homoeopathic remedy borax has increased rapidly in past weeks. There is some anecdotal evidence of its beneficial use during the last foot and mouth epidemic in the 1960s but the Faculty of Homoeopathy, the governing body for medical and veterinary homoeopathy, feels that this is insufficient to claim its effectiveness in preventing the disease.

According to Chris Day (veterinary dean, Faculty of Homoeopathy), the danger of using any potentially prophylactic medicine is that, if it is effective, it might render animals able to harbour the virus and to shed it while remaining symptom-free themselves. It is recommended that pharmacists direct enquiries for homoeopathic borax to a suitably qualified veterinary surgeon. A list of such persons is maintained by the faculty, which can be contacted on 020 7566 7810.
— Contributed.

The MAFF says that borax has not been authorised for use under the terms of the Marketing Authorisations for Veterinary Medicinal Products Regulations. Products must be authorised under these regulations before they can be legally sold or supplied in the UK.

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New product for preventing traveller's thrombosis

Compression hosiery to prevent traveller's thrombosis was launched this week by Scholl. The launch follows advice by a House of Lords report at the end of last year that people at risk of developing deep vein thrombosis (DVT) should consider using compression hosiery. However, it gave no advice on the type of stocking to use. In January, Mr Stephen Barker (consultant vascular surgeon, Middlesex hospital, University College London hospitals NHS trust) told The Journal that a below-the-knee fitting was adequate for preventing flight-related DVT. He also said that class I compression was sufficient for this purpose and that the degree of compression offered by class II stockings was unnecessary (PJ, January 27, p116).

The Scholl stockings, marketed as Flight Socks, provide slightly less than class I compression (10mmHg compression at the ankle compared with class I compression of 14-17mmHg). They are a below-the-knee fitting and come in three sizes (shoe size 3-6, 6-9 and 9-12). Scholl says that these sizes will fit people with normal ankle diameter, which it suggests are 21.5-26.5cm for shoe size 3-6; 23.5-29cm for shoe size 6-9; and 26.5-32cm for shoe size 9-12. Ms Karen Woosey (senior product manager, Scholl) told The Journal this week that ankle diameter was more important than shoe sizes. Therefore, if someone falls out of the ankle range for their shoe size, they should be advised to select Flight Socks according to their ankle measurement.

She added that there were certain groups of people for whom compression stockings were not appropriate, including people with diabetes or peripheral vascular disease. In addition, a “very small number of people” might experience pain or leg discolouration when wearing the flight socks. Ms Woosey said that pharmacists should refer both these groups to practice nurses. Patients assessed to be at low risk of developing DVT could be referred to pharmacists to obtain flight socks, she added.

At the launch of the stockings, Professor Kevin Burnand (professor of vascular surgery, Guy's, King's and St Thomas's school of medicine, London) said that there was no need for children to wear stockings because the risk of DVT in children was “miniscule”. There was a lack of evidence in terms of how long compression hosiery should be worn after a flight but he suggested for the duration of the flight and for 24 hours afterwards.

Scholl will be providing pharmacists with a guide on use of the Flight Socks, including which patients need to be referred. In addition, it will be producing a consumer leaflet about DVT and flying.

Scholl says that its Flight Socks, which will retail at £11.95, will be marketed through “all good pharmacies” and Scholl footcare centres. In particular, it is hoped that the socks will be available at airports.

Correction This news report should refer to ankle cirumference, not to ankle diameter.

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UK names for BP monitors

The blood pressure self-measurement devices recommended by the European Society of Hypertension (PJ, March 10, p306) are known in the United Kingdom as follows:

Omron told The Journal that the HEM-713C model was no longer marketed but was equivalent to the MX-3 and that the Omron HEM-735 was not available in Europe.
00

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Most benzodiazepines not linked to hip fractures

In general, exposure to benzodiazepines does not increase the risk of hip fracture in elderly people, according to French researchers. The only benzodiazepine that was significantly associated with hip fractures was lorazepam, they say.

Dr Corinne Pierfitte (University of Bordeaux, France) and colleagues assessed all patients over the age of 65 who presented at two hospital emergency departments, between 1996 and 1997, with an acute hip fracture that was not related to cancer, a traffic accident or aggression.

An association between reported use of two or more benzodiazepines and an increased risk of hip fracture was found. But this was not significant when the researchers considered only benzodiazepines found in blood samples.

The researchers suggest that although benzodiazepines may increase the risk of falling, their muscle relaxant properties may decrease the risk of fracture when a fall occurs. They also confirmed a protective effect from diuretics and an increased risk from tricyclic antidepressants, but not from serotonin reuptake inhibitors.

The researchers comment that, because of study limitations, their findings must remain tentative (British Medical Journal 2001;322:704).

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Continuing education of pharmacists and GPs improves prescribing

The value of continuing professional development for pharmacists has been highlighted in a study published in last week's British Medical Journal (2001;322:654). The study showed that educational visits to pharmacists and general practitioners improved antidepressant prescribing in elderly people. Visits reduced the prescribing of highly anticholinergic antidepressants and increased the prescribing of less anticholinergic antidepressants.

Dutch researchers conducted a randomised, controlled trial to study the effects of individual and group educational visits on antidepressant prescribing, at which the prescribing of highly anticholinergic antidepressants in elderly people was discussed.

A total of 37 pharmacists and 190 general practitioners organised in 21 peer review groups were assigned to receive educational visits either individually or as a group. The researchers found that following the visits there was a reduction in the number of patients being starting on treatment with highly anticholinergic antidepressants in both the individual intervention arm (26 per cent) and the group intervention arm (45 per cent). In addition, the use of less anticholinergic antidepressants increased by 40 per cent in the individual intervention arm compared with 29 per cent in the group intervention arm.

The researchers conclude that both individual and group educational visits can improve the clinical appropriateness of prescribing behaviour in an area of suboptimal prescribing. “Audit and feedback are becoming increasingly important to help professionals keep up with evolving knowledge and implement new findings.” They add that group approaches are likely to be a useful and cost effective way of making prescribing more evidence based.

Mr David Taylor (chief pharmacist, Maudsley hospital, London) told The Journal this week that it might not always be appropriate for pharmacists to intervene when elderly patients were prescribed a highly anticholinergic antidepressant but it was an important area where pharmacists could have a positive effect on prescribing. “When highly anticholinergic antidepressants are prescribed there is potential for a lower quality of life for elderly patients should an intervention not take place.” This was largely because of the negative effects anticholinergic drugs could have on cognitive function and also because elderly people were more prone to constipation and their vision was less good so they could be more hampered by anticholinergic side effects, he said.

The antidepressants used in the study that were classified as highly anticholinergic were amitriptyline, clomipramine, doxepin, imipramine and maprotiline.

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Mycobacterial antigens associated with improvement in dermatitis

Administration of a Mycobacterium vaccae suspension improves the symptoms of moderate to severe atopic dermatitis in children, according to a study at the Booth Hall Children's Hospital, Manchester.

Dr Peter D. Arkwright and colleagues randomly assigned 41 children, aged between five and 18 years, to receive either a single intradermal injection of killed M vaccae or a buffer solution. They suggest that if reduced exposure to mycobacterial antigens is causally related to an increased prevalence of atopy, then immunising atopic individuals with these antigens might improve their disease.

At three months after treatment the researchers found a mean 48 per cent reduction in surface area affected by dermatitis compared with a mean 4 per cent reduction for the placebo group. A local inflammatory reaction was seen in 13 out of 21 of the children given M vaccae. The researchers comment that further studies are required to determine whether the effect of M vaccae is sustained after three months. Disease suppression with topical steriods is the conventional treatment for atopic dermatitis, but therapy with mycobacterial antigens might provide a simple adjuvant, they say. (Journal of Allergy and Clinical Immunology 2001;107:531).

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Chief pharmacist to present the Pharmaceutical Care Awards 2000

Applicants have only one week left to enter the 2000 Pharmaceutical Care Awards, which recognise excellence in the development of pharmaceutical services. Entries must relate to initiatives that were begun during 2000. The awards are sponsored jointly by The Pharmaceutical Journal and Glaxosmithkline and will be presented by the chief pharmacist at the Department of Health, Dr Jim Smith, at a ceremony in London on June 22.

Entrants should supply a description of their initiative along with the entry form published as an advertisement in the issue of March 3.

The application form is also available as a PDF file (106K).
It requires Acrobat Reader 4 (or later).

To download the form, click here

Entries must be sent to
the Editor
The Pharmaceutical Journal
1 Lambeth High Street
London SE1 7JN

and be received by March 30. The winners in each category will receive an engraved plaque plus £1,000 to use in developing professional services. Runners-up will receive £500. Judging will be by a panel comprising representatives from professional bodies and Glaxosmithkline. The editor of The Pharmaceutical Journal will be in the chair.

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Accessing evidence on clinical effectiveness

Advice on where to find the best available health research evidence is given in the February issue of Effectiveness Matters.

The report, produced by the NHS Centre for Reviews and Dissemination, suggests that the best strategy for locating evidence from health research is to search key focused resources or to use support services offered by librarians.

It lists selected clinical effectiveness resources including the Cochrane Library, summaries and indexes of research evidence, and details of journal clubs and critical appraisal journals.

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Clopidogrel reduces cardiovascular incidents by one-fifth

Adding clopidogrel (Plavix) to standard treatment for acute coronary syndromes reduces the risk of serious cardiovascular incidents by a fifth, the results of a new study have shown.

The CURE (clopidogrel in unstable angina to prevent recurrent ischaemic events) trial involved 12,562 patients with acute coronary syndromes who were randomised to receive either clopidogrel or placebo. The overall primary outcome was reduction in the incidence of cardiovascular death, myocardial infarction (MI) and stroke.

Dr Salim Yusuf (Hamilton general hospital, Ontario, Canada), who presented the results of the trial at the 50th American College of Cardiology meeting on March 19, said that the overall relative risk for patients taking clopidogrel was 0.81 compared with those taking placebo. The figures for mortality, MI and stroke were 0.92, 0.77 and 0.85, respectively, he said.

The finding that clopidogrel provides added benefits over standard treatment “is one of the most significant advances for patients with acute coronary syndromes since aspirin,” he said. Patients recruited into the trial were randomised to receive either standard treatment alone (such as beta-blockers, low-molecular weight heparin or angiotensin converting enzyme inhibitors) or standard treatment plus clopidogrel. The patients receiving clopidogrel were given a loading dose of 300mg, followed by 75mg daily for between three months and one year. The trial investigators recommend that patients in both groups receive aspirin.

Dr Yusuf said that when survival curves were plotted for the two patient groups, divergence (indicating clopidogrel's benefit) was seen within the first 30 days. The most common adverse effect experienced by patients taking clopidogrel was bleeding (overall relative risk = 1.34). The investigators subdivided the types of bleed into life-threatening, other major, and minor. For each type, the risk was higher in the clopidogrel group. Dr Yusuf said that the increased risk of major bleeds was “small but significant” but there was no significant increase in life-threatening bleeds. He added that most of the life-threatening bleeds had occurred early in treatment and had been “easily reversed” by transfusion.

“Treating 1,000 patients for nine months prevents 28 major [cardiovascular] events in 23 patients and causes three life-threatening bleeds. This equates to preventing 50,000 to 100,000 heart attacks, strokes or deaths every year in North America,” he said.

The trial results reported here were presented at the 50th American College of Cardiology meeting in Florida from March 18 to 21. The Journal's attendance was made possible by AstraZeneca UK Ltd

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Study confirms beta-blockers post-MI

Patients who develop heart failure following a myocardial infarction (MI) should receive beta-blockers, the results of the CAPRICORN study suggest. The carvedilol post-infarct survival control in left ventricular dysfunction study involved 1,959 patients who had left ventricular dysfunction following a confirmed MI. Dr Henry Dargie (University of Glasgow) said, at the 50th American College of Cardiology meeting on March 20, that patients with severe heart failure and those with heart failure post-MI had traditionally been excluded from trials because they were too ill. CAPRICORN specifically targeted these patients. All subjects were given standard treatment post-MI (including angiotensin converting enzyme [ACE] inhibitors) but were randomised to receive either placebo or carvedilol (up to 25mg bd) in addition.

After 1.3 years of follow-up, the carvedilol group had a 23 per cent relative reduction in mortality (0.77 risk ratio) compared with the placebo group. In addition, there were 26 per cent fewer sudden deaths and 14 per cent fewer admissions to hospital in the carvedilol group. However, Dr Dargie said that the most dramatic effect was the reduction of non-fatal MI (risk ratio 0.52). He added that the results indicated that 34 deaths had been prevented per 1,000 patients treated over the 1.3-year period.

Commenting on the study, Professor John McMurray (Western Infirmary, Glasgow) told The Journal on March 20: “The national service framework got it right when it recommended beta-blockers first-line, along with ACE inhibitors. This trial confirms that beta-blockers have the same or slightly greater benefit than ACE inhibitors. There is little excuse now for not using beta-blockers with ACE inhibitors in these very ill patients. Although there will always be exceptions, standard treatment for MI should be aspirin and thrombolytics initially, followed by continuous aspirin, an ACE inhibitor, a beta-blocker and a statin. Pharmacists are already making an invaluable contribution by making sure patients receive appropriate treatment, now they can help by reminding doctors of these results.” Carvedilol is not licensed for used in this group of patients. Roche, the UK manufacturer, told The Journal that a licence application had not yet been made as the results of the CAPRICORN study were still new.

The trial results reported on this page were presented at the 50th American College of Cardiology meeting in Florida from March 18 to 21. The Journal's attendance was made possible by AstraZeneca UK Ltd

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Use beta-blockers for patients with severe heart failure

Carvedilol reduces mortality and decreases the frequency of hospital admissions in patients with severe congestive heart failure (CHF), secondary findings from the COPERNICUS trial have shown. Dr Milton Packer (Columbia University, New York City, United States) presented the secondary endpoint results of the carvedilol prospective randomised cumulative survival trial, which involved 2,289 patients with advanced CHF, on March 20 at the 50th American College of Cardiology meeting. The results for the primary endpoint had been reported previously (see PJ, November 25, 2000, p785) and had shown that carvedilol treatment resulted in a 35 per cent decrease in mortality in treated patients, he said.

Subjects were followed up for 29 months, on average, and the secondary endpoints included death or hospital admissions resulting from all causes, from cardiovascular problems, or from CHF problems. ln each of the three categories, the reduction in incidence was 20 per cent, 28 per cent and 33 per cent, respectively. In addition, the number of drugs and intravenous treatments was fewer, which, Dr Packer said, indicated that the severity of problems was lower in treated patients. More patients in the treatment group rated their conditions as being improved and fewer as having deteriorated.

Although the overall likelihood of suffering an adverse event was similar in the treated and placebo groups, the types of reaction experienced were different. Patients receiving carvedilol were more likely to suffer from bradycardia, dizziness and hypotension (especially initially and after a dose increase) but those in the placebo group suffered more episodes of worsening CHF, cardiogenic shock, atrial fibrillation, supraventricular tachycardia and sudden death. Any cases of worsening CHF that occurred in the treatment group tended to occur with long-term therapy, not at initiation of treatment. During the first 12 weeks of the trial, 73 per cent of the carvedilol group tolerated the highest target dose (25mg) and, at the end of the trial period, 65 per cent remained on this dose. “Even in this very ill poulation, the highest doses are achievable," Dr Packer concluded.

The trial results reported on this page were presented at the 50th American College of Cardiology meeting in Florida from March 18 to 21. The Journal's attendance was made possible by AstraZeneca UK Ltd

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DTB recommends simvastatin use first

Simvastatin should be used as first-line therapy for preventing coronary heart disease events, according to this month's Drug and Therapeutics Bulletin.

The five statins licensed in the United Kingdom (atorvastatin, cerivastatin, fluvastatin, pravastatin and simvastatin) differ in important respects, the bulletin says. “Pravastatin and simvastatin have a clear advantage over the other statins in terms of weight of clinical evidence for long-term efficacy and safety, and are the only statins licensed for secondary prevention of CHD.” In addition, pravastatin is licensed for primary prevention of CHD, it notes.

At current maximum licensed doses, atorvastatin appears to be the most effective in lowering low density lipoprotein (LDL) cholesterol, followed by simvastatin, then cerivastatin, pravastatin and fluvastatin. All lower plasma triglycerides but, at maximum licensed doses, atorvastatin and simvastatin have the greatest effect, the bulletin says. “On current evidence, it seems reasonable to use simvastatin as routine first-line therapy for the prevention of CHD events on the basis of long-term clinical outcome data and efficacy in reducing the serum cholesterol concentrations,” it concludes.

According to the bulletin, initial doses of 20mg simvastatin and 40mg pravastatin should be used, rather than the lowest licensed doses which should be reserved for when the drugs are used in combination with other lipid lowering agents. Statins should be taken in the evening for maximum effect and monitoring is required to ensure than all patients receive optimum doses.

The bulletin says that, in England, only 30 per cent of patients with established CHD and raised serum lipids receive lipid lowering therapy. Worse still, only 4 per cent of patients eligible for primary prevention receive treatment.

Statins provide useful preventive benefit for patients with a risk of CHD greater than 15 per cent over 10 years, it says. However, this number of patients could not be treated under current levels of NHS funding. Therefore, the bulletin suggests that patients with an absolute risk above 30 per cent over 10 years should receive statin therapy and advice on non-drug measures (see below). Special consideration should be given to patients with diabetes, those of South Asian descent and those with familial hypercholesterolaemia. The bulletin recommends that in terms of primary prevention, statins should be used to treat patients with an estimated CHD risk of above 30 per cent over 10 years. In terms of secondary prevention, all patients with clinically obvious atherosclerotic disease should be started on a statin.

In all patients, statins should be used to lower cholesterol concentrations to below 5mmol/L or by 20-25 per cent, whichever is greater. The National Service Framework for CHD recommends that statins should be used to lower cholesterol to below 5mmol/L or by 30 per cent, whichever is greater.

The benefits of statins have been demonstrated by five trials involving over 30,000 patients, says the bulletin. These showed that statin treatment reduced the risk of developing major coronary events by 34 per cent in primary prevention and by 30 per cent in secondary prevention. Treatment benefits appeared similar in men and women and were independent of age up until 75 years after which data were lacking (2001;39:17).

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Lifestyle measures and vitamin supplements

The March issue of the Drug and Therapeutics Bulletin also covers lifestyle measures to tackle atherosclerotic disease (2001;39:21). In patients with evidence of atherosclerotic disease, such measures should be initiated in parallel with, and not delay the starting of, appropriate drug treatment, it says. In terms of supplements, studies have not confirmed the use of b-carotene, vitamin C or vitamin E in preventing cardiovascular disease, although some had shown that fruit and vegetables, which are rich sources of these vitamins, do have a protective effect. In addition, the bulletin says that it is not yet clear whether or not fish oil supplements have a beneficial effect on CHD risk although including oily fish in the diet did.

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Self-monitoring of cholesterol levels improves compliance

Patients with familial hypercholesterolaemia (FH) are more likely to achieve target lipid levels if they monitor their own levels, researchers from Germany have found. Dr Johannes Schaar (University of Essen) said on March 20 at the American College of Cardiology meeting that only 20 per cent of patients with FH achieve target lipid levels, often because of non-compliance with treatment.

He enrolled 135 patients with FH into a study that compared the effect of patient education only (n=69) with education and self-monitoring of lipid levels (n=66). Initially, the two groups had similar lipid levels and, although these levels decreased in both groups throughout the study, at the end of six months, the self-monitoring group had a 55 per cent reduction in total cholesterol levels, whereas the education-only group had a 36 per cent reduction.

“Self-monitoring is simple — the device required is almost identical to that used by diabetics, and it improves the levels achieved. Self-monitoring is a strategy used for patients with other diseases — it was now time to start using it for patients with FH,” Dr Schaar concluded.

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Endothelin antagonist safe and effective in heart failure

Tezosentan, an endothelin receptor antagonist, significantly improves cardiac index values in patients with moderate to severe heart failure, say researchers from America.

Endothelin-1 is a powerful vasoconstrictor whose levels are increased in patients with congestive heart failure. Professor Guillermo Torre-Amione (Baylor College of Medicine, Houston, Texas) and colleagues say that the increase in levels appears to be strongly correlated with the severity of the disease. In a randomised, placebo-controlled study, they evaluated the effects of 6-hour infusions of tezosentan (at doses of 5, 20, 50 and 100mg/h) in 61 patients with New York Heart Association class III or IV heart failure.

They found that the drug caused a dose-dependent increase in cardiac index ranging from 24.4 to 49.9 per cent compared with a 3.0 per cent increase seen with placebo. There were no episodes of ventricular tachycardia or hypotension, and heart rate did not change, they say. The researchers conclude: “Tezosentan can be safely administered to patients with moderate to severe heart failure.”

The study is published in Circulation (2001;103:973).

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