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DTB Select: 3 | March 2013


Every month, DTB scans sources of information on treatments, disease management and other healthcare topics for key items to bring to our readers' attention and help them keep up to date. To do this, we produce succinct, contextualised summaries of the information concerned. We also include comments on, for example, the strengths of the information, whether it contains anomalies, ambiguities, apparent error or omissions, or whether or how it affects current practice.

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Simple interventions to reduce hazardous drinking?

‘Hazardous’ consumption of alcohol puts drinkers at increased risk of a variety of short-term and long-term health problems including trauma-related injuries, mental health problems and liver disease.

Previous studies have suggested that brief interventions in primary care, such as lifestyle advice from a GP, can reduce levels of hazardous drinking. A study published in the BMJ looked at whether more intensive interventions have a greater impact.1

This cluster trial, carried out in 24 UK general practices based in the north east and south east of England and London, screened 2,991 patients aged 18 years and over for signs of hazardous drinking, using the alcohol use disorders identification test (AUDIT, score range 0–40; a score of ≥8 indicates hazardous or harmful drinking or the likelihood of dependent drinking). Immediately after screening (in the same consultation), trial participants received a short assessment and feedback of their drinking behaviour. General practices were randomised to give participants an information leaflet describing the effects of alcohol on health (control); the leaflet plus 5-minutes of structured advice on reducing harmful drinking; or the leaflet plus 5 minutes of structured advice and a follow-up consultation consisting of 20-minutes of lifestyle advice. In total, 900 (31%) people screened were identified as hazardous drinkers, of whom 756 (84%) agreed to take part in the study. The primary outcome was drinking status at 6 months as measured by the AUDIT tool.

Participants were contacted twice over the following year and the AUDIT screening tool administered on each occasion. At 6 months, more people reported drinking at non-hazardous or non-harmful levels in each of the three intervention groups compared with baseline (36% vs. 20% for the control group; 29% vs. 20% for the group receiving leaflet and structured advice; 29% vs. 15% for the group receiving leaflet, structured advice and lifestyle advice). But there was no significant difference between the control group and the two more intensive interventions (brief advice, odds ratio [OR] 0.85, 95% CI 0.52 to 1.39; brief advice plus follow-up lifestyle advice, OR 0.78, 95% CI 0.48 to 1.25). After 12 months the results were similar, with no significant difference between the interventions.

Comment: The research demonstrated improvement in AUDIT scores in the control group who received a simple information leaflet with no additional benefit with more intensive intervention. Screening patients, providing feedback on their drinking behaviour and an information leaflet may be seen as an attractive option in primary care where consultation times are limited. However, this study only looked at patient-reported drinking habits rather than hard health outcomes.


ACE inhibitors prevent kidney disease and death in people with diabetes

Current guidance from the National Institute for Health and Clinical Excellence (NICE) recommends that people with diabetes should be offered medication if lifestyle advice does not reduce blood pressure to below 140/80mmHg (or 130/80mmHg if there is kidney damage).1 For most people with diabetes, first-line blood-pressure-lowering therapy should be a once-daily, generic angiotensin-converting enzyme (ACE) inhibitor.

An updated Cochrane systematic review has analysed data for evidence of benefit from antihypertensive medications in people with diabetes but no kidney disease, measuring kidney- and patient-related outcomes.2 Outcomes included:

  • Development of microalbuminuria or macroalbuminuria or both

  • All cause mortality

  • Doubling of serum creatinine and progression to end-stage kidney disease.

The review identified 26 trials (involving 61,264 participants) and calculated risk ratios (RR) and 95% confidence intervals (CI). In patients with or without hypertension, ACE inhibitors effectively reduced new-onset micro- or macroalbuminuria compared with placebo (RR 0.71, 95% CI 0.56 to 0.89) and calcium channel blockers (RR 0.60, 95% CI 0.42 to 0.85). ACE inhibitors also reduced mortality compared with placebo (RR 0.84, 95% CI 0.73 to 0.97).

Angiotensin-II receptor antagonists had no significant effect on mortality, or new-onset microalbuminurea, macroalbuminuria or both (RR 0.90, 95% CI 0.68 to 1.19) or death (RR 1.12, 95% CI 0.88 to 1.41).

The authors found that the risk of cough was significantly increased with ACE inhibitors when compared with placebo (RR 1.84, 95% CI 1.24 to 2.72), but that there was no significant difference in the risk of headache or hyperkalaemia.

Comment: Diabetes is the leading cause of kidney disease in the UK, so finding the optimal treatment to prevent renal complications is a priority. This review provides further evidence that ACE inhibitors reduce the chances of new kidney disease in people with diabetes and should continue to be preferred to angiotensin-II receptor antagonists as first-line treatment.


Benefit of nutritional supplementation for people with COPD

Malnutrition is common in patients with chronic obstructive pulmonary disease (COPD), and is associated with decreased health-related quality of life and higher mortality. National Institute for Health and Clinical Excellence (NICE) guidance recommends that nutritional supplementation be given to people with COPD who have a low body mass index (BMI) to increase their total calorific intake.1

A recent Cochrane Review sought to assess the impact of nutritional support on a range of measures in patients with COPD.2 The authors identified 17 randomised controlled trials (632 participants) where nutritional support (defined as any caloric supplement given for more than 2 weeks) was provided to patients with stable COPD. The primary outcomes were body measurements (including weight and fat-free mass index) and functional exercise capacity (timed walk test). Nutritional support was provided as oral supplementation in 15 trials (mostly liquid pre-prepared supplement), one used nocturnal enteral tube feeding and one used a tailored and fortified diet with milk products; in five trials, nutrition was combined with exercise.

The authors found moderate quality evidence that supplementation encourages significant weight gain among malnourished and undernourished patients with COPD (mean difference [MD] from baseline 1.65kg, 95% CI 0.14 to 3.16). Low-quality evidence suggested that nutritional support improved 6-minute walk distance from baseline (MD 40m, 95% CI 23 to 57).

The study also reported significant improvements in secondary outcomes, such as health related quality of life and respiratory muscle strength.

All the trials reported an increase in calorie intake for the supplementation group. The weighted average of calories at the end of treatment for the intervention group was 2,065kcal compared with 1,918kcal for the control group.

Comment: Much of the evidence found by the authors of this review was low-quality. Nonetheless, the results suggest that nutritional supplementation should be considered as part of a care programme for patients with stable COPD and low body mass. Healthcare professionals are encouraged to identify and address barriers to maintaining adequate nutrition, including depression and fatigue. Patients should be given advice on increasing the calorific intake of their normal diet before the use of commercial nutritional supplements is considered.


Estimate of size of analgesic effect of amitriptyline

Amitriptyline has been prescribed, off-label, for neuropathic pain and fibromyalgia for decades. Although there is some evidence for the analgesic benefits of amitriptyline (and other tricyclic antidepressants), a new review suggests that the treatment effect may have been overstated.1

A Cochrane Review examined evidence from 21 randomised double-blind studies (1,437 participants) comparing amitriptyline with placebo or active therapy in the treatment of chronic neuropathic pain or fibromyalgia. Doses ranged from 25–125mg, with dose escalation reported in many studies.

The studies were generally small (median study size was 44 participants), of short duration (median duration of 6 weeks) or poorly reported. The authors warned of potential bias.

There was some evidence of analgesic effect in painful diabetic neuropathy, mixed neuropathic pain and fibromyalgia. However, amitriptyline did not benefit patients with cancer-related neuropathic pain or HIV-related neuropathic pain.

Combining data from studies (687 participants) of painful diabetic neuropathy, postherpetic neuralgia, post-stroke pain and fibromyalgia, the authors found that amitriptyline reduced pain compared with placebo or other active treatment (risk ratio 2.3, 95% CI 1.8 to 3.1). The number needed to treat was 5 (4–7).

More participants had effective pain relief from amitriptyline compared with placebo (38% vs. 16%). Despite the likely over-estimation of treatment effects, the authors concluded that the “magnitude and consistency of effect” in the eight studies at least provided some confidence that the analgesic benefits of amitriptyline are real, “at least for some patients”.

Comment: In our article ‘An update on the drug treatment of neuropathic pain. Part 1: antidepressants’, we noted that the previous Cochrane review (published in 2007) showed that amitriptyline had an NNT to achieve moderate pain relief or better of 3 (95% CI 2.5 to 4.2) based on 10 studies (288 patients).2

Although there is a debate over the magnitude of benefit to patients, the results from this updated Cochrane review suggest that amitriptyline remains a reasonable first-line option for some forms of neuropathic pain.


Preventing relapse in schizophrenia: injectable or oral antipsychotics?

The proven benefits of antipsychotic agents may be compromised in practice by high rates of non-adherence to oral therapy, which can reach 50%. Long-acting injectable (LAI) agents have been developed to try and improve adherence and treatment outcomes. Evidence from two meta-analyses, including one which specifically compared outcomes in trials of patients treated with oral versus depot antipsychotic drugs, showed that depot formulations were more effective in reducing relapse rates. In the latter review it was estimated that there was a 10% absolute reduction in relapse rates associated with use of the depot formulation compared with oral regimens (22% vs. 33%, p = 0.0009).1,2

A more recent meta-analysis (by some of the same researchers of one of the previous meta-analyses)2 comparing LAIs versus oral antipsychotics for relapse prevention in schizophrenia has found no significant difference in efficacy between formulations.3

The meta-analysis found that LAIs (fluphenazine, haloperidol, zuclopenthixol, risperidone, ▼olanzapine) were no more effective than oral antipsychotics (fluphenazine, pimozide, haloperidol, trifluoperazine, zuclopenthixol, olanzapine, quetiapine, risperidone, aripiprazole) at preventing relapse (at longest time point studied, 21 studies; 4,950 people; risk ratio [RR] 0.93, 95% CI 0.80 to 1.08). Nor were they any better when analysis was restricted to outpatient studies lasting at least 1 year (12 studies; RR 0.93, 95% CI 0.71 to 1.07; p = 0.31), or for secondary outcomes (relapse at 3, 6, 12, 18 and 24 months, all-cause discontinuation, discontinuation due to adverse events, drug inefficacy, hospitalisation and non-adherence).

The authors comment that they broadened the inclusion criteria over their previous analysis to include studies that enrolled inpatients and outpatients, and also by including studies lasting 6 months to <1 year. However, they comment that these changes did not account for the difference in outcome compared to their previous review.

Comment: By way of explanation, the authors suggest that results from controlled clinical trials, where intensive monitoring and regular interaction with healthcare professionals contribute to improved treatment adherence, are not consistent with findings from large, naturalistic studies that are more representative of ‘real world’ conditions. While there will be community-based patients at risk of relapse who have a record of poor adherence to oral antipsychotic medications, who would benefit from being prescribed a LAI antipsychotic, the absolute benefit across a population is unclear.


Levonorgestrel-IUS versus standard treatment for menorrhagia

For clinical purposes, heavy menstrual bleeding is defined as ‘excessive menstrual blood loss which interferes with the woman's physical, emotional, social and material quality of life, and which can occur alone or in combination with other symptoms’.1 Pharmaceutical treatment includes hormonal and non-hormonal options.

The levonorgestrel-releasing intrauterine system (LNG-IUS) is more effective than usual medical treatment in improving quality of life for women with heavy menstrual bleeding, reports a recent study.2

These findings come from a UK multicentre trial that randomised 571 women with menorrhagia to treatment with LNG-IUS or usual medical treatment (tranexamic acid, mefenamic acid, combined oestrogen-progestogen or progestogen-only oral contraceptive pill, or medroxypreogesterone acetate injection). The women were followed for 2 years; the primary outcome was change in score on the 100-point Menorrhagia Multi-Attribute Scale (MMAS), which measures the impact of the condition on daily life.

MMAS scores were improved in both groups over 6 months, with the improvements maintained over the 2 year follow-up period. However, improvements were significantly greater in the LNG-IUS group than in the usual care group (mean between-group difference 13 points; 95% CI 10 to 17). Women in the LNG-IUS group also scored higher on all MMAS domains (practical difficulties, social life, family life, work and daily routine, psychological well-being and physical health).

After 2 years, more women were still using LNG-IUS compared with usual care (64% vs. 38%, p < 0.001). There was no difference between the groups in serious adverse events, rates of surgery for menstrual bleeding or sexual-activity scores.

The benefit with LNG-IUS was greater for women with a BMI above 25 than for those with a BMI of 25 or less. This may mean that standard medical treatments are more effective than LNG-IUS for leaner women, say the researchers. However, they caution that this finding needs to be confirmed.

Comment: Current National Institute for Health and Clinical Excellence (NICE) guidance recommends that LNG-IUS should be considered for women with menorrhagia provided long-term (at least 12 months) use is anticipated.3 This study provides further evidence in support of the NICE guidance.


FDA reduces dosage for zolpidem

New data show that blood concentrations of zolpidem can remain sufficiently high upon waking to impair driving and other activities requiring mental alertness. This has prompted the US Food and Drug Administration (FDA) to recommend a lower dose of the drug.1

Zolpidem is widely prescribed as a short-term treatment for insomnia and in England 750,000 prescriptions were dispensed in 2011.2 In the US, the FDA has logged approximately 700 reports of impaired driving or traffic accidents following zolipdem use, but has been unable to definitively link the drug to these incidents. However, new findings from laboratory studies and driving simulations have suggested that zolpidem blood concentration higher than approximately 50ng/mL can impair driving to a degree that increases the risk of motor vehicle accidents. In studies using 10mg, approximately 15% of women and 3% of men had zolpidem concentrations exceeding 50ng/mL 8 hours after dosing. The agency warns that people with high concentrations of zolpidem can be impaired even if they feel fully awake.

The FDA has requested that manufacturers:

  • lower the recommended dose for women from 10mg to 5mg.

  • include the 5mg dose as an option for men.

The FDA also requires lower doses for zolpidem extended-release formulations, but these are not available in the UK.

Comment: A recent meta-analysis submitted to the FDA found that zolpidem and other ‘Z’ drugs can modestly reduce the amount of time it takes to fall asleep.3 These new findings suggest a relationship between zolpidem blood concentration and driving impairment, and underline the need for caution, both for doctors prescribing the medication and for patients taking it. In the UK, zolpidem is licensed for ‘the short-term treatment of insomnia in situations where the insomnia is debilitating or is causing severe distress for the patient’.4 The British National Formulary warns of next-day drowsiness that can affect performance of skilled tasks such as driving.5 These risks should be emphasised to patients, with the understanding that impairment can be present despite feeling awake.


Does amoxicillin help patients with acute LRTI?

A large, multicentre, placebo-controlled randomised trial has found that amoxicillin is ineffective in patients with uncomplicated respiratory tract infection.1

Lower respiratory tract infections (LRTIs) are commonly managed by GPs, yet few adequately-powered trials have examined the effect of antibiotics on symptoms. The trial randomly assigned 2,061 primary care patients with an acute LRTI (in whom pneumonia was excluded – no focal chest signs or systemic features) to 1,000mg amoxicillin three times daily for 7 days or to placebo. Patients were aged 18 years or older and consulting for the first time with either an acute cough (≤28 days' duration) as their main symptom, for which non-infective diagnoses were judged very unlikely, or an illness in which cough was not the most prominent symptom but the clinician thought acute lower respiratory tract infection the most probable diagnosis. The primary outcome was the duration of symptoms rated by patients as ‘moderately bad’ on a symptom severity scale from 0–6.

The authors found no significant difference in mean symptom duration (median 7 days with placebo vs. median 6 days with amoxicillin; hazard ratio [HR] 1.06, 95% CI 0.96 to 1.18) or severity (1.69 with placebo vs. 1.62 with amoxicillin; difference –0.07, 95% CI –0.15 to 0.007) between treatment and control groups. New or worsening symptoms were slightly less likely in patients who took amoxicillin compared with those on placebo (HR 0.79, 95% CI 0.63 to 0.99; p = 0.043). In a prespecified analysis of participants who were aged 60 years or above (n = 550), amoxicillin failed to reduce symptom severity or duration or to protect against new symptom onset or worsening of symptoms. Nausea, rash and diarrhoea were significantly more common in the amoxicillin than placebo group, suggesting that adverse effects outweigh the potential benefit of amoxicillin in ambulatory patients with uncomplicated LRTI.

An accompanying editorial raised doubts about whether the findings apply more widely because the study was restricted to a low-risk primary care population.

Comment: This study provides welcome evidence that the risk of antibiotic-related harm outweighs potential benefits in low-risk primary care patients with uncomplicated LRTI.


Cough persists far longer than patients expect

Patients' lack of knowledge about the average duration of an acute cough may be fuelling demand for unnecessary antibiotics, a study shows.1

To compare patient expectations about acute cough duration with evidence from the literature, researchers conducted a population-based survey of 493 randomly selected adults in Georgia, US. The respondents reported an expected mean duration of 7–9 days. The mean duration of cough in the 19 published studies included in the systematic review was 18 days. Published studies that used the validated Bronchitis Severity Score found that symptoms often persisted for longer than 2 weeks in many patients.

Respondents were also asked the extent to which they believed antibiotics were helpful for a cough. They were more likely to expect an antibiotic to be helpful if they had previously been prescribed an antibiotic for acute cough.

Comment: These findings are unlikely to surprise many healthcare professionals. Reducing unnecessary prescriptions and repeat visits is difficult, but it may help to elicit patients' expectations and concerns that they may have about their cough. Explaining that acute cough invariably resolves without a prescription, but that this may take up to 3 weeks, may provide some reassurance. Current guidance from the National Institute for Health and Clinical Excellence recommends that all patients are told that the average duration of acute cough/bronchitis is about 3 weeks.2


Blood glucose monitoring for people with type 1 diabetes

The Department of Health (DH) has issued a letter reminding healthcare professionals of the need to ensure that people with type 1 diabetes have access to blood glucose monitoring strips.1 The letter highlights concerns raised that some patients have experienced difficulties in accessing sufficient quantities of blood glucose testing strips on prescription.

The letter issued by the National Clinical Director for Diabetes, Chief Pharmaceutical Officer, QIPP National Lead for Medicines Use and Procurement and DH Principal Pharmacist is addressed to all GPs, hospital doctors, community pharmacists, Chief Executives and PCTs. It concludes ‘GPs and pharmacists should work collaboratively with patients to ensure the optimal amount of testing strips are prescribed and supplied to type 1 diabetics. Too few can lead to serious clinical consequences. Too many can lead to wastage.’

Comment: The evidence and need for blood glucose testing by people with type 1 diabetes is well established and should be part of routine clinical care. Patients and healthcare professionals should ensure that there is sufficient access to blood glucose testing strips, taking the needs of the individual into account.

The place of blood glucose monitoring in people with type 2 diabetes is sometimes less clear and has been identified as an area where there may be scope for rationalisation.2 In order to prevent people with diabetes from receiving conflicting messages about the role of blood glucose monitoring, prescribers, pharmacists and nurses should share local policies and agree priority areas for action.