Clinic Book Ragama – QUIZ 1

Evidence based medicinekmendis content 05/01/2020admin  1 CommentQUIZEdit

1. People who take blood pressure medications at bedtime were almost 50% less likely to experience a major cardiovascular outcome, such as heart attack or stroke, compared with people who took them in the morning.  

What does current guidance say on this issue?

NICE hypertension guidelines (2019) cover the diagnosis of the condition and assessment of cardiovascular risk. Recommendations are given on starting antihypertensive medication alongside lifestyle adjustment, stepwise selection of drug treatment, and ongoing monitoring.

No recommendations are given on the timing of drug administration.

What are the implications?

This trial builds on previous research findings, adding strength with its large sample size and long duration of follow-up. This was a well-conducted trial in primary care, and it was not possible to analyse whether there may be a difference according to drug regimen and/or associated patient characteristics.

The findings seem to provide strong evidence. Unless there is a reason to take antihypertensive medications at another time of the day, taking them at bedtime may be beneficial and is not expected to cause harm.

Citation and Funding

Hermida RC, Crespo JJ, Domínguez-Sardiña M et al. Bedtime hypertension treatment improves cardiovascular risk reduction: the Hygia Chronotherapy Trial. Eur Heart J. 2019;Oct 22. [Epub ahead of print]

2. In mild to moderate asthma, “As Needed” combination asthma inhalers (budesonide-formoterol) can be more effective than “Regular” inhaled steroids

What does current guidance say on this issue?

In its guideline published in November 2017, NICE states that adults whose asthma is not controlled with a SABA alone, and whose symptoms clearly indicate the need for maintenance therapy (for example, symptoms are present three times a week or more), should be offered regular low-dose inhaled corticosteroid maintenance treatment.

NICE suggests that where inhaled corticosteroid maintenance therapy is needed, patients should be prescribed a regular, daily dose rather than ‘when required’ steroid therapy.

The dose should be adjusted over time, with the aim that the patient has the lowest dose required for effective asthma control. Combination inhalers are to be used when regular maintenance therapy with two other agents is not sufficient and in addition to regular maintenance inhaled steroid.

What are the implications?

This study provides additional evidence to support prescribing a combination inhaler for symptom relief for adults with mild to moderate asthma, earlier in the stepped care pathway and possibly in place of regular maintenance inhaled steroid. 

It is not clear if the as-needed use of combination inhalers will come at a higher or lower cost overall than maintenance steroids plus SABA inhalers separately, but, based on this trial, better symptom control does seem possible.

Citation and Funding

Hardy J, Baggott C, Fingleton J et al. Budesonide-formoterol reliever therapy versus maintenance budesonide plus terbutaline reliever therapy in adults with mild to moderate asthma (PRACTICAL): a 52-week, open-label, multicentre, superiority, randomised controlled trial. Lancet. 2019;394:919-28.

This study was funded by the Health Research Council of New Zealand.

3. A less healthy lifestyle will increase the risk of dementia

What does current guidance say on this issue?

NICE recommends in its 2015 guideline that adults in mid-life are encouraged to adopt healthy behaviours that can reduce their risk of dementia, and be made aware of the links between lifestyle and later-life dementia.

NICE advises that public health bodies should commission initiatives and campaigns aimed at helping people to stop smoking, be more active, reduce their alcohol consumption, improve their diet and achieve and maintain a healthy weight.

NICE states that commissioners should include dementia risk reduction when developing strategies to address other chronic health conditions such as cardiovascular disease and diabetes.

What are the implications?

The consistent relationship demonstrated between lifestyle risk factors and dementia provides further evidence for public health organisations in terms of raising awareness. The overlap with risk factors for cardiovascular disease and cancer is likely to mean that lifestyle public health interventions could benefit all of them.

This meta-analysis is a useful attempt to quantify the effect of risk factor accrual for dementia. It looked only at widely known and accepted ‘modifiable risk factors’. So, for example, risk factors such as air pollution weren’t included. Further research will be needed to effectively target the most at-risk groups of people.

Citation and Funding

Peters R, Booth A, Rockwood K et al. Combining modifiable risk factors and risk of dementia: a systematic review and meta-analysis. BMJ Open. 2019;9:e022846.

No specific funding was received for this study. Individual authors are funded by a range of institutions including the Australian Dementia Collaborative Research Centre; the University of Sheffield; the Dalhousie Medical Research Foundation; the Canadian Institutes of Health Research, the Canadian Frailty Network and the Fountain Family Research Fund of the Queen Elizabeth II Health Sciences Centre.

4. Telephone delivered cognitive behavioural therapy (CBT) is less likely to provide lasting benefits for people with irritable bowel syndrome (IBS)

Why was this study needed?

As many as 10 to 20% of the population is affected by IBS. Symptoms include diarrhoea, bloating and constipation. Usual treatment includes maintaining a healthy lifestyle, and medication such as laxatives and antispasmodics. However, these only manage the condition and many people experience recurrent flare-ups.

Face-to-face CBT has been shown to help, but NHS availability is limited, and some people can struggle to attend appointments. Remote delivery options, such as web and telephone therapy, have been shown to help overcome these barriers, but their long-term effectiveness has yet to be established. This study aimed to demonstrate whether the effectiveness of CBT continues in the months after sessions have ceased.

What did this study do?

The original study involved 558 people with IBS that had not responded to the usual treatment. They were randomised to continue to receive usual care alone or to have either telephone-CBT or web-based CBT in addition.

A limitation of this study is the number of people lost to follow-up (42%). The researchers used the data they had to take this missing data into account and avoid bias in their analyses.

What did it find?

Symptoms were assessed by the IBS Symptom Severity Score (IBS-SSS), scale 0 (not affected) to 500 (most severely affected). More participants experienced a clinically significant IBS-SSS improvement (≥50 points) from baseline to 24 months with CBT: 84 (71%) of 119 participants in the telephone-CBT group, 62 (63%) of 99 in the web-CBT group, and in 48 (46%) of 105 in the usual care group.

What does current guidance say on this issue?

The NICE 2008 guideline (updated in 2017) on the management of IBS recommends dietary and lifestyle changes, such as increasing physical activity. Dietary advice includes having regular meals, limiting high-fibre and “resistant starch” foods, caffeine and fizzy drinks. If these measures are unsuccessful, single food avoidance or exclusion diets such as the low FODMAP diet (see Definitions tab) may be suggested under professional guidance.

Laxatives and other medications may also be prescribed, and if these do not work, antidepressants can be given as they can help reduce pain. If the above treatments do not improve symptoms after 12 months, people can be referred for psychological treatment such as CBT.

What are the implications?

The present study provides further evidence of the effectiveness of CBT for alleviating the symptoms of IBS. It is important to note the increased effectiveness of telephone-delivered therapy, even if not face-to-face, actual contact with a therapist is crucial and highlights the need for appropriately trained staff rather than predominantly web-based options.

Citation and Funding

Everitt H, Landau S, O’Reilly G et al. Cognitive behavioural therapy for irritable bowel syndrome: 24-month follow-up of participants in the ACTIB randomised trial. Lancet Gastroenterol Hepatol. 2019;4(11).863-72.

This project was funded by the NIHR Health Technology Assessment Programme (project number 11/69/02).

5. Boosting omega-3 fatty acid intake is likely to delay the onset of type 2 diabetes

People with diabetes are often advised to eat plenty of oily fish and plant oils. These are rich in polyunsaturated fatty acids (PUFA), such as omega-3 and omega-6 fatty acids, but the impact of these substances on diabetes development and glucose metabolism is unclear. Some experimental data has suggested that omega-3 may worsen the control of diabetes.

What does current guidance say on this issue?

The NICE guideline on cardiovascular disease risk assessment and reduction states that omega-3 fatty acids should not be offered to people with type 2 diabetes. However, NICE’s guideline on the management of adults with type 2 diabetes advises including oily fish in the diet.

The American Diabetes Association also recommends consuming a Mediterranean-style diet high in polyunsaturated fats, omega-3, and α-linolenic acid, without taking supplements.

What are the implications?

This study supports recommendations that omega-3 fatty acid supplements should not be offered to people with type 2 diabetes, for their diabetes. Neither should the supplements be offered to prevent diabetes in people at high risk of developing the disease.

People with diabetes or at risk of developing it should still be encouraged to eat a healthy Mediterranean-style diet, including oily fish, as part of a healthy lifestyle.

Citation and Funding

Brown TJ, Brainard J, Song F et al. Omega-3, omega-6, and total dietary polyunsaturated fat for prevention and treatment of type 2 diabetes mellitus: systematic review and meta-analysis of randomised controlled trials. BMJ. 2019;366:14697.

The study was funded by the World Health Organization’s Nutrition Guidance Expert Advisory Group (NUGAG) subgroup on Diet and Health.

6. Longterm macrolide antibiotics reduce the risk of exacerbations of bronchiectasis

Why was this study needed?

Bronchiectasis is a condition where the ends of the airways in the lungs are permanently dilated and inflamed. This allows the build-up of mucus that can get infected. Bronchiectasis has varied causes, including previous lung infections and immune system disorders, though often the cause cannot be identified. Cystic fibrosis is a common genetic condition that also causes bronchiectasis. Overall, bronchiectasis is thought to affect 1 in 1,000 people in the UK.

What does current guidance say on this issue?

NICE provides guidelines on the management of acute exacerbations of bronchiectasis (not caused by cystic fibrosis) including first-choice options for oral or intravenous antibiotics. NICE advises against routine prescription of antibiotic prophylaxis, and suggest a trial only in people with repeated exacerbations. The potential adverse effects and the need for regular review are highlighted. A 2014 NICE evidence summary on the effect of long-term azithromycin is also available, informed by two of these three trials.

NICE endorses the recommendations of the British Thoracic Society, which advises considering long-term antibiotics for people with three or more exacerbations per year. Provided the patient is not colonised with Pseudomonas aeruginosa, azithromycin or erythromycin is advised first-line (inhaled colistin is recommended if they are colonised). 

What are the implications?

Like previous studies, this meta-analysis suggests that long-term macrolides may reduce exacerbation frequency in bronchiectasis. It benefits from analysing individual patient data, indicating that prophylaxis may help wider patient groups than previously thought.

However, there are limitations, including the small patient subgroups and the fact that most evidence has looked at azithromycin. This makes it difficult to consider this strong conclusive evidence, but it may be the best that can be currently obtained for this rare condition.

Any decisions on prophylaxis will need to be made on an individual basis, considering the potential risks. These include adverse effects and the risk of antibiotic resistance and reduced susceptibility in future infections.

Citation and Funding

Chalmers JD, Boersma W, Lonergan M et al. Long-term macrolide antibiotics for the treatment of bronchiectasis in adults: an individual participant data meta-analysis. Lancet Respir Med. 2019;7(10):845-54.

Funding was provided by the European Respiratory Society.

7. C-reactive protein (CRP) testing in general practice safely reduces antibiotic use for COPD flare-ups

Why was this study needed?

COPD is a progressive lung disease affecting at least 1.2 million people in the UK and causing around 30,000 deaths annually. Each year around half of the people living with COPD will experience a flare-up of their symptoms (called an exacerbation).

Flare-ups can be caused by bacterial or viral infections of the airways or environmental triggers such as smoking. As it is not easy to rapidly identify the cause of a flare-up, antibiotics are often prescribed in case a bacterial infection of the airways is the cause. However, this may not be the case. Such unnecessary prescriptions can contribute to increases in drug-resistant bacteria.

A previous study has suggested that patients who have raised levels of CRP in their blood are most likely to need antibiotics. This well-conducted trial tested whether rapid CRP testing in general practice can safely reduce unnecessary prescribing of antibiotics to patients with COPD flare-ups.

What does current guidance say on this issue?

The NICE guidelines on COPD management state that for patients with acute exacerbations sending sputum samples for culture is not recommended as routine practice in primary care. They do not include recommendations on the use of CRP testing to guide antibiotic prescribing.

NICE has developed Medtech Innovation Briefings on two rapid CRP tests that can be used during primary care consultations. These briefings are not guidance, but describe the technologies and appraise the existing studies assessing their use. In both cases, the briefings looked at suspected lower respiratory tract infections as a whole rather than COPD exacerbations specifically.

What are the implications?

Overuse of antibiotics is a major concern globally, due to the increase in drug-resistant bacteria. There is also a drive to reduce overtreatment and unnecessary prescribing. To do this in patients with COPD exacerbations, in whom there is a high level of antibiotic use, clinicians ideally need point-of-care tools that can quickly identify bacterial infections in general practice.

This study provides strong evidence to suggest that rapid point-of-care CRP testing for these patients may help with antibiotic stewardship, without compromising patient outcomes or safety. The findings seem likely to influence future guidance and practice.

Citation and Funding

Butler CC, Gillespie D, White P et al. C-reactive protein testing to guide antibiotic prescribing for COPD exacerbations. New Engl J Med. 2019: 381: 111-120

This research was funded by the NIHR Technology Assessment Programme (project number 12/33/12). The testing machines used in the study were loaned to researchers by the manufacturer, who also provided training on their use. The manufacturer had no other role in any part of the trial.

8.Four-drug treatment for HIV offers significant benefits over standard three drug treatment

Previous systematic evidence demonstrated triple antiretroviral therapy to be more effective than double therapy (which was more effective than single therapy). As such, triple therapy has been consistently recommended as first-line treatment. However, there has been speculation whether quadruple therapy may be even more effective than triple. Individual trials have been small, so this comprehensive review aimed to answer the question by pooling the results of studies.

What did this study do?

This systematic review and meta-analysis included 12 randomised controlled trials, including 4,251 treatment-naïve people with HIV. Eligible trials assigned people to either quadruple or triple antiretroviral therapy and assessed at least one effectiveness or safety outcome.

What are the implications?

This review provides evidence in support of the current recommended triple drug therapy as first-line treatment for HIV.

There is probably no benefit to be gained from routinely increasing the number of drugs. This would add costs and unnecessary extra daily medication for the patient. It also reduces the options for second-line treatment.

Due to the varied combinations used, the review is unable to conclude whether there is a difference in effectiveness or safety between specific combinations of NRTI and third agent regimens.

Citation and Funding

Feng Q, Zhou A et al. Quadruple versus triple combination antiretroviral therapies for treatment naive people with HIV: systematic review and meta-analysis of randomised controlled trials. BMJ. 2019;366:l4179.

9. Mucous-thining drugs have no effect on COPD symptom flare-ups.

Why was this study needed?

Around 1.2 million people in the UK have COPD, making it the second most common respiratory disease after asthma. Exacerbation of symptoms such as breathlessness and sputum production can lead to emergency hospital treatment and account for much of the cost of managing COPD.

Reducing exacerbations is a major aim of COPD treatment. Inhaled bronchodilators and steroids are the main drug treatments which are used to keep the airways open and reduce inflammation. Mucolytic drugs, on the other hand, aim to thin mucus to make it easier to cough up.

So far, it has been unclear how well mucolytic drugs such as carbocysteine and N-acetylcysteine reduce exacerbations. Guidelines differ in their recommendations about the place of mucolytic drugs in COPD treatment. This review aimed to summarise the evidence to show whether mucolytics reduce exacerbations or days of disability for COPD patients.

What did it find?

People receiving mucolytic drugs were more likely to remain free of exacerbation of symptoms (50.9%) than people receiving placebo (38.6%) during the study period (odds ratio [OR] for being exacerbation-free 1.73, 95% confidence interval [CI] 1.56 to 1.91; 28 trials, 6,723 participants).

What does current guidance say on this issue?

The NICE 2018 guideline only recommends considering mucolytic drug therapy for people with a chronic cough productive of sputum. Mucolytic drugs should be stopped if there is no improvement in symptoms such as cough frequency or sputum production. The guideline does not recommend their routine use to prevent exacerbations for all people with COPD.

What are the implications?

This updated Cochrane review suggests that the NICE guideline hits the right balance in its recommendation that mucolytics may be of help for some people with COPD, but should not be prescribed routinely.

It confirms that mucolytics may offer a small reduction in risk of an exacerbation of COPD symptoms, with few adverse effects, but authors add that the results may be driven by older studies that could have been subject to publication bias.

Citation and Funding

Poole P, Sathananthan K and Fortescue R. Mucolytic agents versus placebo for chronic bronchitis or chronic obstructive pulmonary disease. Cochrane Database Syst Rev. 2019;(5):CD001287.

Cochrane UK and the Cochrane Airways Review Group are supported by NIHR infrastructure funding.

10. Routine use of progesterone will increase the chance of a live birth among women presenting with vaginal bleeding in the first 12 weeks of pregnancy.

Why was this study needed?

It is estimated that around 20% of pregnant women experience ‘threatened miscarriage’, vaginal bleeding before the time when a fetus would be able to survive outside of the uterus (24 weeks usually).

Progesterone, produced by the ovaries, prepares the uterus lining (endometrium) for implantation of the embryo and supports early placental development. After around 12 weeks, the placenta becomes the main source of progesterone, and levels continue to rise throughout pregnancy.

What did this study do?

This double-blind, randomised placebo-controlled trial included 4,153 women recruited from 48 hospitals across the UK. Participants were aged 16 to 39, less than 12 weeks pregnant, with vaginal bleeding, and a gestational sac visible on ultrasound. They were assigned to receive twice-daily vaginal suppositories containing either 400mg of progesterone or matching placebo, until 16 completed weeks of pregnancy.

What did it find?

  • There was no statistically significant difference in the live birth rate between groups, which was 75% in the progesterone group and 72% in the placebo group (relative rate [RR] 1.03, 95% confidence interval [CI] 1.00 to 1.07).What does current guidance say on this issue?The NICE guideline on ectopic pregnancy and miscarriage (2019) does not give any recommendation for preventing miscarriage. NICE recommends that women with threatened miscarriage and a fetal heartbeat are assessed if bleeding persists beyond 14 days, and to continue with normal antenatal care if bleeding stops.NICE noted that meta-analysis of several small studies indicated that progestogens might be better than placebo for threatened miscarriage. However, they stated that several biases, the lack of strong evidence and the theoretical risks of prescribing in early pregnancy made this uncertain and a research priority.Earlier guidance from the Royal College of Obstetricians and Gynaecologists similarly noted the insufficient evidence for progesterone.What are the implications?This well-designed and conducted trial provides the best evidence so far on the effect of progesterone for threatened miscarriage.A Cochrane systematic review found a more pronounced effect of progesterone in women following three or more miscarriages, but noted need for caution due to differing results from individual studies.There is no evidence supporting the routine use of progesterone for women who bleed in early pregnancy for the first time.There may be a place for progesterone for some women who have had previous miscarriages but more, reliable evidence is needed.Citation and FundingCoomarasamy A, Devall AJ, Cheed V et al. A randomized trial of progesterone in women with bleeding in early pregnancy. N Engl J Med. 2019;380(19).This project was funded by the NIHR Health Technology Assessment Programme (project number 12/167/26).

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Kumara Mendis

This QUIZ was based on the NIHR Signals website for Primary Care. LINK

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