Ezetimibe▼ in hypercholesterolaemia: NICE guidance
Safety concerns with rimonabant▼
Paediatric cough and cold medicines – no help, some harm?
NICE has published a technology appraisal of ezetimibe▼ (Ezetrol®) in hypercholesterolaemia.1 Ezetimibe monotherapy is an option for the treatment of adults with primary hypercholesterolaemia who would otherwise be initiated on statin therapy (as in NICE technology appraisal 942), but statins are contraindicated or not tolerated.1
Ezetimibe may also be used in combination with a statin in some patients with primary hypercholesterolaemia. This option should be considered only where statin therapy has not appropriately controlled serum total or low-density lipoprotein (LDL)-cholesterol despite appropriate statin dose titration (or in people who cannot tolerate higher doses of a statin) and consideration has been given to changing from the initial statin used to an alternative statin.1
‘Intolerance’ to statin therapy was defined by NICE as the presence of clinically significant adverse effects that are considered to represent an unacceptable risk to the patient, or that may result in compliance with therapy being compromised. Adverse effects include new-onset muscle pain (often associated with levels of muscle enzymes in the blood indicative of muscle damage), significant gastrointestinal disturbance or alterations of liver function tests.1
The guidance on ezetimibe states that consideration of ‘appropriate control of cholesterol concentrations’ should be based on individualised risk assessment in accordance with national guidance on the management of cardiovascular disease for the relevant population.1 The NICE lipid modification guideline, which will address the control of cholesterol concentrations, is due to be published in May 20083 and this should be referred to once available.
More information on lipid management, including the arguments for and against fixed cholesterol targets or aiming for a ‘meaningful drop’ in cholesterol concentrations, can be found on the lipids floor of NPCi.4 The great majority of patients will achieve a good reduction in their total cholesterol, and meet the Quality and Outcomes Framework (QOF) standard of 5mmol/l total cholesterol or less,5 on simvastatin 40mg a day alone. This dose of simvastatin is widely tolerated and of reasonable cost to the NHS.
When the decision has been made to treat a patient with ezetimibe plus a statin, NICE recommends that ezetimibe should be prescribed on the basis of lowest acquisition cost.1 Prescribing simvastatin and ezetimibe as separate components is cheaper than prescribing the combined simvastatin/ezetimibe product, Inegy®▼.6
It is worth noting that ezetimibe is licensed for use in primary (heterozygous-familial and non-familial) hypercholesterolaemia i.e. patients with high (undefined) cholesterol concentrations not due to an underlying cause. Clinical trial data has shown that ezetimibe reduces cholesterol levels, but there are no published outcome studies which examine whether it reduces morbidity or mortality outcomes, such as heart attacks or cardiovascular deaths. Therefore, ezetimibe is not licensed for the primary or secondary prevention of cardiovascular events.
Results from the ENHANCE study have recently shown no benefit for the combination of ezetimibe 10mg plus simvastatin 80mg compared with simvastatin 80mg alone on carotid artery intima media thickness.7 Whilst this is not a clinical outcome study, its results are, nonetheless, disappointing for ezetimibe.
Action
Statins remain the treatment of choice in most patients. Ezetimibe has a role, as supported by NICE guidance, for those with primary hypercholesterolaemia who are truly intolerant of statin treatment or where statins are contraindicated; or for those whose cholesterol levels are still high despite being prescribed an appropriate dose of a statin. Ezetimibe▼ is a “black triangle” drug. Therefore, healthcare professionals (and patients) are requested to report all suspected adverse reactions through the Yellow Card Scheme.
- Ezetimibe for the treatment of primary (heterozygous-familial and non-familial) hypercholesterolaemia. NICE technology appraisal guidance 132. November 2007. Accessed from www.nice.org.uk/guidance/index.jsp?action=byID&o=11886#documents on 26/02/08
- Statins for cardiovascular events in patients at increased risk of developing cardiovascular disease or those with established cardiovascular disease. NICE technology appraisal guidance 94. January 2006. Accessed from www.nice.org.uk/guidance/index.jsp ?action=byID&o=11564 on 26/02/08
- Cardiovascular risk assessment: the modification of blood lipids for the primary and secondary prevention of cardiovascular disease. Guideline in progress. More information accessed from www.nice.org.uk/guidance/index.jsp?action=byID&o=11628 on 26/02/08
- Lipids floor of NPCi. Accessed from www.npci.org.uk/therapeutics/cardio/cdlipids/room_cdlipids.php on 26/02/08
- Quality and outcomes framework website. Accessed from www.dh.gov.uk/en/Healthcare/Primarycare/Primarycarecontracting/QOF/index.htm on 26/02/08
- Drug Tariff. February 2008
- Ezetimibe? doesn’t ENHANCE statins. NPCi blog 11th February 2008. Accessed from www.npci.org.uk/blog/?p=70 on 26/02/08
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Safety concerns with rimonabant▼
In July 2007, the Medicines and Healthcare products Regulatory Agency (MHRA) warned that rimonabant▼ (Acomplia®) must not be used by patients with major depression or those being treated with antidepressants, because of the risk of psychiatric side effects. They reported that one in ten people who take rimonabant may develop psychiatric side effects, including low mood and depression, and around one in every hundred may experience suicidal thoughts.1
A recent meta-analysis provides evidence of the increased risk of psychiatric side effects. Evidence for the efficacy and safety of rimonabant 20mg per day from four randomised controlled trials (n=4105, 12–24 months duration) was examined. Patients receiving rimonabant lost, on average, 4.7kg more weight in the first year than those receiving placebo (95%CI 4.1–5.3kg, P<0.0001). However, its use was associated with considerably more adverse events (odds ratio [OR] 1.4, P=0.0007) and serious adverse events (OR 1.4, P=0.03). The estimated numbers needed to harm (NNHs) were 25 and 59, respectively. Withdrawals from the study due to depression or anxiety were more likely in patients receiving rimonabant than placebo (depression: OR 2.5, P=0.01, NNH 49; anxiety OR 3.0, P=0.03, NNH 166).2
A further meta-analysis of the same four rimonabant trials, reporting similar results, has been published as a Cochrane review.3
NICE technology appraisal of rimonabant
A NICE technology appraisal of rimonabant for the treatment of overweight and obese patients is ongoing. The NICE Appraisal Committee’s preliminary recommendations stated that they were minded not to recommend its use.4 However, this is not the Institute's formal guidance and recommendations may change after consultation.
Action
Caution is necessary before prescribing rimonabant for the treatment of overweight or obese patients. Prescribers should be alert to the increased risk of psychiatric side effects, and rimonabant must not be used by patients with major depression or those being treated with antidepressants. As rimonabant▼ is a “black triangle drug”, any incidences of suspected adverse reactions should be reported through the Yellow Card Scheme.
- New advice concerning the use of Acomplia (rimonabant) for weight loss in patients taking antidepressants or those with major depression. Medicines and Healthcare products Regulatory Agency. July 2007. Accessed from www.mhra.gov.uk/home/idcplg?IdcService=SS_GET_PAGE&ssDocName=CON2031809 &ssSourceNodeId=221&ssTargetNodeId=221 on 26/02/08
- Christensen R, Kristensen PK, Bartels EM, et al. Efficacy and safety of the weight-loss drug rimonabant: a meta-analysis of randomised trials. Lancet 2007;370:1706–13 Accessed from www.thelancet.com/journals/lancet/article/PIIS0140673607617218/abstract on 26/02/08
- Curioni C, André C. Rimonabant for overweight or obesity. Cochrane Database of Systematic Reviews 2006, Issue 4. Art. No.: CD006162. DOI: 10.1002/14651858.CD006162.pub2. Accessed from www.mrw.interscience.wiley.com/cochrane/clsysrev/articles/CD006162/frame.html on 26/02/08
- Rimonabant for the treatment of overweight and obese patients (Appraisal consultation document). National Institute for Health and Clinical Excellence. December 2007. Accessed from http://www.nice.org.uk/guidance/index.jsp?action=byID&o=11738 on 26/02/08
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Paediatric cough and cold medicines – no help, some harm?
The New England Journal of Medicine has published an article that gives an insight into recent concerns raised in the United States (US) over the risk-benefit profile of children’s cough and cold medications.1 The products discussed are widely available direct to the public in both the US and the UK, and contain antihistamines, decongestants, antitussives, and expectorants. Details of these are given on the Proprietary Association of Great Britain’s website (www.pagb.co.uk).
Despite the huge range of cough and cold products available for children, and their widespread use, there is little evidence to support the current level of use. A Cochrane review, which looked at over the counter (OTC) medicines for acute cough, found that studies of these therapies were small, difficult to compare and often had conflicting results.2 A guideline from the British Thoracic Society (BTS) on the management of cough in adults advises that the simplest and cheapest treatment for cough may be a home remedy such as honey and lemon.3 A BTS guideline on the management of cough in children is expected in early 2008. With regard to the potential harm from cough and cold products, the article gives worrying US data around the number of calls to poison centres, the number of visits to accident and emergency departments, and the number of deaths related to the use of cough and cold products in children.1 It would be interesting to analyse comparable data from the UK.
Action
Cough and cold medicines have been widely bought over the counter and prescribed for generations. Our understanding of the balance of benefits and harms in young children seems to be shifting and, despite their popularity, community pharmacists and prescribers should consider re-evaluating their advice to patients and parents concerning these products.
- Sharfstein, JM, North M, Serwint JR. Over the counter but no longer under the radar — pediatric cough and cold medications. N Engl J Med 2007;357:2321–4. Accessed from http://content.nejm.org/cgi/reprint/357/23/2321.pdf on 26/02/08
- Smith SM, Schroeder K, Fahey T. Over-the-counter medications for acute cough in children and adults in ambulatory settings. Cochrane Database of Systematic Reviews 2008, Issue 1. Art. No.: CD001831. DOI: 10.1002/14651858.CD001831.pub3. Accessed from www.mrw.interscience.wiley.com/cochrane/clsysrev/articles/CD001831/frame.html on 26/02/08
- British Thoracic Society Cough Guideline Group. Recommendations for the management of cough in adults. Thorax 2006;61(suppl 1):i1–i24. Accessed from www.brit-thoracic.org.uk/ClinicalInformation/Cough/tabid/94/Default.aspx on 26/02/08
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