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Answered questions

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Should all patients over 65 be co-prescribed a PPI with aspirin?

Should all patients over 65 be co-prescribed a PPI with aspirin?

Specialist’s response: No! There is little doubt that even low-dose aspirin (75mg) increases the risk of upper gastrointestinal bleeding by about two-fold (from 1.4 to 2.5 per cent).1 However, the only prospective endoscopic trial that I am aware of, published in 2006, showed the risk of developing peptic ulceration was not significantly different between the control group and those on enteric-coated aspirin (6 vs 7 per cent).2 It may be that older patients are more at risk but there is little evidence that adding a gastroprotective agent such as a PPI makes much difference to the risk.
    Patients being treated with aspirin after a stroke or ischaemic heart disease are always going to be on a whole array of different drugs. Adding in yet another treatment not only increases the risk of being noncompliant with the important drugs but also increases the risk of drug interactions.
    Recent National Institute for Health and Clinical Excellence (NICE) guidance on poststroke use of antiplatelet drugs now recommends clopidogrel as the first-line treatment in preference to aspirin. It is known that PPIs reduce the efficacy of clopidogrel and so are contraindicated. Therefore the question as to what to do with aspirin is now less relevant, but for those who do remain on it as a single agent or in combination with dipyridamole should, in my view, not be routinely treated with a PPI.

References
1. García Rodríguez LA, et al. Circulation 2011;123(10):1108–15. Epub 28 Feb 2011.
2. Laine L. Alimentary Pharmacology & Therapeutics 2006;24(6):897–908.

Dr Anthony Rudd FRCP is a consultant stroke physician at Guy’s and St Thomas’ NHS Foundation Trust, London

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Can aspirin be taken every other day?

Given aspirin’s irreversible inhibition of platelets, can it be taken every other day?

Specialist’s response: Low-dose aspirin (75mg daily) is widely used for secondary prevention of serious vascular events in patients with prior history of occlusive vascular disease and for primary prevention in people at high risk. Much higher multiple daily doses are needed when aspirin is used for analgesia or anti-inflammatory effects.
    The vascular protective effects of aspirin are mediated by actions on platelets. Aspirin acetylates and inactivates irreversibly cyclo-oxygenase (COX) via the key COX-1 isoenzyme in the platelet biosynthetic pathway for the proaggregatory prostaglandin thromboxane A2. As platelets are anucleate, recovery of thromboxane synthesis is dependent on the appearance of a new platelet population over about 10 days.1
The antiplatelet effects of aspirin are seen at doses as low as 30mg daily.2 However, bleeding complications are dose dependent. Therefore, the irreversible inhibitory effect of aspirin on platelets might be utilised by administering aspirin every other day to avoid side-effects but retaining benefit.
    Alternative-day aspirin regimens were used in two large outcome studies3,4 but results were inconsistent and had a major influence on a recent meta-analysis,5 which questioned the value of aspirin in primary prevention. About 10 per cent of total COX-1 activity in platelets is restored each day due to platelet turnover and entry of new platelets into the circulation. Increased platelet turnover and inadequate dosage may partly explain treatment failure with aspirin. A typical regimen of aspirin 75mg once daily exceeds the maximal effective dose required for a fixed pharmacological effect, thus accommodating some degree of interindividual variability in platelet turnover rate and drug response.2,6
    For these reasons, a once-a-day regimen is preferable to an every-other-day regimen.2 Furthermore, nonadherence is likely to be a factor in treatment failure and it is uncertain whether this would be better if aspirin is taken on alternate days when a missed dose might have serious consequences.

References
1. Roth GJ, et al. Proc Nutl Acad Sci USA 1975;72:3073–6.
2. Patrono C, et al. N Engl J Med 2005;353:2373–83.
3. Steering Committee of the Physicians’ Health Study Research Group. N Engl J Med 1989;321:129–35.
4. Ridker PM, et al. N Engl J Med 2005;352:1293–04.
5. Antithrombotic Trialists’ (ATT) Collaboration. Lancet 2009;373: 1849–60.
6. Patrono C, et al. Circulation 1985;72:1177–84.

Gordon McInnes BSc, MD, FRCP, FFPM, FBPharmacolS is professor of clinical pharmacology and honorary consultant physician in the Division of Cardiovascular and Medical Sciences, Western Infirmary, University of Glasgow, president of the BHS, member of the steering committee of ASCOT and executive committee of VALUE, and UK national co-ordinator of HOT

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Do patients with migraine become pharmacologically dependent on triptans?

Codeine is widely understood to cause chronic daily headache. Is there any evidence that patients with migraine become pharmacologically dependent on triptans?

Specialist’s response: The simple answer is: yes, yes and absolutely yes! And this understanding is sadly not widely enough understood.
The complicated answer is that it is unclear whether this is a pharmacological or a behavioural dependence, or indeed whether these are simply people with very frequent headache who unsurprisingly take very frequent medication. I don’t think it is the latter, but have no data to disprove that possibility.
    In my practice (secondary and tertiary), 40 per cent of headache referrals have medication-overuse headache (MOH), but this diagnosis is suggested in only 5 per cent of referral letters. In those cases where the referring doctor raises the possibility of MOH, I find it is correct 90 per cent of the time. About 10 per cent of my MOH patients are overusing triptans; most are on codeine combinations, some on aspirin, paracetamol or NSAIDs, some on opiates such as morphine, pethidine or tramadol!
    Any ingested chemical (ie drug) used for short-term headache relief can trigger MOH. Curiously, regular NSAIDs don’t cause MOH but as-required NSAIDs do. Some people use sedatives or hypnotics as migraine rescue and I am beginning to think these can also cause MOH though this is not, I think, the consensus opinion. Topical applications do not cause MOH.
    It can be difficult to obtain the history of MOH from patients who ‘don’t like tablets – I keep it to a minimum’. Almost always, enquiry of benefit reveals ‘it takes the edge off it’. Pain duration is typically reported in terms of ‘when I take the tablets . . .’. They often have plenty of pills in their briefcase or handbag, acknowledge that they have a small stash of pills at home, at work, in the car and at their friend’s place; their partner will give a clear account ‘he/she lives on pills’.
    The threshold for MOH is amazingly low – only two or three doses a week, every week for three months, is enough to convert acute onto chronic headache. The problem arises more with broadly continuous daily use than with clustered use of medications.
    MOH is probably confined to patients with underlying migraine. It is not, for example, seen in cluster headache patients who can use a sumatriptan injection three times daily for a few weeks without acquiring MOH (though there are better ways to manage cluster than just with sumatriptan, eg short-course steroids, medium-course verapamil).

Dr Giles Elrington MD, FRCP, consultant neurologist at Barts and the London NHS Trust and Colchester General Hospital

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GLP-1 agonists

Which patients are candidates for GLP-1 agonists?

Specialist’s response: GLP-1 (glucagon-like peptide-1) agonists (or incretin mimetics) increase insulin secretion after meals, suppress glucagon secretion and in addition reduce appetite and slow gastric emptying by up to one to two hours, preventing the rise in postprandial glucose. Two preparations are available – exenatide (Byetta), injected twice daily, and liraglutide (Victoza), injected once daily. A once-weekly injection of exenatide (Bydureon) has now been approved for use in the UK.
    These drugs are seen as alternatives to long-acting insulins such as glargine (Lantus) or biphasic insulins such as insulin aspart (Novomix). The advantages of GLP-1 agonists over insulin therapy include weight reduction, less risk of hypoglycaemia and less need for blood glucose monitoring. In the author’s experience it is the weight loss that is most appealing to patients with type 2 diabetes.
    In type 2 diabetes, their use should be considered as third-line treatment (HbA1c ≥7.5 per cent) to metformin and a sulfonylurea if a patient has a body mass index (BMI) >35kg per m2. They can also be used in combination with pioglitazone. A lower BMI may be considered in non-European ethnic groups such as South Asian adults. The most recent National Institute for Health and Clinical Excellence (NICE) guidelines published in 20091 allow a BMI of <35.0 to be considered in those patients in whom insulin would have substantial occupational implications (ie hypoglycaemia risk) or weight loss would benefit other serious morbidities.
    The NICE guidelines conclude that the continuation of a GLP-1 agonist is dependent on a beneficial metabolic response (a reduction of at least 1.0 percentage point in HbA1c) and a weight loss of at least 3 per cent of initial body weight over six months.

Reference
1. Adler A, et al. BMJ 2009;338:1328–9.

Ian Campbell MD, FRCP Emeritus Professor of Medicine at the Medical School, University of St Andrews, Fife

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H. pylori and NSAID-induced peptic ulceration

Does eradicating Helicobacter pylori protect against NSAID-induced peptic ulceration?

Specialist’s response: Both Helicobacter pylori and NSAIDs are recognised as major causes of gastroduodenal ulceration. The presence of H. pylori increases the risk of peptic ulcer bleeding by 1.8-fold; NSAIDs increase bleeding risk by five times. When both factors are present, the risk increases to a factor of 6.1. This combination effect is relatively modest and suggests that effects of H. pylori and NSAID are partially additive, but not synergistic.
    The reasons for this observation may relate to their different mechanisms of action. NSAIDs act through cyclo-oxygenase-2 (COX-2) to reduce prostaglandin synthesis in the gastric mucosa. This leads to a reduction in mucosal blood flow and reduced mucus and bicarbonate secretion. By contrast, H. pylori causes damage by mucosal inflammation and by cytotoxin. This chronic inflammation may actually help to restore prostaglandin levels.
    Early studies looking at the benefits of H. pylori eradication in patients taking NSAIDs were conflicting. More recent work has clarified that eradication of H. pylori before or at initiation of chronic NSAID therapy does reduce the rate of future gastroduodenal ulceration. However, there seems to be no benefit in patients who are already taking and tolerating their NSAID treatment.

Mike Plant MD, FRCP is consultant rheumatologist at the James Cook University Hospital, Middlesbrough

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Safety of trimethoprim in pregnancy

Can trimethoprim be safely used in pregnancy for treating UTIs? 

Specialist’s response: Folate deficiency in pregnancy has been linked to the development of neural tube defects, and folic acid supplementation is internationally recommended for all women in the periconceptional period and during the first trimester of pregnancy.
    Folic acid antagonists include a variety of drugs that can be divided into two loosely defined groups. The first, the dihydro­folate reductase (DHFR) inhibitors, eg sulphonamides, trimethoprim and methotrexate, block the conversion of folate to its more active metabolites. The second group produce low serum and tissue concentrations of folate due to various pharmacokinetic mechanisms, and mainly include antiepileptics – carbamazepine, phenytoin, lamotrigine, primidone (Mysoline), valproic acid and phenobarbital – and colestyramine.
    Trimethoprim is an inhibitor of bacterial DHFR, and remains a useful antimicrobial agent for the treatment of uncomplicated lower urinary tract infections. In humans, the reduction of dihydrofolate is also catalysed by DHFR, although trimethoprim has at least 10 000-fold more inhibitory effect on the bacterial enzyme than on the corresponding mammalian enzyme.
As trimethoprim is a folic acid antagonist, concerns have been raised about its use in pregnancy. The current BNF states that there is a teratogenic risk if trimethoprim is used in the first trimester,1 and the US Food and Drug Administration (FDA) classifies it into Category C (should be given only if the potential benefits outweigh the potential risks to the fetus). The summary of product characteristics (SPC) recommends that trimethoprim should not be administered to pregnant women.2
    Although trimethoprim appears to be teratogenic in rats, when given at doses that far exceed the normal human dose, there is little evidence of teratogenicity in humans. A review of the literature by the UK Teratology Information Service (UKTIS, formally the National Teratology Information Service) in 2008 concluded that there was no significant risk of congenital malformation following exposure to trimethoprim. It recommended that in cases where there was a compelling indication for trimethoprim in pregnancy, it should not be withheld in pregnant women receiving folate supplements.3
    Recent retrospective studies examining the use of folic acid antagonists, predominantly in the form of co-trimoxazole (trimethoprim/sulfamethoxazole) in pregnancy have found associations with increased risks of congenital malformations4 and adverse pregnancy outcomes including pre-eclampsia and fetal growth restriction.5
    It is currently recommended that trimethoprim may be used for treating urinary tract infections in the first trimester of pregnancy, but only when the sensitivities of the isolate are known, and when no alternatives exist.6 In women who are well nourished and not folate deficient (or taking another folate antagonist) it is unlikely that a short course of trimethoprim will cause folate deficiency. If trimethoprim is to be used in the first trimester, then folic acid supplementation is recommended.6 In the UK most women routinely receive folic acid supplementation, although the prescriber should ensure that the woman is receiving a standard dose of folic acid (400µg per day). Women perceived to be at higher risk of neural tube defects should be offered a higher dose of folic acid (5mg per day).

References
1. British National Formulary. BNF 61. March 2011.
2. Trimethoprim. Summary of product characteristics. www.medicines.org.uk/emc.
3. National Teratology Information Service. Use of trimethoprim in pregnancy. TOXBASE. 2008. www.toxbase.org.
4. Matok I, et al. Br J Clin Pharm 2009;68:956–62.
5. Wen SW, et al. CMAJ 2008:179:1263–8.
6. NHS Clinical Knowledge Summaries. Urinary tract infection (lower) – women – management. http://bit.ly/kSFUSm.

Martin Williams PhD, MRCP, FRCPath is consultant in medical microbiology and infectious diseases at the HPA Regional Microbiology Laboratory South West, Bristol   

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Dianette for acne and hirsutism in a 42 year old

A slim, nonsmoking 42-year-old woman is asking for help with acne and hirsutism. She was diagnosed to have polycystic ovary syndrome on the basis of an ultrasound scan and these symptoms 12 years ago. Since then she has had two successful pregnancies.
    Before the pregnancies she responded well to the use of Dianette (co-cyprindiol). Is it appropriate to offer this treatment again, or would a lower-dose third-generation pill be just as likely to help? She is happy with her current condom use for contraception.

Specialist’s response: Co-cyprindiol contains 35μg ethinylestradiol (EE) and 2mg cyproterone acetate (CPA). Co-cyprindiol is licensed as a second-line treatment for women with moderately severe hirsutism or with severe acne that has not responded to oral antibiotics. It also acts as a contraceptive.
    COCs, including co-cyprindiol, can be continued up to the age of 50 years if there are no medical or lifestyle contraindications to use.1 For mild androgenic symptoms, standard COCs may suffice. A Cochrane Systematic review published in 2007 concluded that, overall, COCs evaluated in placebo-controlled trials are effective in reducing acne with few differences between COC types.2 For more severe symptoms it would be reasonable to consider co-cyprindiol.
    The Commission on Human Medicines reviewed evidence to suggest that the risk of venous thromboembolism is higher with co-cyprindiol than with conventional low-dose COCs.2 However, it is unclear how much of this extra risk is due to higher cardiovascular risk of women with polycystic ovary syndrome. The recommendation is that co-cyprindiol:
• should be used only in its licensed indication
• should not be used solely for contraception
• should be discontinued three to four months after complete resolution of symptoms.3
    Changing to a different COC may sustain benefit. If symptoms recur, co-cyprindiol can be restarted and continued under specialist supervision.

References
1. Faculty of Sexual and Reproductive Health. UK medical eligibility criteria for contraceptive use 2009. www.fsrh.org.
2. Arowojolu AO, et al. Cochrane Database of Systematic Reviews 2009, Issue 3. Art. No.: CD004425. DOI: 10.1002/ 14651858.CD004425.pub4.
3. MHRA. Drug Safety Update 2008;1(issue 9):4. www.mhra. gov.uk/Safetyinformation/DrugSafetyUpdate/CON084884.

Anne MacGregor MD, MFSRH, MICR is associate specialist at Barts Sexual Health Centre and honorary professor at Barts and the London School of Medicine and Dentistry

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Hospital admission for very high blood pressure

When should hospital admission be considered for patients with very high blood pressure?

Specialist’s response: High blood pressure per se is rarely, if ever, a reason for hospital admission. With improvements in the management of hypertension, severe hypertension is rare. No more than 1 per cent of people with high blood pressure ever require hospitalisation.1
    The British Hypertension Society guidelines2 recommend urgent specialist referral for three categories of hypertension:
• accelerated hypertension, ie severe hypertension (BP ≥180/100mmHg) with grade III or IV hypertensive retinopathy (fundal haemorrhages and exudates with or without papilloedema)
• particularly severe hypertension (BP ≥220/110mmHg)
• hypertension with impending complications
    Immediate admission is mandatory for patients with accelerated (malignant) hypertension or with cardiovascular complications.
    Hypertensive crises are conventionally divided into two types.3
• Hypertensive emergencies are defined as severe hypertension, which requires titrated intravenous antihypertensive drugs in an intensive care unit to arrest progressive organ damage. Examples include hypertensive encephalopathy, severe hypertension associated with cerebrovascular disease, pulmonary oedema, acute coronary syndromes, dissecting aortic aneurysm, acute renal failure or use of recreational drugs (eg cocaine), phaeochromocytoma crisis, eclampsia or severe pre-eclampsia
• Hypertensive urgencies are defined as severe hypertension without symptoms or signs of acute target organ involvement where blood pressure lowering over 24–48 hours using oral drugs is necessary, eg severe hypertension associated with severe epistaxis.
    Accelerated hypertension might be considered as a hypertensive emergency but intravenous drug therapy is not indicated. Immediate hospital admission is generally recommended because of the risk of rapid loss of renal function that can be irreversible of blood pressure is uncontrolled, and the risk of development of hypertensive encephalopathy and consequent stroke.
    Differential diagnosis is based on clinical evidence of acute end organ damage more than the degree of elevation of blood pressure per se.4 Severe blood pressure elevation in the absence of acute neurological, vascular or cardiac damage disease not represent an immediate risk for the patient and can be managed by orally administered antihypertensive drugs without hospital admission, eg an asymptomatic man with BP 230/130 mmHg and no evidence of compromised end organs should not be hospitalised if urgent follow up as an outpatient is feasible after initiation of oral treatment; rapid blood pressure reduction may represent an unwarranted risk.5
    In contrast, a man with BP 180/100 mmHg and pulmonary oedema constitutes a hypertensive emergency and requires prompt hospitalisation.
    Hypertensive emergencies may be missed in previously normotensive individuals who have a sudden rise in blood pressure that may induce encephalopathy at only modest levels, eg 160/100mmHg or lower such as children with acute glomerulonephritis, young women with eclampsia and young people who take cocaine.3
    In normotension, the upper limit of autoregulation of cerebral blood flow may be as low as mean arterial pressure 120mmHg (BP 160/100mmHg); the upper limit is substantially higher in chronic hypertension.
    The GP has a key role in identifying patients who require hospitalisation. It is the presence or absence of acute and progressive target organ damage and not the level of blood pressure which determines whether hospital admission or out patient care is appropriate.4
    Even among specialists, there is considerable variability in the secondary care provided for hypertensive crises.6 Since few centres in the UK have expertise in the management of hypertension, the GP also needs to know where to refer.

References
1. Zampagliome B, et al. Hypertension 1996;27:144–7.
2. Williams B, et al. J Human Hypertens 2004;18:139–85.
3. Kaplan NM. Lancet 1994;344:1335–8.
4. Gifford RW. JAMA 1991;266:829–35.
5. Fagan TC. Arch Intern Med 1989;149:2169–70.
6. Katz JN, et al. Am Heart J 2009;158:599–606.el.

Gordon McInnes BSc, MD, FRCP, FFPM, FBPharmacolS is professor of clinical pharmacology and honorary consultant physician in the Division of Cardiovascular and Medical Sciences, Western Infirmary, University of Glasgow, president of the BHS, member of the steering committee of ASCOT and executive committee of VALUE, and UK national co-ordinator of HOT

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Does taking statins increase your chance of dying of cancer?

I am a GP who has been prescribing statins routinely for a decade and support their use in reducing the risk of premature death in patients with CVD and prescribe for other patients with a high risk quotient. However given that the chance of dying of mythical old age in ones sleep at the age of 100 is remote, and accepting one has to die of something, the question often asked but not scientifically answered is ‘does taking statins increase your chance of dying of cancer?’

Specialist’s response: This is an interesting question. Firstly, it is worth pointing out that the use of statins themselves does not seem to be associated with an increased risk of cancer.1 However, given that the use of statins in high-risk populations reduces the chances of death from cardiovascular disease, the implication would be that deaths from other types of disease, including cancer, would be increased but occur later (given the point made in the question that one has to die of something).
    Statins hopefully allow you to live longer but don't stop you dying.

Reference
1. Hippisley-Cox J, et al. BMJ 2010;340:c2197.

Tony Avery DM, FRCGP, BMedSci, DCH, DGM is a GP and professor of primary health care, University of Nottingham Medical School, Queen’s Medical Centre

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Sexual dysfunction with SSRIs

How common is sexual dysfunction with SSRIs?

Specialist’s response: Sexual dysfunction is common in depressed patients and, conversely, the presence of such problems, with obvious impact on self-esteem and relationships, may act as a trigger for depression. The most commonly reported symptom of impaired sexual functioning in depression is reduced desire. Since most studies reporting sexual functioning in patients on antidepressants rely on self-reports, rather than interview-based questionnaires, impaired functioning is often under-reported. It is therefore important to specifically question such patients for such problems.
    SSRIs frequently cause sexual dysfunction with up to 60 per cent of patients reporting delayed or absent orgasm, reduced vaginal lubrication, premature ejaculation and reduced libido. Impaired sexual functioning is most likely to be linked with serotonin stimulation induced by the SSRIs, especially agonistic activity at the 5HT2 receptor site.
    There is probably little to choose between the SSRIs in terms of induction of sexual dysfunction. Switching from one to another may not improve the side effect or simply swap one sexual side effect for another. Both duloxetine (Cymbalta) and mirtazapine, of the newer antidepressants, seem a good second choice if treatment emergent sexual dysfunction is reported or elicited.

Dr Martin Livingston MD, FRCPsych is consultant psychiatrist and honorary senior clinical lecturer, Southern General Hospital, Glasgow

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Indefinite licence for atrophic veginitis

I’ve heard Vagifem (estradiol; unopposed HRT) now has an indefinite licence for atrophic vaginitis. Is this true for all local vaginal oestrogen preparations and what checks, if any, should GPs do on these women when repeat prescribing? 

Specialist’s response: It is only Vagifem that has an indefinite licence. No special checks for estriol preparations used in low dose are required as there is no evidence they stimulate the endometrium. However, conjugated oestrogen cream (Premarin) does and should be avoided in women who have not had a hysterectomy.

Professor Margaret Rees DPhil, FRCOG is a reader in reproductive medicine at the University of Oxford, honorary consultant and visiting professor at the Faculty of Medicine, University of Glasgow, and adjunct associate professor at the Department of Obstetrics, Gynecology and Reproductive Sciences, University of Medicine and Dentistry of New Jersey, USA

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Higher dose etoricoxib in RA 

Following an EMEA review, different maximum daily doses of etoricoxib (Arcoxia) are recommended for different indications. Since this is based on heart disease risk associated with etoricoxib use, why is a higher dose deemed safe in people with rheumatoid arthritis (RA) who already have a higher cardiovascular risk?  

Specialist’s response: A trend seen with the newer cyclo-oxygenase-2 (COX-2) selective inhibitors (coxibs) has been for the recommended dose to be related to the underlying condition. Hence, etoricoxib has a recommended dose of 30mg daily for patients with osteoarthritis (OA, with option of increase to 60mg), 90mg for patients with RA or ankylosing spondylitis (AS) and 120mg for acute gout. This is based on several factors including efficacy, expected duration of treatment and cardiovascular risk.
    First of all, it is important to state that COX-2 selective inhibitors should not be used in patients with pre-existing ischaemic heart disease, cerebrovascular disease or peripheral arterial disease. That caution would also apply to patients at high risk of vascular disease. For acute gout, a higher dose can be used as the drug is only likely to be used until symptoms settle in 7–10 days. For patients with inflammatory rheumatic disease (RA and AS), the intermediate dose of 90mg etoricoxib is usually required to obtain reasonable symptom relief. About 50 per cent of patients with OA respond to NSAID therapy – a lower proportion than for RA – and that improvement can be gained at lower doses. One explanation for that paradox is that the analgesic effect of NSAIDs reaches a plateau at a lower dose than does the anti-inflammatory effect.
    Initially, etoricoxib 60mg was recommended for OA. But, with increasing concern over adverse effects of COX-2 inhibitors, the manufacturers switched their recommendation to the lower 30mg dose; this dosage is certainly more effective than placebo, although not as effective as the 60mg dose. Numbers needed to treat to achieve a halving of pain intensity are 4.2 for 30mg etoricoxib daily and 2.6 for 60mg.

Mike Plant MD, FRCP is consultant rheumatologist at the James Cook University Hospital, Middlesbrough 

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Statins and muscle pain

Many patients come in complaining about a range of problems that they blame on their statin (usually simvastatin). Can you offer some guidance on how to manage such patients?

Specialist’s response: Cardiovascular disease (CVD) has become the world’s major cause of death. It was responsible for one-third of total global deaths in 2001, and the expectation is that by 2010 its continuing increase in incidence will have resulted in it far exceeding all other causes of death and disability.1 Those of us living in developed countries have been facing this problem for many years.
    It is also clear that cardiovascular mortality is rising exponentially in developing countries, largely due to changes in lifestyle such as poor dietary habits and lack of exercise leading to obesity. Smoking prevalence is also high in these countries. Ethnic minorities in developed countries have been shown to be at increased risk for CVD.2,3
    Statins were introduced for the treatment of hyper­cholesterolaemia in 1987. They are the most effective lipid-lowering agents available and are used by more than 100 million people each year.4 In addition to their lipid-lowering effects, statins also have pleiotropic effects that provide additional benefits.
    A recent meta-analysis performed by the Cholesterol Treatment Trialists’ (CTT) Collaboration found that when they examined more versus less intensive statin regimens, further reductions in low-density lipoprotein (LDL) cholesterol safely produced definite further reductions in the incidence of heart attack, revascularisation and ischaemic stroke. Each 1.0mmol per litre reduction in LDL cholesterol reduced the annual rate of these major vascular events by just over one-fifth. There was no evidence of any threshold within the cholesterol range studied, suggesting that a reduction of LDL cholesterol by 2–3mmol per litre could  reduce CVD risk by about 40–50 per cent.5
    Bearing this fact in mind, clearly for patients with significant risk of CVD, encouraging and enabling them to continue statin therapy is vital. There has been much media publicity about the problem of myopathy, muscle pain and rhabdomyolysis caused by statins. Approximately 1.5–3 per cent of patients prescribed statins in randomised controlled trials, and a larger number of participants (10–13 per cent) enrolled in prospective clinical studies, develop myalgia.4,6–8
    In a review of a population-based cohort study of patients from general practices in the UK that was performed between 1991 and 1997, the mean incidence of myopathy in patients taking statins was 1.2 per 10 000 person years. Myopathy was defined as muscle weakness and raised concentrations of creatinine kinase (CK).9
    In a systematic review of 21 clinical trials, which provided 180 000 person years of follow-up in patients treated with statins or placebo, myalgia affected 19 patients per 10 000 person years, myopathy 0.5 patients per 10 000 person years and rhabdomyolysis 0.16 patients per 10 000 person years. All figures were placebo corrected.4
    The PRIMO (Prediction of Muscular Risk in Observational Conditions) study enrolled an unselected population of 7924 French adults who had hypercholesterolaemia and were receiving high-dose statin therapy for three or more months before the study started. In this study, a total of 832 patients (10.5 per cent) reported muscle-related symptoms,6 which is at least twice as high as the number seen in randomised clinical trials involving statins (1–5 per cent).10 The figures were 5.1 per cent for fluvastatin (80mg), 10.9 per cent for high-dose pravastatin (40mg), 14.9 per cent for atorvastatin (Lipitor, 40–80mg) and 18.2 per cent for simvastatin (40–80mg).
    The myalgia tended to start fairly early after the initiation of high-dose statins (median time of onset approximately one month following treatment initiation or intensification). Approximately 15 per cent of patients reported muscle-related symptoms that appeared more than six months after treatment initiation. Less than half the patients could identify a particular trigger for their muscle-related symptoms (41.3 per cent) but, of the precipitants reported, unusual physical exertion and taking a new medication were the most common.
    A few patients had a family history of muscle pain during lipid-lowering therapy and this risk factor nearly doubled the risk of muscle-related symptoms. A personal history of elevated CK concentrations also predicted muscle-related symptoms.6 Other known risk factors for muscle pain include female sex, frailty or low body mass index (BMI), hypothyroidism, concomitant treatment with certain cytochrome P (CYP) 450 inhibitors, polypharmacy, and impaired hepatic and renal function (see Table 1). Changes in lean body mass versus body fat ratio alter the distribution of hydrophilic – eg pravastatin, fluvastatin and rosuvastatin (Crestor) – and lipophilic – eg simvastatin and atorvastatin – drugs and may be contributory to the onset of symptoms.11

• family history of statin-related muscle symptoms
• history of elevated CK
• female sex
• frailty or low BMI
• hypothyroidism
• polypharmacy
• impaired hepatic/renal function
Table 1. Factors that may increase the likelihood of statin-related muscle symptoms

    The National Lipid Association has some sensible advice to deal with this issue (see Table 2):
• measuring baseline creatinine kinase (CK) levels is not routinely necessary but is wise in high-risk patients in whom it provides a useful baseline since there are individual variations and ethnic differences
• routine CK measurements in asymptomatic patients are not necessary
• patients should be advised to report muscle symptoms when they occur, and in this situation CK measurements should be obtained.

• measure CK in symptomatic patients
• continue statin at same or reduced dose if symptoms are tolerable and CK <10 x ULN
• discontinue statin if muscle pain is intolerable with or without CK elevation or CK >10 x ULN
• seek other causes for symptoms or CK elevation
• if pain settles try an alternative statin, eg fluvastatin with or without ezetimibe
• if statins continue not to be tolerated try ezetimibe monotherapy
Table 2. Suggested management of statin-related muscle pain

    Statin therapy can be continued at the same or reduced doses in patients who develop tolerable muscle symptoms or are asymptomatic with a CK level of less than 10 times the upper limit of normal (ULN). Statins should be discontinued if patients develop intolerable muscle-related symptoms with or without CK elevation or if CK is >10 x ULN.
    An enquiry regarding the colour of the urine is helpful as rhabdomyolysis causes dark coloration of the urine. At this stage other causes for the symptoms and/or CK rise need to be established.12
    Causes may include hypothyroidism, hepatic or renal disease, high alcohol intake and drug interactions, particularly with fibrates, nicotinic acid, calcium-channel blockers, ciclosporin, amiodarone, thiazolidinediones, macrolide antibiotics, azole antifungals, protease inhibitors and warfarin.13
    Once the patient’s muscle pain has settled, statin therapy, possibly with an alternative agent, can be recommenced, either at the same dose to test reproducibility or at a lower dose.12
    If a patient is able to tolerate a lower dose of statin but is not at the LDL-C goal, ezetimibe (Ezetrol) can be added to statin therapy to reduce the risk of recurrent muscle symptoms while retaining efficacy.14,15
    The theory of prescribing fluvastatin 80mg and/or ezetimibe in patients with statin-induced, muscle-related adverse events was tested in a randomised controlled trial. The study found that this combination was effective and well tolerated over 12 weeks.16 If a trial of fluvastatin 80mg is unsuccessful, alternative options are to switch to low-dose rosuvastatin regimens (5–10mg daily) or alternate-day or weekly rosuvastatin.14 This approach has only been tested in an open-label pilot study.17
    If muscle symptoms recur with trials of multiple statins and doses, nonstatin lipid-lowering therapy must be considered.14 The efficacy of ezetimibe monotherapy15 and ezetimibe in combination with colesevelam (Cholestagel)18 has been studied in statin-intolerant patients.
    Lifestyle advice is clearly very important in patients who cannot tolerate statins. This should include reduced intake of saturated fats and cholesterol, increased physical activity and weight control. Plant stanols and sterols are another option.19 There are several randomised trials looking at whether the addition of co-enzyme Q10 to statin therapy can reduce muscle pain. These have yielded equivocal results.20–22
    For those who want more information on what to do when patients on statins develop muscle pain, Terry Jacobsen has provided an excellent review in the Mayo Clinic Proceedings14 on which this paper is based, and there is also a helpful clinical review in the BMJ by Sivakumar Sathasivam and Bryan Lecky.13

References
1. Ballantyne C, et al. Eur Heart J 2005;26:2224–31.
2. Watanabe H, et al. J Atheroscler Thromb 2004;11:330–4.
3. Sekikawa A, et al. J Am Coll Cardiol 2008;52:417–24.
4. Law M, et al. Am J Cardiol 2006;97(suppl 8A):52–60c.
5. Cholesterol Treatment Trialists (CTT) Collaboration. Lancet 2010;376:1670–81.
6. Bruckert E, et al. Cardiovasc Drugs Ther 2005;19:403–14.
7. Scott RS, et al. New Zealand Med J 1991;104:493–5.
8. Bays H. Am J Cardiol 2006;97 (suppl 8A):6–26C.
9. Gaist D, et al. Epidemiology 2001;12:565–9.
10. Thompson PD, et al. JAMA 2003;289(13):1681–90.
11. Jacobsen TA. Drug Saf 2006;29(5):421–48.
12. McKenney JM, et al. Am J Cardiol 2006;97(suppl 8A):89C–94C.
13. Sathasivam S, et al. BMJ 2008;337:1159–62.
14. Jacobsen TA. Mayo Clin Proc 2008;83(6):687–700.
15. Gazi IF, et al. Curr Med Res Opin 2007;23(9):2183–92.
16. Stein EA, et al. J Cardiol 2008;101(4):490–6.
17. Glueck CJ, et al. Clin Ther 2006;28(6):933–42.
18. Rivers SM, et al. Endocr Pract 2007;13(1):11–16.
19. Expert panel on detection, evaluation and treatment of high blood cholesterol in adults. JAMA 2001;285(19):2486–97.
20. Marcoff L, et al. J Am Coll Cardiol 2007;49(23):2231–7.
21. Young JM, et al. Am J Cardiol 2007;100(9):1400–3.
22. Caso G, et al. Am J Cardiol 2007;99(10):1409–12.

Mike Kirby FRCP, visiting professor to the Faculty of Health & Human Sciences, University of Hertfordshire and the Prostate Centre  

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Minimising weight gain with antipsychotics

How can weight gain be minimised on antipsychotics?

Specialist’s response: Weight gain is a frequently reported adverse effect in patients on antipsychotics and as many as 60 per cent of medicated schizophrenic patients may be obese. Weight gain is greater in women and less likely in older people. It may be more severe in bipolar patients who also take mood stabilisers that induce weight gain, eg lithium.
    The relationship between the weight gain and anti­psychotic drug dose is unclear. In the short term clozapine is most likely to induce clinically significant weight gain, followed by olanzapine, quetiapine (Seroquel), risperidone, amisulpride and aripiprazole (Abilify). In the longer term clozapine remains at the highest risk but the rank order of the other drugs becomes less clear. Prescribers can minimise the risk of obesity by choosing a drug less likely to induce weight gain, where feasible. Unfortunately clozapine, initiated by specialists, is the only drug option for treatment-resistant cases of schizophrenia. The older antipsychotics may also be useful in minimising weight gain, eg haloperidol.
    Patients should be weighed regularly and annual blood glucose and lipids performed. Obesity is highly resistant to treatment but efforts should be made to counter the inactivity of many patients who suffer from psychosis and to educate them about healthy eating. Exercise and sports groups provide social opportunities as well as increasing energy output.

Dr Martin Livingston MD, FRCPsych is consultant psychiatrist and honorary senior clinical lecturer, Southern General Hospital, Glasgow

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Nonhormonal treatment options for women with heavy periods

A lot of women have painful heavy periods but do not want to use any form of hormonal contraception, either because they are trying to conceive or they just ‘don’t want hormones’. What are the treatment options for this group?

Specialist’s response: The options are either NSAIDs such as mefenamic acid or tranexamic acid, which can be taken alone or combined.

Professor Margaret Rees DPhil, FRCOG is a reader in reproductive medicine at the University of Oxford, honorary consultant and visiting professor at the Faculty of Medicine, University of Glasgow, and adjunct associate professor at the Department of Obstetrics, Gynecology and Reproductive Sciences, University of Medicine and Dentistry of New Jersey, USA

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Beta-blockers for essential tremor

Do beta-blockers remain the best treatment for essential tremor?

Specialist’s response: Essential tremor is often best left untreated as it is usually more embarrassing than disabling.
    Embarrassment at social events because of essential tremor is often best targeted with a small (one unit) dose of alcohol as long as this is no more than three times weekly.
    Otherwise yes, I would start with a beta-blocker before considering other agents such as barbiturates, gabapentin or topiramate (unlicensed).
    Occasionally experts are caught out by ‘benign tremulous Parkinson’s’, which can look remarkably like an essential tremor and respond well to antiparkinson’s drugs, which are best initiated by a specialist. Other specialist treatment for tremor includes deep brain stimulation, which can be very effective for severely disabled patients.

Giles Elrington MD, FRCP, consultant neurologist at Barts and the London NHS Trust and Colchester General Hospital

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Why is Mirena only licensed for four years as HRT?

Why is the levonorgestrel intrauterine system (Mirena) licensed for five years as a contraceptive but only four years as the progestogenic part of HRT, when a lot of women use it for both at the same time? It is very confusing.

Specialist’s response: The clinical studies lasted 60 28-day cycles on average, so never quite achieved the five years. Pragmatically, you could change the Mirena every five years, but I would advise not going outside the licence in case there was a problem.

Professor Margaret Rees DPhil, FRCOG is a reader in reproductive medicine at the University of Oxford, honorary consultant and visiting professor at the Faculty of Medicine, University of Glasgow and adjunct associate professor at the Department of Obstetrics, Gynecology and Reproductive Sciences, University of Medicine and Dentistry of New Jersey

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What drugs are to be preferred for second-line treatment of diabetic hypertensive patients?

ACE inhibitors are first line for diabetic hypertensive patients but are any other drugs to be preferred for second-line treatment?

Specialist’s response: The choice of drugs for people with hypertension and diabetes is confused by many myths and misconceptions. The recommendation for ACE inhibitors as first-line therapy is supported by limited evidence.1 The most convincing evidence is for renoprotection with no substantial support for cardiovascular protection beyond that attributable to improved blood pressure control.
    The British Hypertension Society (BHS) guidelines1 recommend ACE inhibitors in diabetic hypertensive patients particularly if cardiovascular risk is high by virtue of target organ damage; nephropathy in type 1 diabetes is a compelling indication, while nephropathy in type 2 diabetes is a possible indication for ACE inhibition.
    In diabetes with nephropathy or microalbuminuria, ACE inhibitor therapy should be introduced regardless of the level of blood pressure and titrated to the maximum tolerated dose. Even here, it is unclear whether the benefits are independent of blood pressure control or complementary to the more substantial benefits achieved by blood pressure reduction.
    The primary objective of treatment for diabetic hypertensive patients is rigorous blood pressure control.2 Tight control of blood pressure reduces cardiovascular complications and mortality and the progression of retinopathy, albuminuria and nephropathy.3 People with diabetes exhibit disturbances of blood pressure regulation and vascular function that increases vulnerability to hypertensive injury.4 However, only about 50 per cent of diabetic patients with elevated blood pressure receive a treatment change and consultation because of uncertainty about the importance of tight blood pressure control.5
    Therapeutic inertia in the management of diabetic hypertensives is made worse by unnecessary concerns about the diabetogenic potential of diuretics and beta-blockers.6 These effects are of uncertain significance in established diabetes and are likely to be more than compensated by improved blood pressure control. Almost all patients with hypertension and diabetes will require a combination of blood pressure lowering drugs and many require three or more.7 The combination is likely to include a thiazide or thiazide-like diuretic.
    In renal impairment and/or oedema, a loop diuretic as an alternative or addition to a thiazide or thiazide-like diuretic might be needed to reduce fluid overload and adequately control blood pressure. Other suitable add-on drugs are long-acting calcium-channel blockers, beta-blockers if there is coronary heart disease and alpha-blockers. It is reasonable to follow the National Institute for Health and Clinical Excellence (NICE)/BHS ACD algorithm8 unless there is a compelling contraindication for a particular drug class.

References
1. Williams B, et al. J Human Hypertens 2004;18:139-85.
2. Blood Pressure Lowering Treatment Trialists’ Collaboration. J Hypertens 2007;25:951-8.
3. UK Prospective Diabetes Study Group. BMJ 1998;317:703-13.
4. Williams B. J Hum Hypertens 1999;13:S3-8.
5. Kerr EA, et al. Ann Intern Med 2008;148:717-27.
6. Lam SK, et al. Lancet 2007;369:1513-14.
7. Hansson L, et al. Lancet 1998;351:1755-62.
8. NICE. Management of hypertension in adults in primary care. CG34. June 2006.

Gordon McInnes BSc, MD, FRCP, FFPM, FBPharmacolS is professor of clinical pharmacology and honorary consultant physician in the Division of Cardiovascular and Medical Sciences, Western Infirmary, University of Glasgow, president of the BHS, member of the steering committee of ASCOT and executive committee of VALUE, and UK national co-ordinator of HOT

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When would you consider an oral typhoid vaccine?

When would you consider an oral typhoid vaccine over the injection, and is it as good?

Specialist’s response: Typhoid fever is a serious systemic infection caused by Salmonella enterica serovar Typhi. S. typhi is spread by the faecal-oral route and humans are the only source of infection. It remains a significant public health problem in South and East Asia, Africa, Latin America, the Caribbean and Oceania (except Australia and New Zealand) and has an estimated global incidence of 22 million cases and 200 000 deaths per year.
    There are currently two vaccine preparations available in the UK: the oral vaccine (Vivotif) and the Vi capsular polysaccharide vaccine.

The oral typhoid vaccine
The oral typhoid vaccine contains a live, attenuated strain of S. typhi (Ty21a) in an enteric-coated capsule. It is licensed for use in adults and children from six years of age, and has a three-dose regimen (one capsule on day 0, 2 and 4). The capsules must be stored in a refrigerator and should be swallowed as soon as possible after placing in the mouth.
    Protective immunity is achieved 7-10 days after the last dose and may persist for three years in those exposed constantly (or repeatedly), but occasional travellers require repeat vaccine courses at intervals of one year. The cumulative three-year efficacy of three doses of the Ty21a vaccine is 51 per cent (95 per cent CI 36-62 per cent).1
    The use of Ty21a provides modest protection against S. enterica serovar Paratyphi B disease, and its use for large-scale vaccination appears to confer some herd protection.2
    Adverse reactions to the Ty21a vaccine are usually mild and include gastrointestinal upset, fever, influenza-like symptoms and headache. The oral typhoid vaccine is unlikely to be effective if administered at the time of ongoing diarrhoea, and antibacterials should be avoided for three days before and three days after oral typhoid vaccine. Antimalarials – other than proguanil with atovaquone (Malarone) – should only be given three days after the last dose of vaccine.
    It is not known whether the live, attenuated vaccine can cause fetal harm when administered in pregnancy, but could be considered during pregnancy and breast feeding if the risk of disease significantly outweighs the risk to the fetus.

The Vi capsular polysaccharide vaccine
The Vi capsular polysaccharide vaccine is given as an intramuscular injection and is licensed for use in children age two years or more and adults. The vaccine can be given to children between one and two years of age when the risk of typhoid is considered high, but it is recognised that the vaccine response may be suboptimal in this age group.
    A single dose of vaccine is required and confers protection 7-14 days after injection. A booster dose is required every three years to maintain protection. The cumulative efficacy for three years is 55 per cent (95 per cent CI 30-70 per cent), although protective levels of antibodies can be detected in >50 per cent of individuals up to 10 years after vaccination.
    The vaccines (Typherix and Typhim Vi) contain 50µg per ml of antigen and are presented in 0.5ml prefilled syringes. The vaccine is stable for six months at 37°C and for three years at 22°C, but the recommended storage temperature is 2-8°C.
    Vi vaccines are also available combined with hepatitis A vaccine (25µg per ml of Vi antigen) as Hepatyrix and ViATIM.
    The Vi polysaccharide vaccines are usually well tolerated and are not associated with serious adverse effects. Local reactions at the injection site are relatively common, although usually mild. Gastrointestinal disturbances, fever, headache, irritability, loss of appetite, fatigue, myalgia and malaise are among the most commonly reported side-effects.

The question
So, when would you consider using an oral typhoid vaccine over the injection? The characteristics of both vaccines are compared in Table 1. Both preparations offer a similar level of protection, although neither is 100 per cent effective and should not be seen as a substitute for scrupulous attention to hygiene.
    The use of the oral preparation would clearly be favoured by the needle-phobic patient, and it would be more acceptable to younger children (and their parents), although the current licensed indications restrict its use to children six years and older. The vaccine-’naïve’ traveller would almost certainly require additional cover mandating some form of injection, limiting the usefulness of the oral typhoid vaccine.
    The more ‘seasoned’ traveller might see advantages in the use of the oral vaccine as a short-term boost, but the restrictions of use, cost and the required frequency of repeated dosing to maintain immunity may make this formulation less attractive to the wider population.

References
1. Fraser A, et al. Vaccine 2007;25:7848-57.
2. WHO. Wkly Epidemiol Rec 2008:83;49-60.
British national formulary (www.BNF.org); accessed 31 July 2010.
Immunisation against infectious disease - ‘The Green Book’. Chapter 33. Typhoid (updated 9 February 2009). (www.dh. gov.uk/en/Publicationsandstatistics/Publications/Publications Policy AndGuidance/DH_079917); accessed 31 July 2010.

Martin Williams PhD, MRCP, FRCPath is consultant in medical microbiology and infectious diseases at the HPA Regional Microbiology Laboratory South West, Bristol  

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Are topical NSAIDs effective as oral NSAIDs and in which situations?

Our local prescribing advisers previously discouraged our use of topical NSAIDs, stating that they were expensive and there was no evidence to support their use. NICE now recommends their use for osteo­arthritis. Are they as effective as oral NSAIDs and, if so, in which situations and for which joints?

Specialist’s response: Contrary to early scepticism, topical NSAIDs do work. However, the benefit is rather modest and may not last beyond a few weeks. Placebo-controlled studies have indicated NNTs of 4-5 for clinically significant pain relief. Overall, topicals are not as effective as oral NSAIDs, but they do have the advantage of almost no side-effects.
    NICE has included topical NSAIDs as an early step in the management of osteoarthritis. Anecdotally, topical NSAIDs may be more helpful in soft-tissue conditions such as injuries, sprains, bursitis and tenosynovitis.    For arthritic conditions, the smaller joints seem to respond better. Individual patient factors will be important in prescribing, as considerable motivation is required to massage the cream or gel regularly into the affected area to achieve the desired response.

Mike Plant MD, FRCP is consultant rheumatologist at the James Cook University Hospital, Middlesbrough

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Should topiramate (Topamax) only be initiated under 'specialist' supervision?

Topiramate (Topamax) has a licence for the treatment of migraine but this specifies that it should be initiated under ‘specialist’ supervision. Given that many of us would regard migraine as a ‘primary-care condition’, is this justified?

Specialist’s response: I don’t understand this advice, which I think cannot be evidence based. I completely agree that migraine is so common its management belongs in primary care. Many GPs may properly be considered specialists in headache.
    But remember that the most common cause of intractable headache is medication overuse (40 per cent of referrals) and the common error is to layer on drug after drug, when the correct management is complete cessation of overused (more than two or three per week – a surprisingly low threshold) acute remedies. This includes over-the-counter drugs, which are easily overlooked.
    Topiramate is better than placebo in the management of medication-overuse headache (MOH), but not much better, so adding topiramate in MOH patients is often disappointing unless the medication overuse is addressed. This usually means absolutely zero acute rescue medication.
    Topiramate has provided a great step forward in migraine management, but is not free from rare serious side-effects so it is always best to address MOH with ‘cold turkey’ for a good two months before considering adding a preventive such as topiramate.
It is often good to get patients to keep a migraine diary (eg download from www.migraineclinic.org.uk) before starting any preventive as benefit is typically relative, not absolute.

Dr Giles Elrington MD, FRCP, consultant neurologist at Barts and the London NHS Trust and Colchester General Hospital  

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How effective are nitrates in heart failure?

The textbooks advocate the theoretical benefits of nitrates in heart failure but these drugs do not seem to be much used in practice. How effective are they?

Specialist’s response: Nitrates (glyceryl trinitrate, isosorbide dinitrate and isosorbide mononitrate) are vasodilator agents with predominant action on the venous circulation. Direct relaxation of smooth muscle of the systemic venous system decreases preload, thus enhancing cardiac function. A lesser atrial vasodilator effect reduces afterload. As a result, the haemodynamic profile of nitrates is highly appropriate for the drug treatment of heart failure.
    In acute heart failure, venous pooling subsequent to veno­dilatation leads to a reduction in left ventricular end-diastolic pressure and volume, reducing pulmonary congestion without an associated rise in cardiac output. Nitrates are safe and effective in acute heart failure with a haemodynamic effect that may be better than that of furosemide, the usual first-line choice, while additionally reducing myocardial ischaemia that is often a co-existing problem.1
    Administration of glyceryl trinitrate by the sublingual route is convenient in the community but is rarely adequate alone for acute preliminary oedema. However, the combination of intravenous nitrate and a loop diuretic is better than high-dose diuretic alone.
    Nitrates should only be used if systolic blood pressure is above 90-100mmHg and obstructive valve disease has been excluded. Headache is common after nitrates and tachyphylaxis usually arises after 24 hours, necessitating an increased dose.
    The combination of hydralazine and isosorbide dinitrate was shown to reduce mortality in chronic heart failure in a trial conducted before the widespread use of ACE inhibitors.2 This combination is less effective than ACE inhibition3 but reduced symptoms, reduced worsening heart failure and improved survival in African-Americans treated with an ACE inhibitor, beta-blocker and, in many cases, spironolactone.4
Thus, adding the combination of hydralazine and isosorbide dinitrate should be considered in patients with persistent symptoms despite treatment with ACE inhibitor, beta-blocker and angiotensin-II receptor blocker (ARB) or aldosterone antagonist, or if ACE inhibitor, ARB or spironolactone is not tolerated.5 Nitrates also have a role in patients with chronic heart failure who have raised arterial pressure or angina despite standard therapy.

References
1. Northridge D. Lancet 1996;347:667-8.
2. Cohn JN, et al. N Engl J Med 1986;314:1547-52.
3. Cohn JN, et al. N Engl J Med 1991;325:303-10.
4. Taylor AL, et al. N Engl J Med 2004;351:2049-57.
5. Dickstein K, et al. Eur Heart J 2008;29:2388-442.

Gordon McInnes BSc, MD, FRCP, FFPM, FBPharmacolS is professor of clinical pharmacology and honorary consultant physician in the Division of Cardiovascular and Medical Sciences, Western Infirmary, University of Glasgow, president of the BHS, member of the steering committee of ASCOT and executive committee of VALUE, and UK national co-ordinator of HOT

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Is it safe to use etoricoxib (Arcoxia) 120mg daily in patients with gout?

How long is it safe to use etoricoxib (Arcoxia) at 120mg daily in patients with gout, and how do efficacy and side-effects compare with use of conventional NSAIDs such as naproxen? Are these drugs safe to combine with colchicine or oral steroids?

Specialist’s response: Most acute attacks of gout will last between 7 and 10 days. Etoricoxib is certainly a good option in that situation, bearing in mind that it should not be used in patients with cardio­vascular disease such as angina or stroke.
    A head-to-head comparison has shown that 120mg daily of etoricoxib is just as effective for relief of pain and swelling as full-dose indometacin 50mg three times daily.1 This is a significant piece of work as indometacin is generally agreed to be one of the more potent NSAIDs. In this study, etoricoxib or indometacin was given for eight days and by then 90 per cent of patients had responded. Etoricoxib was better tolerated than indometacin with a lower incidence of dizziness, headache, somnolence and digestive symptoms in particular.
    Colchicine and oral steroids are other useful therapeutic options for acute gout. Steroids can be combined with NSAIDs and COX-2 inhibitors, but this does come with an increased risk of GI bleeding and ulceration.
Similarly one would tend to use NSAID therapy or colchicine but not both, although the aforementioned trial did allow concomitant low-dose colchicine and no major problems were described.

Reference
1. Schumacher HR, et al. BMJ 2002;324:1488-92.

Mike Plant MD, FRCP is consultant rheumatologist at the James Cook University Hospital, Middlesbrough

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Why did the Human Medicines Commission include all HRTs in their warning to GPs in 2003?

Why did the Human Medicines Commission lump all HRTs together in their warning to GPs in 2003?1 Both the Women’s Health Institute (WHI) and the Million Women Study (MWS) show very different risks for oestrogen alone versus combined HRT? Why has it never been updated?

Specialist's response: In 2003 the MWS had just been published and queries about its design were only starting. More differences between preparations were shown by WHI than MWS. MWS was dominating UK thinking at the time. This 2003 guidance was a knee-jerk reaction to MWS. We now know from WHI as well as other studies that there are different risks between oral, transdermal, oestrogen alone and combined HRT, but this literature really only became evident from about 2004 onwards. There was an update in September 2007; here there is differentiation between oestrogen alone and combined HRT.

Reference
1. Committee on Safety of Medicines. HRT should be given for the shortest possible duration at the lowest possible dose: further advice on safety of HRT: risk-benefit unfavourable for first-line use in prevention of osteoporosis. 2003. CSM 3.12.03 CEM/CMO/2003/191.  

Professor Margaret Rees DPhil FRCOG is a reader in reproductive medicine at the University of Oxford, honorary consultant and visiting professor at the Faculty of Medicine, University of Glasgow and adjunct associate professor at the Department of Obstetrics, Gynecology and Reproductive Sciences, University of Medicine and Dentistry of New Jersey

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Is there a significant difference between melatonin and other hypnotics?

Do you think at a practical level, there is any significant difference between melatonin (Circadin) and other hypnotic drugs? Does it have real benefit over short-acting hypnotics?

Specialist’s response: The choice of medications to treat insomnia includes benzodiazepines such as temazepam, the so-called Z drugs – zaleplon (Sonata), zolpidem and zopiclone – melatonin, a pineal hormone, and sedative antidepressants such as mirtazapine and trazodone.
    Once it has been established that the sleep dysfunction is primary and not secondary to another physical or mental illness that requires treatment an hypnotic may be necessary, especially if simple sleep hygiene measures are ineffective.
    The aim should be to prescribe for the short term. Problems arise with this strategy where, for example, patients are at high risk of developing dependency. This is the case with the alcohol-dependent patient and benzodiazepines and is likely to be so with the Z drugs, which also act at the benzodiazepine receptor.
    Another factor is the need to avoid daytime sedation, which can be a problem even with short-acting hypnotics, and of course patients sometimes exceed the dose or take an extra tablet if awake through the night.
    Melatonin provides information about day length by its pattern of secretion, regulating core body temperature, alertness and many metabolic functions. Melatonin may be prescribed for patients aged 55 and over. It regulates the sleep-wake cycle without causing daytime sedation and is nonaddictive.1 Melatonin is not likely to be as strong a sleep inducer as the benzodiazepines and its main role may be to re-regulate sleep disrupted by shift working and long distance aircraft travel.2

References
1. Arendt J, et al. Br J Psychiatry 2008;193:267-9.
2. Cardinali DP, et al. Lancet 2008;373:439-41.

Dr Martin Livingston MD, FRCPsych is consultant psychiatrist and honorary senior clinical lecturer

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How should digoxin be initiated for housebound patients with atrial fibrillation and heart failure?

What is the best way of initiating digoxin in the community for housebound patients with atrial fibrillation and heart failure, bearing in mind that very frequent monitoring of digoxin levels may not always be practical?

Specialist's response: Along with thromboprophylaxis, rate control is an appropriate and safe option for the older, sedentary, asymptomatic individual with atrial fibrillation and heart failure.1 Current guidelines recommend both beta-blockers and digoxin for heart rate control,2 although digoxin may be inadequate for control of ventricular rate during exercise or when sympathetic tone is increased.3 Breakthrough tachycardia may be associated with fatigue and/or dyspnea but these considerations are less important in housebound patients. Digoxin is a rational choice since cardiac function will be improved by slowing of ventricular rate and positive inotropism while avoiding a potentially deleterious excess decrease in blood pressure induced by beta-blockade.
    Conventionally, digoxin is initiated by means of a loading dose but this is unnecessary in people with chronic atrial fibrillation unless symptoms are problematic. The usual maintenance dose is 125-250µg per day, although 62.5µg may be adequate in older subjects with poor renal function. If a maintenance dose is employed without a loading dose, drug accumulation and activity develop slowly because steady state is not reached for 4-5 half-lifes (about one week).
    Adjustment of digoxin dosage should be based on clinical judgement. Target resting heart rate in atrial fibrillation is less than 80-100bpm,4 although there are little data in patients with heart failure. Toxicity is best judged by occurrence of rare side-effects (anorexia/nausea). Monitoring of digoxin levels is of limited use since there is a poor relation between therapeutic (or unwanted) efforts and drug concentrations. However, monitoring for toxicity may be warranted if there is renal failure and in older patients when the first sign of toxicity may be a serious arrhythmia. The normal therapeutic range is 1-2µg per litre in a venous sample 6-8 hours after an oral dose.
    To avoid toxicity, lower doses are recommended in renal impairment (reduced digoxin clearance), in congestive heart failure (reduced metabolic clearance) and in hypokalaemia or hypercalcaemia (potentiation of toxicity). Since heart failure patients will usually be taking diuretics and drugs which block the renin angiotensin system, serum potassium should be monitored to adjust digoxin dose. Low dose beta-blocker is also a recommended component of management of chronic stable heart failure. Combination therapy with digoxin and a beta-blocker provides better control of heart rate with a lower risk of toxicity than with high-dose digoxin.1 Furthermore, digoxin in combination with beta-blocker is associated with a mortality rate less than that observed with digoxin alone.5

References
1. Roy D, et al. N Engl J Med 2008;358:2667-77.
2. Dickstein K, et al. Eur Heart J 2008;29:2388-442.
3. Farshi R, et al. J Am Coll Cardiol 1999;33:304-10.
4. Rawles JM. Br Heart J 1990;63:157-61.
5. Fauchier L, et al. Am J Cardiol 2009;103:248-54.

Gordon McInnes BSc, MD, FRCP, FFPM, FBPharmacolS is professor of clinical pharmacology and honorary consultant physician in the Division of Cardiovascular and Medical Sciences, Western Infirmary, University of Glasgow, president of the BHS, member of the steering committee of ASCOT and executive committee of VALUE, and UK national co-ordinator of HOT

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How should lamotrigine medication timing be adjusted for travels abroad?

How would you advise a patient taking once daily lamotrigine for her epilepsy to adjust the timing of her medication when she travels to the west coast of America for a 10 day holiday?

Specialist's response: The simplest answer is to take the medication every 24 hours – so for example an evening dose in the UK becomes a midday dose in California. Suggest that she set a reminder on her mobile phone and leave the phone on UK time while away.
    Alternatively, it probably matters little if the dose is a few hours late on the trip out and a few hours early on the trip back.
    A third option is to top up with an approximately one-third dose on the way out to accommodate the long day, then skip that one-third dose on the way back.
    Much hangs on whether the patient is seizure free and driving; whether lamotrigine dose is maximal (500mg daily) or not, and whether there are any side-effects. In epilepsy management it often helpful to consider whether the priority is to minimise seizures or side-effects.
    Sleep deprivation and alcohol – both of which are an agenda with foreign travel – may worsen epilepsy, particularly primary epilepsies such as juvenile myoclonic epilepsy. So be more than usually cautious about alcohol on the flight and while away; when jet lagged, err on the side of too much not too little sleep.

Dr Giles Elrington MD, FRCP, consultant neurologist at Barts and the London NHS Trust and Colchester General Hospital.

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How to explain the long-term osteoporosis risk to teenagers for Depo-Provera?

What is the current state of play with depot medroxyprogesterone acetate (DMPA; Depo-Provera) and the risk of long-term osteoporosis? How do we explain this to all the feckless 15 year olds for who it is the only thing that seems to work?

Specialist's response: Depot medroxyprogesterone acetate (DMPA; Depo-Provera) use remains a valid contraceptive option for women. Its potential impact on bone mineral density (BMD) must be balanced against the consequences of unintended pregnancy. The use of DMPA is associated with a slight decrease in BMD, which is largely, if not completely, reversible when it is stopped. I would advise the feckless girls to stop smoking. This is an excellent article you might want to refer to: The use of depot-medroxyprogesterone acetate in contraception and its potential impact on skeletal health. Guilbert ER, et al. Contraception 2009;79(3):167-77.

Professor Margaret Rees DPhil FRCOG is a reader in reproductive medicine at the University of Oxford, honorary consultant and visiting professor at the Faculty of Medicine, University of Glasgow and adjunct associate professor at the Department of Obstetrics, Gynecology and Reproductive Sciences, University of Medicine and Dentistry of New Jersey

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Why are first-generation antihistamines used in an emergency setting?

The main difference between first-, and second- and third-generation antihistamines is in sedation. Why in an emergency setting, is oral Piriton (chlorphenamine) still used instead of a second- or third-generation drug? Is the older drug more effective or does it work faster?

Specialist's response: The antihistamines used in an emergency setting will depend on whether the patient is self-treating or not. Early intramuscular adrenaline, is the first-line treatment for an anaphylactic reaction and antihistamines are a second-line treatment only.1
    In primary or secondary care, a parenteral antihistamine should be used to treat anaphylaxis because rapid onset of action is very important. Second generation, antihistamines are not widely available as parenteral preparations; therefore the current Advanced Life Support (ALS) guidelines recommend intravenous or intramuscular chlorphenamine as a secondary treatment for anaphylaxis. Oral chlorphenamine is not recommended for use in an emergency.1
    In the community, prescribing oral antihistamines for treating early symptoms of anaphylaxis is controversial – as it is argued that this can potentially delay the timely administration of adrenaline. However, most allergists will co-prescribe an EpiPen (adrenaline) and antihistamine for their patients but provide a clear action plan so that patients know the exact indications for self-administering adrenaline.
    The ideal antihistamine should be rapid in onset, nonsedating, long lasting and in liquid form (if prescribed for children). Oral chlorphenamine should not be prescribed for the emergency treatment of anaphylaxis in the community because it has a slower onset of action compared to second-generation antihistamines and side-effects including sedation. In contrast, second-generation antihistamines – eg certirizine and fexofenadine – have a rapid onset of action compared to first-generation antihistamines, are less likely to interact with other prescribed medications and also have fewer side-effects.2 Therefore second-generation antihistamines are the preferable treatment option.

References
1. Soar J, Pumphrey R, Cant A, et al.; Working Group of the Resuscitation Council (UK). Emergency treatment of anaphylactic reactions – guidelines for healthcare providers. Resuscitation 2008;77:157-69.
2. Simons FE. Advances in H1-antihistamines. N Engl J Med 2004;351:2203-17.

Dr Sophie Farooque MRCP is an allergist and clinical research fellow at the MRC Centre and Asthma UK Centre in Allergic Mechanisms for Asthma (King’s College London); she is also a member of the BSACI’s Standards of Care Committee and is an author of the BSACI guidelines for the management of allergic and nonallergic rhinitis

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Can dopamine agonists precipitate behavioural changes?

I have a patient in her mid 60s with Parkinson’s disease (PD). After some years on a dopamine agonist she is now taking levodopa. At a recent consultation she told me that her husband and friends have all noticed that she is much more confident to the point of being quite aggressive at times. She is also full of energy. Before her diagnosis she was quite timid and easy going. She wondered if it might be the pills that had caused this change?

Specialist's response: Cognitive change is common in people with PD, including those on no treatment, but is typically worsened by drugs that treat the movement disorder. This applies less to levodopa than to other PD drugs.
    Dopamine agonists are reported occasionally to worsen or trigger risk-taking behaviour, particularly gambling, sometimes other related behaviour such as excessive eBay use. So it is reasonable to consider that her medication may be contributing to her behavioural change, though it is not the only possible cause. I would see her with her husband, check bloods including thyroid, enquire about memory inefficiency, sleep disturbance (excess by day, less by night), hallucinosis (people and animals – which patients often don't volunteer) and delusional beliefs. I would also review safety as a driver.
    If there is significant or disabling cognitive change I would gradually reduce or stop medication, particularly the dopamine agonist and any other nonlevodopa drugs for PD, and consider later if necessary a prescription of Rivastigmine (Exelon). Cognitive change in PD tends to fluctuate and vary though the underlying trend is progressive worsening over years, and is usually the reason why people with PD can no longer cope in their own home; so early detection, careful support, and minimising drug risks with sacrifice of mobility to preserve cognition, is important.

Dr Giles Elrington MD, FRCP, consultant neurologist at Barts and the London NHS Trust and Colchester General Hospital.

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When should patients take a triptan for a migraine attack?

The BNF states that they should be taken during the headache phase of the attack. Do they work if taken during the aura phase? The patient information leaflet for some triptans states that they should be taken at “onset of attack”.

Specialist's response: Triptans should be taken when the headache has started and the patient is sure of a pending migraine. Clinical trials have shown that triptans taken during the aura before the headache has started do not reduce the headache whereas when taken when the headache has started the response is good. This is also our clinical experience. Taking a triptan too early is actually a frequent reason for ineffectiveness of triptans which can be resolved by treating only when the headache has started.
    The pharmacological reason is thought to be that the triptan-specific receptors on the trigeminovascular system only become externalised,and thus available for interaction, when the trigeminovascular system is activated (which is clinically reflected as having headache).
    Patients who have aura would regard that as the start of the attack so should be told to take triptans only at the start of the headache not at the start of the aura.

Professor Michel D. Ferrari MD, PhD, Leiden University Medical Centre, Leiden, The Netherlands

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