19th November 2009

An article published in the British Medical Journal has noted the high cost of newer biological drugs and offers suggestions for potential ways of making such healthcare more affordable. One option, suggested by the authors, for helping resources go further is the use of biosimilar products, but this should not be viewed in the same light as switching to a generic version of a conventional medicinal product.

Current EMEA advice if considering prescribing biosimilars
EMEA guidance notes that biosimilars are not generic medicinal products, due to possible subtle differences between similar biological medicinal products from different manufacturers which may not be fully apparent until they have wider clinical exposure. Therefore, the specific product given to each patient should be clearly identified to support pharmacovigilance monitoring. Prescribing by brand name is recommended.

The EMEA has accepted, for certain biosimilar products e.g. recombinant granulocyte-colony stimulating factor, evidence demonstrating comparability based on healthy volunteer studies. Nonetheless, as has been noted in a rapid response to the British Medical Journal article, it is possible that, over time, clinically meaningful differences could develop that might adversely affect cost-effectiveness.

What is the background to this?
Biological therapies are complex and generally derived from human, animal or micro-organism material. The success of newer biologics, such as monoclonal antibodies, is putting pressure on health care budgets. Although these therapies can offer hope to patients with serious diseases, they are usually considerably more expensive than conventional drugs. This is due to factors such as research and development costs, complex manufacturing processes, perceived value to patients and less competition in the market place. Other costs relate to administering the drugs to patients, usually parentally, in hospital, and the cost of monitoring and managing adverse effects, such as infections.

The NHS spent over £11bn on pharmaceuticals in 2008. All healthcare systems face cost pressures and the authors of this article offer possibilities for reducing costs in the biologics sector. NICE usually recommends treatments which cost no more than £30,000 per quality adjusted life year added (QALY). However, there have been notable exceptions to this limit, including trastuzumab. In addition, new NICE guidelines on use of end-of-life drugs for certain conditions were introduced in January 2009 and the outcomes from this decision remain to be seen.

What is a biosimilar?
A similar biological medicine (biosimilar) is a new biological product that has been developed to be similar to an existing biological product (reference product). When the patent life expires on conventional drugs, then a change to a generic version usually results in savings. Biosimilar versions of biological drugs could potentially reduce costs of therapy and increase access to treatment. Potential cost reductions with biosimilars have been estimated at 18 to 50%. However, unlike traditional generic drug substitutions, there are concerns that even the smallest variability in production conditions in banks of living cells used to produce biologics can lead to important differences in efficacy and safety. Therefore, the EMEA has produced guidelines on biosimilars. Due to their complexity, manufacturers are being asked to provide comparability studies to demonstrate equivalent efficacy, safety and quality for any new biosimilar.

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18 November 2009,

Two one-year RCTs (AURA and HERMES) showed that roflumilast modestly improved lung function in patients with severe COPD who were symptomatic and not using an inhaled steroid. A reduction in moderate-to-severe exacerbations was also reported (NNT=5 over one year). Two six-month RCTs (EOS and HELIOS) found similar benefits in lung function when roflumilast was added to salmeterol or tiotropium in patients with moderate-to-severe COPD. In all of the studies, more patients discontinued treatment with roflumilast because of adverse effects (NNH=35); the most common of which were GI side effects (e.g. nausea, diarrhoea), weight loss and headache. Further studies are required to establish whether roflumilast offers any meaningful advantages as an alternative, or in addition, to an inhaled steroid.

Level of evidence
Level 2 (limited patient-oriented evidence) according to the SORT criteria

Action
The place of roflumilast in the treatment of patients with COPD is uncertain. The four studies reviewed here provide insufficient evidence to justify its use ahead or instead of inhaled corticosteroids (ICSs), for those people who remain symptomatic or suffer exacerbations on optimal bronchodilator therapy (long-acting beta-agonists and/or tiotropium). Any possible benefits of roflumilast have to be balanced against the possibility of adverse effects, most commonly diarrhoea, nausea, headache, and weight loss.

Roflumilast has been submitted for an EU license, but no NICE guidance is planned currently. Therefore, local decision making bodies on medicines are advised to engage with stakeholders to identify those patients for whom the drug may be appropriate and agree a protocol for use if a license is granted and the product is launched.

What is the background to this?
Roflumilast (Daxas®, Nycomed) is a once-daily, oral phosphodiesterase-4 inhibitor, which has anti-inflammatory properties, being developed for the treatment of COPD. A marketing authorisation application was filed for the EU in May 2009, and if a licence is granted, it is likely to be launched in 2010. This licence application is based on two pivotal one-year, placebo-controlled randomised clinical trials (AURA and HERMES), and supported by two six-month, placebo-controlled trials (EOS and HELIOS), in which it was used with a long-acting bronchodilator (salmeterol or tiotropium). AURA and HERMES compared the effect of roflumilast 500micrograms daily with placebo in patients with severe COPD, bronchitic symptoms and a history of exacerbations. They had identical protocols, but used two geographically different populations. The main difference between the two populations was that HERMES included a greater proportion of people of Asian ethnic origin than AURA (23% vs. <1%). EOS and HELIOS evaluated the addition of roflumilast 500micrograms daily to either salmeterol or tiotropium, respectively, in patents with moderate-to-severe COPD. However, the patients in these latter trials did not necessarily have to have a history of exacerbations.

The current NICE clinical guideline for COPD from 2004 recommends that people with moderate-to-severe COPD, who are still symptomatic despite use of a long-acting bronchodilator should be given a four-week trial of an ICS in addition to a long-acting bronchodilator. Furthermore, the ICS should be discontinued if there is no benefit after four weeks (if still symptomatic then theophylline may be considered in addition). An ICS is also recommended where the forced expiratory volume in one second (FEV1) is £50% predicted and the patient suffers two or more exacerbations in a 12-month period; normally this would be in addition to a long-acting bronchodilator. Note that an update to the NICE clinical guideline is due to be published in June 2010; and there are proposed changes to the currently recommended treatment regimen in the draft consultation guideline.

Further information about COPD can be found on the respiratory tract floor of NPCi.

What do these studies claim?
Similar results for AURA and HERMES for the primary endpoints (change in prebronchodilator FEV1 and rates of exacerbations) were claimed. Pooled results indicated that roflumilast produced a modest improvement in pre-bronchodilator FEV1 compared with placebo of 48mL (95% confidence interval [CI] 35mL to 62mL; P<0.0001); individual results for AURA and HERMES were 39mL and 58mL, respectively. There was a mean reduction in the rate of moderate (i.e. requiring oral corticosteroids or parenteral corticosteroids) or severe exacerbations (i.e. resulting in hospital admission or death) from 1.37 per year to 1.14 per year (rate ratio [RR] 0.83; 95%CI 0.75 to 0.92; P=0.0003) with roflumilast — a reduction of 0.23 exacerbations per year (number needed to treat (NNT) 5 to prevent one exacerbation in a year).

Results of EOS and HELIOS studies are difficult to compare with eachother, because patients in the HELIOS study were more symptomatic than in EOS, and used more as-needed medication. Compared with placebo, roflumilast improved mean prebronchodilator FEV1 (the primary endpoint) by 49mL (95%CI 27 to 71; P<0.0001) when added to salmeterol and 80mL (95%CI 51 to 110; P<0.0001) when added to tiotropium.

Discontinuations due to adverse events were more common with roflumilast than placebo (significant in AURA, HERMES and EOS). Gastrointestinal side-effects (e.g. diarrhoea, nausea), weight loss, or headache were the most common side effects associated with roflumilast.

How does this relate to other studies?
Two one-year, RCTs of roflumilast versus placebo in COPD have been published previously:

• A study of 1,411 patients with moderate-to-severe COPD considered two doses (250 and 500micrograms daily) of roflumilast. It found a statistically significant improvement in postbronchodilator FEV1 with roflumilast compared with placebo (97mL with 500micrograms daily). There was no significant effect on health-related quality of life. Although there was a significant difference in favour of roflumilast with regard to the rate of exacerbation, this was predominantly due to a reduction in mild exacerbations; the rates of moderate or severe exacerbations were similar between groups.
• A study of 1,513 patients with severe, stable COPD demonstrated a statistically significant mean improvement in postbronchodilator FEV1 of 39mL for roflumilast compared with placebo. However no differences were found with regard to the rate of exacerbations or health status. Post-hoc analysis suggested one of the hypotheses tested in the AURA and HERMES studies, i.e. that roflumilast may reduce exacerbations in specific subsets of patients with severe COPD.

So what?
The results of AURA and HERMES suggest that roflumilast modestly improves lung function compared with placebo in patients with severe COPD who have bronchitic symptom, and who have a history of exacerbations. They also demonstrate a reduction in the rate of exacerbations — about five patients would be treated with roflumilast for a year, for one of them to have one fewer moderate or severe exacerbation during that period. Although some patients may obtain benefit in this regard, this potential benefit has to be put into context by considering adverse effects of treatment and the limitations of the study.

Although these were well controlled studies, they do not inform us about whether roflumilast provides any benefits when used instead of, or in addition to, the current NICE recommended treatment regimens. Many of the patients in these studies were already receiving an ICS and long-acting bronchodilators, which were discontinued, although continued use of LABAs was allowed during the studies. Questions remain, therefore, of whether or not roflumilast offers any significant benefit when used instead of inhaled corticosteroids, or when used in addition to inhaled corticosteroids and/or long-acting bronchodilators. Until these questions are answered by further clinical studies it is difficult to see where roflumilast sits in the routine treatment of COPD.

The question of whether there are any benefits when used in addition to long-acting bronchodilators is to some extent answered by the results of the EOS and HELIOS studies. A modest statistically significant improvement in lung function was identified in the patients in both studies of patients who had less severe COPD (mostly moderate). Exacerbation rates were low during both studies, which were underpowered to test differences between treatments in this respect. As in AURA and HERMES, an ICS was not allowed, and they provide no information with which to compare the benefits of roflumilast with an ICS or indeed an additional different class bronchodilator (i.e. when salmeterol or formoterol is used together with tiotropium).

Any potential benefits of roflumilast have to be balanced against the risk of adverse effects. All studies demonstrated increased incidence of adverse effects compared with placebo. Gastrointestinal side effects, headache and weight loss were reported as being significantly more common with roflumilast than with placebo in most or all of the studies. Although these side effects may diminish over time, they may not be tolerated by some patients. In AURA and HERMES more patients discontinued treatment due to adverse events (14% vs. 11%, number needed to harm [NNH] 35).

It is notable that any improvements in AURA and HERMES in overall health utility over placebo were small and not statistically significant.

Study details
1) AURA (M2-124) and HERMES (M2-125)
Calverley PMA, Rabe KF, Goehring U-M, et al. Roflumilast in symptomatic chronic obstructive pulmonary disease: two randomised clinical trials. Lancet, 2009; 374: 685–94

Design: Both studies were multicentre, international, one-year, double-blind, placebo-controlled, randomised clinical trials with identical designs in two different geographical populations. Analysis was by intention to treat. Allocation was concealed.

Patients: Outpatients with severe COPD with chronic cough and sputum production: post-bronchodilator FEV1 £50% predicted with at least one moderate or severe exacerbation in the previous year; older than 40 years of age (average 64 years both studies); 71% men in AURA, 81% men HERMES. In HERMES the proportion of people of Asian origin was higher (23% vs. <1%), mean baseline pre-bronchodilator and post-bronchodilator FEV1 were lower (0.97L vs. 1.07L, and 1.06L vs. 1.16L), there were fewer current smokers (35% vs. 48%) and more patients had very severe COPD (33% vs. 25%). Overall 42% had used ICS previously and 51% used LABAs during the trials.

Interventions/Comparison: After a 4-week run-in on placebo, patients received either roflumilast 500micrograms daily or placebo for 52 weeks. Short-acting beta-agonists, as needed, and regular short-acting and long-acting beta-agonists could be continued throughout the study at stable doses. ICSs and tiotropium were not allowed during the study.

Outcomes and Results:
The primary endpoints were the change in pre-bronchodilator FEV1 during treatments and the rate of COPD exacerbations. Pooled results indicated that roflumilast produced a modest improvement in pre-bronchodilator FEV1 compared with placebo of 48mL (95%CI 35mL to 62mL; P<0.0001); When analysed individually, changes in this primary outcome for AURA and HERMES were also significantly different from roflumilast compared with placebo (39mL and 58mL, respectively; both P<0.001). Pooled results indicated a mean reduction in the rate of moderate (i.e. requiring oral corticosteroids or parenteral corticosteroids) or severe exacerbations (i.e. resulting in hospital admission or death) from 1.37 per year to 1.14 per year (RR 0.83, 95%CI 0.75 to 0.92; P=0.0003) with roflumilast. The mean reduction of 0.23 exacerbations per year (NNT to prevent one exacerbation in a year is 5); reductions in the rates of exacerbations for individual studies were 0.19 and 0.28 (P=0.028 and P=0.0035, respectively). Pooled results (and results from individual studies) did not show a significant difference in the rate of severe exacerbations, although the study was underpowered to evaluate this outcome. Roflumilast did not reduce the median time to first exacerbation (moderate or severe) significantly in the individual studies; pooling of results suggested a reduction of only 9 days on average (71 vs. 80 days, P=0.019).

There was a small but clinically insignificant change (i.e. less than1point) in the transition dyspnoea index, no significant change in time to death, or change in Euroqol-5 dimension score (a measure of health utility).

There were slightly more withdrawals in the roflumilast groups compared with the placebo groups (AURA, 35% vs. 31%; HERMES 32% vs. 31%). Discontinuations associated with adverse events were more common in the pooled roflumilast groups (14% vs. 11% overall [NNH 35]; 8% vs. 3% in the first 12 weeks. With the exception of COPD, the most frequent adverse events leading to discontinuation were diarrhoea, nausea and headache. Significantly more adverse events were identified in both studies for roflumilast with regard to diarrhoea, weight loss (about 2 kg after a year) and decreased appetite. Nausea and headache was only reported significantly more frequently in AURA.

2) EOS (M2-127) and HELIOS (M2-128)
Fabbri LM, Calverley PMA, Izquierdo-Alonso JL, et al. Roflumilast in moderate-to-severe chronic obstructive pulmonary disease treated with longacting bronchodilators: two randomised clinical trials. Lancet 2009; 374:695-703.

Design:
Both studies were multicentre, international, placebo-controlled, 24-week, double-blind, placebo-controlled trials. Analysis was by intention to treat. Allocation was concealed.

Patients: Outpatients with moderate-to-severe COPD: post-bronchodilator FEV1 40–70% predicted; older than 40 years of age. All patients in HELIOS had chronic cough and sputum production (78% in EOS) and were required to use more than 28 puffs per week of as-needed short-acting beta agonists. In EOS and HELIOS, respectively, mean ages were 65 and 64 years and the proportions of men in the studies were 66% and 72%; mean baseline pre-bronchodilator FEV1s were 1.42L and 1.48L. About a third of patients in both studies had severe COPD.

Interventions/comparison: After a four week-run in on placebo, patients were treated with either roflumilast 500micrograms daily or placebo in addition to either salmeterol (EOS) or tiotropium (HELIOS) for 24 weeks. No ICSs, inhaled short-acting bronchodilators, or other respiratory drugs were allowed during the study (although rescue medication was used during the study).

Outcomes and Results:
The primary endpoint was the change in pre-bronchodilator FEV1. Compared with placebo, roflumilast improved mean prebronchodilator FEV1 by 49mL (95%CI 27 to 71; P<0.0001) when added to salmeterol and 80mL (95%CI 51 to 110, P<0.0001) when added to tiotropium. Statistically significant improvements in other measurements of lung function were also identified. The study was not powered to compare the rates of exacerbations or other endpoints, and there were no significant improvements in the rate of mild, moderate or severe exacerbations in either study. Although there were statistically (but not necessarily clinically) significant improvements compared with placebo for roflumilast when added to tiotropium in HELIOS in TDI focal score, shortness of breath questionnaire reduction, and reduction in the use of rescue medication, no significant differences were identified for these secondary endpoints in EOS.

Withdrawals from the study were higher with roflumilast in both studies (23% vs. 18% EOS; 17% vs. 10% HELIOS). Adverse events related to treatment were higher with roflumilast in both studies (EOS, 18% vs. 3%; HELIOS 12% vs. 2%). Diarrhoea, nausea and weight loss (about 2kg during the studies) were significantly more common with roflumilast than placebo in both studies.

Sponsorship:
All four studies were either sponsored by Nycomed or Altana, the previous licensee for the product.

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12 November 2009

The MHRA and CHM have published the November edition of Drug Safety Update (DSU). Highlights include:

• Orciprenaline (Alupent®) will be withdrawn from the UK market over the coming year, due to its unfavourable risk-benefit profile.
• A reminder about the reporting arrangements for suspected adverse reactions to swine flu antivirals and vaccines, and discusses reports received for the antivirals so far.
• Patients receiving bisphosphonates for cancer are at greater risk of jaw osteoneocrosis than patients receiving bisphosphonates for other conditions.
• Narrow therapeutic index of colchicine and its toxicity in overdose
• Movement disorders in children treated with vigabatrin for infantile spasms.
• A ‘Hot topics’ article discusses the current legal situation regarding mixing of medicines, particularly for parenteral administration by and at the request of non-medical prescribers.
• Updates to the patient information leaflets of all statins, and a clarification of advice about aspirin use given in oseltamivir▼ patient information leaflets.

Action
Drug Safety Update (DSU) is an essential read for everyone whose professional practice involves medicines. It is published every month in electronic format only.

Orciprenaline (Alupent®) withdrawal
Orciprenaline is a non-selective, short-acting beta-agonist. It is significantly less effective than salbutamol in the extent and duration of bronchodilation that it achieves. It is also associated with a high risk of cardiac side effects, mainly palpitations and tachycardia, which occur before maximum bronchodilation is achieved because of its non-selectivity. The MHRA is, therefore, working with the manufacturer to achieve a planned voluntary withdrawal of orciprenaline over the next year. The product will continue to be available for several months, but it is recommended that patients are switched to a more selective beta-agonist at the earliest opportunity.

Adverse reactions to swine flu antivirals and vaccines
As we blogged recently, the MHRA has established a safety monitoring programme for swine flu vaccines to capture, evaluate, and monitor suspected adverse drug reactions (ADRs). Members of the public and healthcare professionals should report any suspected adverse reactions to pandemic swine flu vaccines or antiviral medicines used for the treatment or prevention of swine flu through the dedicated online reporting website. Since many patients who receive one of the new swine flu vaccines will also receive a seasonal flu vaccine around the same time the scope of this website has been extended to include reporting for all flu vaccines (ie, both seasonal and swine flu).

The most commonly reported suspected ADRs with oseltamivir▼ and zanamivir▼ are consistent with the signs and symptoms of recognised side effects, many of which can also be caused by flu-like illness. The balance of risks and benefits for both oseltamivir and zanamivir within their licensed indications remain positive. However, both drugs are ‘black triangle’ (▼), indicating that all suspected ADRs should be reported, even if they are already recognised. Reporting suspected ADRs enables the MHRA and CHM to have a better picture of the side effect profile of these drugs

Statin patient information leaflets
Statins are generally well tolerated by most people who use them. However, a review of statin safety from 2008 also identified the need for updates to the product information for all statins. Patients should be made aware that treatment with any statin may be associated with depression, sleep disturbances, memory loss and sexual dysfunction. Statins may very rarely be associated with interstitial lung disease. Patients should seek help from their doctor if they develop presenting features of interstitial lung disease such as dyspnoea, non-productive cough, and deterioration in general health (eg, fatigue, weight loss, and fever). Summaries of Product Characteristics (SPCs) and Patient Information Leaflets are being amended to include the potential for these reactions.

Mixing medicines by medical and non-medical prescribers
In palliative care, it is usual to mix two or more medicines in a syringe driver before administration. Strictly speaking, this creates an unlicensed medicine, which raises legal difficulties particularly for non-medical prescribers. In 2008, the MHRA realised that the legal position could potentially obstruct the provision of effective pain relief and symptom control to patients receiving palliative care. As a holding measure, it issued a statement that enforcement action would not be taken for breaches of medicines legislation by independent prescribers and nurses in palliative care who were engaged in mixing medicines, unless it would be in the public interest to do so. It subsequently became clear that mixing of medicines like this was not restricted to palliative care. The MHRA is pressing ahead with necessary legislative amendments. These include allowing non-medical prescribers to be able to mix medicines and direct others to mix, and allowing nurse and pharmacist independent prescribers to prescribe unlicensed medicines for their patients. The National Prescribing Centre (NPC) will be producing a short good-practice guide to support practice in the mixing of medicines post-legislation.

Bisphosphonates and osteonecrosis of the jaw (ONJ)
The risk of ONJ is greater for patients receiving intravenous bisphosphonates for cancer than for patients receiving oral bisphosphonates for osteoporosis or Paget’s disease. All patients with cancer should have a dental check-up before bisphosphonate treatment. During treatment, patients should be encouraged to maintain good oral hygiene; receive routine dental check-ups; and report any oral symptoms such as dental mobility, pain, or swelling.

Colchicine toxicity
Colchicine has a narrow therapeutic window and is extremely toxic in overdose. Patients at particular risk of toxicity are those with renal or hepatic impairment, gastrointestinal or cardiac disease, and patients at extremes of age. The symptoms of overdose are often delayed and all patients, even in the absence of early symptoms, should be referred for immediate medical assessment.

Vigabatrin for infantile spasms: risk of movement disorders and MRI abnormalities
Movement disorders have been reported in patients treated with vigabatrin for infantile spasms. If new movement disorders occur during treatment with vigabatrin, consideration should be given to dose reduction or a gradual discontinuation of treatment in consultation with specialist advice. Cases of abnormal brain MRI findings have also been reported, in particular in young infants treated for infantile spasms with high doses (≥125 mg/kg/day) of vigabatrin. The clinical significance of these findings is currently unknown.

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12 November 2009

This systematic review found that adding an ACE inhibitor to standard medical therapy reduces the risk of certain serious CV outcomes in patients with stable ischaemic heart disease and preserved ventricular function. Evidence about the effects of angiotensin II receptor antagonists (A2RAs) in these patients is limited – adding an A2RA to an ACE inhibitor in such cases is of no benefit and increases harms.

Level of evidence:
Level 1 (good quality patient-oriented evidence) according to the Sort criteria.

Action
Healthcare professionals should continue to follow the various NICE guidance on the use of ACE inhibitors in patients with or at risk of cardiovascular disease – NICE clinical guidelines on hypertension, chronic heart failure, secondary prevention post-myocardial infarction (MI), type 2 diabetes and chronic kidney disease (CKD). ACE inhibitors are the evidence-based first-line choice over A2RAs in all situations where a renin-angiotensin system (RAS) drug is indicated. A2RAs should be reserved for the small number of patients in whom an ACE inhibitor has to be discontinued because of cough. Combination therapy with an A2RA plus an ACE inhibitor would appear to have a very limited role. It may be a specialist option in patients with heart failure who are still symptomatic despite optimised ACE inhibitor and beta-blocker therapy. However, this requires very careful monitoring for adverse effects, including worsening renal function.

What is the background to this?
There is still debate as to whether patients with stable ischaemic heart disease but no left ventricular systolic dysfunction benefit from treatment with an ACE inhibitor (or an A2RA) in addition to standard medical therapy including aspirin, beta-blockers and statins. This systematic review investigated the clinical effects and harms of using ACE inhibitors, A2RAs or a combination of these drugs in this group of patients. It included seven long-term randomised controlled trials (RCTs) comparing ACE inhibitors with placebo (most data coming from HOPE with ramipril, EUROPA with perindopril and PEACE with trandolapril), one RCT comparing the A2RA, telmisartan, with placebo in patients intolerant of ACE inhibitors (TRANSCEND), and one RCT comparing combination treatment with telmisartan plus ramipril with either drug alone (ONTARGET). See our earlier blog on TRANSCEND and blog on ONTARGET for further details on these studies.

What does this study claim?
This systematic review found that ACE inhibitors reduced the risk of total mortality, MI and stroke in patients with stable ischaemic heart disease and preserved left ventricular function already receiving standard treatments. Moderate to high strength evidence from six RCTs (n=32,210) comparing ACE inhibitors with placebo found relative risks [RR] of 0.87 (95% confidence interval [CI] 0.81 to 0.94) for total mortality, 0.83 (95%CI 0.73 to 0.94) for non-fatal MI and 0.78 (95%CI 0.63 to 0.97) for stroke.

Data were insufficient to adequately assess the benefits of A2RAs, as there was only one trial and the population was limited to patients who could not tolerate ACE inhibitors. Low-strength evidence from this one RCT (TRANSCEND; n=5,926) suggested that A2RAs reduced the composite endpoint of cardiovascular mortality, non-fatal MI or stroke (RR 0.88; 95%CI 0.77 to 1.00) but not the individual components of this endpoint.

Based on one very large RCT, ONTARGET (n=25,620), combination therapy with an A2RA plus an ACE inhibitor was no better than an ACE inhibitor alone and increased harms. There was no significant difference in total mortality (RR 1.07; 95%CI 0.98 to 1.16), MI (RR 1.08; 95%CI 0.94 to 1.23), stroke (RR 0.93; 95%CI 0.81 to 1.07) or a composite of cardiovascular mortality, MI or stroke (RR 1.00; 95%CI 0.93 to 1.09) with telmisartan plus ramipril compared with ramipril alone. Combination therapy was, however, associated with more study discontinuations due to hypotension (P<0.001) and syncope (P=0.03).

So what?
This systematic review adds to the weight of evidence supporting the use of ACE inhibitors in addition to standard medical treatments in patients with stable ischaemic heart disease and preserved ventricular function. This could include patients with a history of coronary artery, peripheral vascular, or cerebrovascular disease, as well as those with diabetes and evidence of end-organ damage (as these were the diverse range of patients recruited in the included trials). The mean age of the trial participants ranged from 57 to 67 years, 57% to 89% of whom were men. In all, 8% to 39% of participants had diabetes, 27% to 100% had hypertension, 7% to 45% had peripheral vascular disease, and 3% to 22% had a previous stroke or transient ischaemic attack. Most patients in the included trials were already receiving aspirin and statins, and about half were being treated with beta-blockers.

The review is limited in its ability to balance the benefits of ACE inhibitor therapy with possible harms, as data reporting on harms were inconsistent and incomplete. Also, there was very little data on which to base conclusions about any differing effects in different patient subgroups. However, it clearly highlights the wealth of data there are for ACE inhibitors in the treatment of patients with ischaemic heart disease compared with the limited data there are for A2RAs. The review also highlights the very important results from the ONTARGET study (discussed in a previous blog), where combination of an ACE inhibitor with an A2RA did not benefit patients with stable ischaemic heart disease without heart failure, but increased their risk of harms compared with use of an ACE inhibitor alone, .

The results from ONTARGET (median follow-up 56 months), particularly those relating to worse major renal outcomes with combination therapy, are changing peoples’ views on what role, if any, combination therapy has. The primary renal outcome (composite of dialysis, doubling of serum creatinine and death) was statistically significantly increased with telmisartan plus ramipril compared with ramipril alone (number needed to harm [NNH] 91), as was the secondary renal outcome of dialysis or doubling of serum creatinine (NNH 215), and the individual endpoint of acute dialysis (NNH 562). However, these latter results need to be viewed with some caution as the number of actual events was very low.

Combination therapy has also come under the spotlight recently, with the retraction from the Lancet of the Japanese COOPERATE trial, originally published in 2003. An investigation into this trial of combination therapy in patients with non-diabetic renal disease found serious issues with the way the trial had been conducted which left the investigators unable to prove the authenticity of the data. These included issues with ethics committee approval, patient consent, statistician involvement and the fact that it was not a double-blind study as the investigator knew the treatment allocation. The retraction of this paper is concerning as it was a ‘landmark study’ favouring combination therapy in CKD. Issues surrounding this trial and further information on the hazards of dual RAS blockade in CKD are discussed in more detail in an Archives of Internal Medicine commentary from earlier this year.

NICE guidance on the use of ACE inhibitors in patients with or at risk of cardiovascular disease is outlined in clinical guidelines on hypertension (CG34), chronic heart failure (CG5), secondary prevention post-MI (CG48), type 2 diabetes (CG87) and chronic kidney disease (CG73). In all these indications, where a RAS drug is recommended, NICE recommend an ACE inhibitor first-line over an A2RA. A2RAs are reserved for patients where a RAS drug is indicated but an ACE inhibitor has to be discontinued because of an intractable ACE-inhibitor induced cough. ACE inhibitors are the evidence-based first line choice over A2RAs as they have a more robust evidence base across all indications, and are unsurpassed by A2RAs in terms of evidence for their efficacy, safety and cost. This systematic review, with its wealth of data for ACE inhibitors in ischaemic heart disease compared with the lack of such data for A2RAs, reinforces this position.

NICE guidance on stable angina is due to be published in 2011. In 2007, SIGN published guidance on the management of stable angina (SIGN 96) which recommended that all patients with stable angina should be considered for treatment with an ACE inhibitor. This was based on an earlier meta-analysis of the HOPE, EUROPA and PEACE trials.

Combination therapy with an A2RA plus an ACE inhibitor would appear to have a very limited role. SIGN guidance on the management of chronic heart failure (SIGN 95) suggests this may be a specialist option in patients with heart failure who are still symptomatic despite optimised ACE inhibitor and beta-blocker therapy. This is based on results from the CHARM-Added trial were the addition of candesartan to ACE inhibitor treatment reduced hospitalisations for heart failure but not all-cause mortality. However, combination therapy in patients with heart failure increases adverse effects, including hypotension, worsening renal function and hyperkalaemia, and requires very careful monitoring.

Study details –
Baker WL, et al. Systematic review: Comparative effectiveness of angiotensin-converting enzyme inhibitors or angiotensin II-receptor blockers for ischaemic heart disease. Ann Intern Med, published online October 19 2009

Design, patients, intervention and comparison: Systematic review and meta-analysis of trials of at least 6 months duration that compared ACE inhibitors, A2RAs or combination therapy with placebo or active control and reported any of several clinical outcomes. Nine RCTs, 2 non-randomised comparative studies and 6 systematic reviews met eligibility criteria. Included RCTs were HOPE (ramipril vs. placebo), PART-2 (ramipril vs. placebo), SCAT (enalapril vs. placebo), EUROPA (perindopril vs. placebo), CAMELOT (enalapril vs. amlodipine vs. placebo), PEACE (trandolapril vs. placebo), SMILE-ISCHEMIA (zofenopril vs. placebo), TRANSCEND (telmisartan vs. placebo) and ONTARGET (ramipril vs. telmisartan vs. both).

Outcomes and results: see above

Sponsorship: funded from the Agency for Healthcare Research and Quality

More information on RAS drugs can be found on the national support materials (RAS drugs) floor of NPCi. These materials are due to be updated shortly.

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11 November 2009

The VULCAN study found no evidence to support the use of silver dressings under compression bandaging for the treatment of venous leg ulcers. Compared with non-silver low-adherent dressings, silver dressings were not more effective in healing ulcers, did not improve quality of life, and were not cost-effective. 

Level of evidence:
Level 2 (limited quality patient-oriented evidence) according to the SORT criteria. 

Action
Healthcare professionals should follow CKS guidance for the management of leg ulcers. Routine use of silver-containing dressings under multilayer compression bandaging is not recommended for the treatment of leg ulcers. In the absence of any evidence for a clinical benefit or cost-effectiveness advantage, healthcare professionals should not use them ahead of less-expensive non-silver wound dressings. 

What is the background to this?
Several systematic reviews (see ‘How does this relate to other studies?’ below) have pointed out the lack of good quality clinical evidence to support the use of modern wound dressings, including the relatively more expensive silver dressings. They highlight the need for prospective randomised controlled trials (RCTs) to evaluate their effectiveness. This publicly funded, pragmatic RCT sought to address the lack of evidence by examining the effectiveness and cost-effectiveness of silver dressings applied beneath compression bandaging in the treatment of venous leg ulcers.

What does this study claim?
The VULCAN study randomised 213 patients to silver-donating dressings (n=107) or non-antimicrobial, low-adherence dressings (n=106). Dressings were changed at least weekly and were covered by multilayer compression bandaging. No evidence was found to support the routine use of silver-donating dressings beneath compression for venous ulceration.

There was no statistically significant difference between the silver and non-silver dressings in the primary outcome of complete ulcer healing after 12 weeks (59.6% silver, 56.7% control; relative risk [RR] 1.06, 95% confidence interval [CI] 0.80 to 1.40; P=0.67) after six months, or after one year. Overall median time to healing was 67 days for the silver dressings and 58 days for control dressings (P=0.41). There was no significant difference in quality of life (EuroQol 5D and Short Form 6D) between groups at any of the follow up times of 1, 3, 6 and 12 months.

Compared with the control group, the silver dressing group had an incremental cost of £98 and an incremental quality-adjusted life year (QALY) gain of 0.0002, giving an incremental cost-effectiveness ratio of £489,250 per QALY gained for the silver dressings. The additional costs for the silver dressing were partly due to an increased cost of dressings (£31 vs. £6 per patient), but also due to an increase in the number of dressing changes in the silver dressing group. 

How does this relate to other studies?
A 2006 Cochrane Review of wound dressings used underneath compression bandaging for the treatment of venous leg ulcers found no, or insufficient, evidence that any one dressing type was better than another with regard to ulcer healing. A previous Rapid Review blog from 2007 considered a systematic review of modern wound dressings for the treatment of acute and chronic wounds. It pointed out the lack of good quality clinical evidence to support the use of modern wound dressings, including the relatively more expensive silver dressings.

A Cochrane Review from 2007 specifically considered the use of silver-containing dressings for treatment of infected or contaminated chronic wounds. Only three trials with a short follow-up duration were found, and insufficient evidence was found to recommend the use of silver-containing dressings or topical agents.

A meta-analysis of the effectiveness of silver-releasing dressings in the management of infected chronic wounds identified some positive effects for silver-containing wound dressings. However, the quality of the trials was limited by the potential for bias associated with inadequate concealment, no detailed description of the outcome measurement and no reported intention-to-treat analysis. Moreover, problems existed in some studies with confounding factors.

There is no NICE guidance on the management of venous leg ulcers, although there is CKS guidance, which is evidence based. 

So what?
Silver dressings are one of the many ‘modern’ or ‘advanced’ dressings available in the UK. Silver is included as an anti-infective agent. There are many silver dressings available and they are expensive; the cost to the NHS on FP10s alone in the year to September 2008 was about £25 million, compared with costs about of £110 million for all wound management dressings.

The results of this study suggest that, when used under compression bandaging, silver-containing dressings are not more effective than unmedicated non-adherent dressings in healing leg ulcers, are not associated with a better quality of life, and are not cost-effective.

In the absence of demonstrating any significant advantage over non-silver containing dressings (i.e. efficacy, safety, patient factors) that might justify their use ahead of less costly non-silver containing dressings, routine use of silver-containing dressings cannot be recommended.

The results of this study are consistent with CKS guidance (last revised 2008) on the management of venous leg ulcers, which points out that ‘there is insufficient evidence to show that any wound dressing (including dressings impregnated with silver) is better than simple low-adherent dressing for the healing of venous leg ulcers’. Healthcare professionals should follow this CKS guidance, which broadly follows 2006 guidance from the Royal College of Nursing Institute.

There are some significant limitations of the study, some of which are discussed by the authors of the paper. These need to be considered when interpreting the results of the study. The lack of blinding of treatment to those providing and assessing the treatments is a major limitation. Also, many types of dressing were used in the study, and it is not known whether there are any advantages of any individual dressing over another (silver or non-silver). Although the study suggests no general benefit of including silver in the dressings, specific clinical trial data is needed to confirm that this is the case for all dressings, which may differ in their characteristics. There were also variations in demographics and healing rates between the two centres, who used a different mix of silver dressings and where wound-care practices may have varied; this may have introduced bias into the study. Despite these limitations, this study is the best evidence we have for the effectiveness of silver dressings in wound care. The study suggests that their routine use is not justified on clinical or cost-effectiveness grounds for the treatment of leg ulcers under compression bandaging. Further well controlled studies are needed to justify their use ahead of non-silver dressings for managing other types of wounds. 

More information on alternative types of advanced wound dressings that are available in the UK and the (limited) clinical evidence supporting their use can be found in Advanced Wound Dressing Buyers’ guide produced by the Centre for Evidence-based Purchasing.

Study details
Michaels JA, et al. Randomized controlled trial and cost-effectiveness analysis of silver-donating antimicrobial dressings for venous leg ulcers (VULCAN trial). Br J Surg 2009;96:1147–56 

Design
Multicentre, pragmatic, prospective, randomised controlled study carried out in two regions of England. 

Patients
The study recruited 213 patients with active ulceration of the lower leg that had been present for more than six weeks. 53% reported previous episodes of leg ulceration, 21% had deep vein thrombosis and 55% had a history of varicose veins. The mean ages were 69 years in the silver dressing group and 72 years in the control group. 

Intervention and comparison
Patients were randomised to receive silver-donating dressings (n=107) or non-antimicrobial, low-adherence dressings (n=106) for 12 weeks. A variety of silver and non-silver dressings types were used according to normal practice beneath multilayer compression. The type of silver dressing was the clinician’s choice from an approved list of six dressings. The non-silver dressings were standard non-antimicrobial low-adherence dressings from any manufacturer (82% were low-adherence knitted viscose dressings). Allocated dressings were applied at each dressing change (at least weekly). Other interventions or treatments could be used (e.g. debridement) if felt to be clinically appropriate. If there was still ulceration after 12 weeks, the clinicians caring for the patients decided whether or not to continue or change the dressings. All patients were followed up for 12 months.

The perspective for the cost-effectiveness analysis was that of the UK NHS and Social Services, will all costs reported in 2007 prices. 

Outcomes and results
Analysis was by intention to treat. There was no statistically significant difference between the dressings in the primary outcome of complete ulcer healing after 12 weeks (59.6% silver, 56.7% control; relative risk [RR] 1.06 95%CI 0.80 to 1.40; P=0.67). There were also no significant differences at six and twelve months, Overall median time to healing was 67 days for the silver dressings and 58 days for control dressings (P=0.41). Among the 185 patients whose ulcers healed within the first year, 24 (11 silver, 13 control) had recurrent ulceration. There was no significant difference in quality of life (EuroQol 5D and Short Form 6D) between groups at any of the follow up times of 1, 3, 6 and 12 months.

The biggest single contributor to costs for both groups was the cost of attending clinics, accounting for 61–66% of the total costs. The mean cost per clinic visit for the silver group was £275 compared with £196 for the control group. The mean cost of silver dressings was £30.62 compared with £5.73 for the control dressings. The mean total cost per patient was £418 for the silver group and £320 for the control group (an incremental cost increase of £98). Compared with the control group the silver dressing group had an incremental QALY gain of 0.0002, giving an incremental cost-effectiveness ratio of £489,250 per QALY gained for the silver dressings. 

Sponsorship
The trial was funded by the NHS Heath Technology Assessment Programme.

More information on wound dressings is/will soon be available on the ‘Other therapeutics’ floor of NPCi.

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11th November 2009

Introduction
In October 2009 the results from the study ‘Medicines reconciliation in ambulatory care: attempts at improvement’¹ were published. The objective of the study was to improve the overall accuracy of medication lists in an outpatient setting by providing performance feedback and training to the healthcare team and increasing patient participation in the medication reconciliation process. The study was carried out in outpatient clinics in Rochester, U.S.A.

The authors of the study focused on medicine list completeness, correctness and accuracy using a random selection of patients for each of the 3 separate measurement periods: pre-intervention (n=108), and 2 immediate post interventions — firstly a licensed practical nurse (LPN) intervention (n=102), followed by a patient awareness intervention (n=115). The study aimed to test the authors’ hypothesis that medication list accuracy would improve by including patients in the process. The results were:

• Completeness of medication lists improved from 20.4% pre-intervention, to 45.1% post LPN intervention, and 50.4% following the patient awareness intervention
• Correctness of medication lists improved from 23.1% post LPN intervention, to 37.7% following the patient intervention.
• The medication list accuracy improved from 11.5% pre-intervention, to 19.2% post LPN intervention, and 29.0% following the patient intervention.¹

Action
Medicines reconciliation is as important in the outpatient setting as it is during the admission or discharge stages of an inpatient episode.

The authors of this study have demonstrated that, by involving and training all members of the healthcare team, providing performance feedback and increasing patient involvement in the process, the accuracy of medication lists in outpatient settings can be significantly improved.

Outpatient healthcare teams should review their procedures to ensure that they are doing all they can to train their staff and encourage patient involvement in the medicines reconciliation process.

Background
Medication error can result in harm to patients. The NPSA reported the number of incidents of medication errors involving admission and discharge as 7070, with 2 fatalities and 30 that caused severe harm (figures from November 2003 and March 2007).²

It is important that healthcare professionals and managers from different care settings agree on a minimum dataset of information to support the medicines reconciliation process. Once that has been agreed, all staff involved in a patient’s transfer of care should work together to make sure that this information is effectively communicated across all care interfaces. Involving the patient in this process will lead to further improvements to the accuracy and completeness of information.

How does this relate to other publications or evidence?
In October 2009 the Care Quality Commission (CQC) produced its review ‘Managing patients’ medicines after discharge’³ which shows how, to prevent harm to patients from medicines, the NHS needs to improve the sharing of vital information when people move between services. In this review the CQC makes several recommendations for organisations to ensure that care becomes safer for patients.

The CQC review supports the recommendations from the NPSA and NICE in December 2007 ‘Technical patient safety solutions for medicines reconciliation on admission of adults to hospital’⁴ on the need for healthcare organisations to put policies in place to support the process of medicines reconciliation.

In addition to these recommendations, the NPC 2008 guide – Medicines Reconciliation: A Guide to Implementation, gives hints and tips on the practical aspects of the medicines reconciliation process. The guide suggests minimum datasets needed to enable medicines reconciliation to take place; discusses the reliability of information sources that are available to healthcare professionals trying to reconcile lists of medicines; and proposes key skills that are needed to carry out the reconciliation process.

There is an NPCi (www.npci.org.uk) floor dedicated to Medicines Reconciliation which includes a range of resources that can help busy healthcare professionals to learn about the topic in small, bite-sized chunks. The NPCi floor, Reducing Medication Errors, also provides information, tools and resources which can support effective medicines reconciliation.

References
1. Nassaralla CL, Naessens JM, Hunt VL, Bhagra A, Chaudhry R, Hansen MA, Tulledge-Scheitel SM. Medicines reconciliation in ambulatory care: attempts at improvement. Quality and Safety in Health Care 2009;18: 402-407.
2. NPSA (2007). ‘NICE/NPSA issues its first patient safety solution guidance to improve medicines reconciliation at hospital admission’ [Last accessed 9th November 2009].
3. Care Quality Commission national report. Managing patients’ medicines after discharge from hospital. Care Quality Commission, 2009
4. NPSA and NICE (2007). ‘Technical patient safety solutions for medicines reconciliation on admission of adults to hospital’ [Last accessed 9th November 2009].

Feedback
Please comment on this blog in the NPCi discussion rooms, or using our feedback form.

9 November 2009

This meta-analysis found that high-dose vitamin D supplements reduced the relative risk of falling by 19% in individuals aged 65 years or more. Eleven people would need to be treated with 700 to 1000 units of vitamin D daily to prevent one fall over about 21 months*. Falls were not significantly reduced by low-dose vitamin D supplements.

* The average duration of treatment that the patients in the trials included in the meta-analysis received.

Level of evidence:
Level 2 (limited-quality patient-oriented evidence) according to the SORT criteria.

Action
Healthcare professionals should follow the NICE guideline on the assessment and prevention of falls in older people, and the two NICE technology appraisals on the use of drugs for the primary and secondary prevention of osteoporotic fragility fractures in postmenopausal women with osteoporosis. The technology appraisals assume that women who receive treatment have an adequate calcium intake and are vitamin D replete. Unless clinicians are confident that women who receive treatment meet these criteria, calcium and/or vitamin D supplementation should be considered. There are a number of licensed preparations that will supply the evidence-based doses of 1g per day for calcium (measured as elemental calcium) and 700 to 1000 units per day for vitamin D.

What is the background to this?
Vitamin D supplementation can improve muscle strength, function and balance in a dose-related manner in older individuals at risk of vitamin D deficiency. However, it is unclear whether vitamin D can prevent falls because results from studies have been inconclusive. This meta-analysis assessed the efficacy of supplemental vitamin D and active forms of vitamin D, with and without calcium, for the prevention of falls among older people, by dose and by serum concentration of 25-hydroxyvitamin D3.

What does this study claim?
This study found that doses of vitamin D supplements in the range of 700 to 1000 units daily gave a relative risk reduction (RRR) of falling by 19% (7 randomised controlled trials [RCTs], n=1,921; relative risk [RR] 0.81, 95%CI 0.71 to 0.92; pooled risk difference 9.4%, 95%CI 5.1% to 13.7%; number needed to treat [NNT] 11, 95%CI 7 to 20) over about 21 months* (range 2 to 36 months). Doses of less than 700 units daily did not significantly reduce fall risk.

So what?
The NICE guidance on falls prevention does not currently make any recommendations on the use of vitamin D. It points out that there is evidence that vitamin D deficiency and insufficiency are common among older people and that, when present, they impair muscle strength and possibly neuromuscular function. Although, as this meta-analysis shows, there is emerging evidence that correction of vitamin D deficiency or insufficiency may reduce the propensity for falling, there remains uncertainty about the relative contribution to fracture reduction. Combined calcium and vitamin D supplementation has been shown to prevent fractures in studies of people living in care homes and/or the frail elderly. However, it is unclear whether the results are generalisable to women living in the wider community.

Risk assessment is important in osteoporosis to target the effective therapies to those at highest risk of falls and fracture. For the lower-risk population, advice to ensure sufficient calcium and vitamin D intake, perhaps using educational materials, is probably appropriate. Supplementation may be considered for those with diets that have poor intake of calcium-rich foods or who have limited exposure to sunlight. The Food Standards Agency website outlines which foods are good sources of calcium and vitamin D.

Those at higher risk of falls and fracture, such as those in nursing or residential homes, should be considered for additional supplementation, at an evidence-based dose. Importantly, this includes those on a bisphosphonate or other osteoporosis treatment, as all of the trials were conducted in people with optimal calcium and vitamin D intake. For postmenopausal women receiving treatment for the primary or secondary prevention of osteoporotic fractures, NICE states that supplements may be considered for those who do not have an adequate calcium intake and who may not be vitamin D replete. There are a number of licensed preparations that will supply the evidence-based doses of 1g per day for calcium and 700 to 1000 units per day for vitamin D, and practitioners should ensure that this is the case when prescribing, dispensing or administering this treatment. See the BNF for more details.

NICE is developing a clinical guideline on ‘Osteoporosis: assessment of fracture risk and the prevention of osteoporotic fractures in individuals at high risk’. The development of this is currently being reviewed following the publication of the technology appraisals.

A suite of educational materials on osteoporosis, including a <60minute eLearning event, is now available on NPCi.

Study details:
Bischoff-Ferrari HA, et al. Fall prevention with supplemental and active forms of vitamin D: a meta-analysis of randomised controlled trials. BMJ 2009;339:b3692

Design: Meta-analysis of 10 RCTs of fall prevention (sufficiently specified) with a defined oral dose of vitamin D supplement (D2 or D3) or active vitamin D and a minimum follow-up of 3 months.

Patients: 3,050 individuals aged 65 years or older.

Intervention and comparison: The primary outcome measure was the relative risk of having at least one fall among persons receiving vitamin D, with or without calcium, compared with the risk among those receiving placebo or calcium supplementation alone.

Outcomes and results: Heterogeneity was found among the results for the 8 RCTs looking at fall prevention with any dose of supplemental vitamin D. However this was resolved after stratifying trials by daily dose.

Doses of vitamin D supplements in the range of 700 to 1000 units daily reduced the relative risk of falling by 19% (7 RCTs, n=1,921; RR 0.81, 95%CI 0.71 to 0.92; pooled risk difference 9.4%, 95%CI 5.1% to 13.7%; P<0.0001; NNT 11, 95%CI 7 to 20) for a treatment duration of about 21 months* (range 2 to 36 months). Doses of less than 700 units daily did not significantly reduce fall risk (2 RCTs, n=505; RR 1.10, 95%CI 0.89 to 1.35). Similarly, achieving a serum concentration of 25-hydroxyvitamin D3 of 60nmol/L or more significantly reduced the risk of falling (RR 0.77, 95%CI 0.65 to 0.90) whereas a concentration of less than 60nmol/L did not (RR 1.35, 95%CI 0.98 to 1.84).

Subgroup analysis suggested that the benefit of high-dose vitamin D was not significantly affected by type of vitamin D (D2 or D3), gender, age, or level of independence and was attained with only 2 to 5 months of treatment and sustained for 12 to 36 months. In addition, fall prevention with a high dose may not depend on additional calcium supplementation. However, because these results are based on subgroup analyses, they should only be regarded as hypothesis generating.

Oral active forms of vitamin D significantly reduced the risk of falling (2 RCTs, n=624; RR 0.78, 95%CI 0.64 to 0.94)

Sponsorship: Swiss National Foundations Professorship Grant , Velux Foundation, Baugarten Foundation, Vontobel Foundation, fellowship from Robert Bosch Foundation, National Institute on Aging

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27 October 2009,

An indirect comparison meta-analysis found that dronedarone was significantly less effective than amiodarone in preventing recurrence of AF, but was associated with fewer side effects requiring discontinuation. It was predicted that for every 100 people treated for one year for AF with dronedarone rather than amiodarone, there would be 23 more recurrences of AF and 6 fewer adverse events requiring discontinuation. 

Level of evidence
Level 2 (limited quality, patient-orientated evidence) according to the SORT criteria

Action
Dronedarone may be launched in the UK by the end of 2009. It is likely to be indicated in clinically stable adult patients with history of, or current non-permanent atrial fibrillation (AF) to prevent recurrence of AF or to lower ventricular rate. Contraindications, special warnings, and monitoring requirements (as will be described in the summary of product characteristics [SPC]) are not yet published.

The exact place in therapy of dronedarone is uncertain. Until NICE guidance on dronedarone is published (due June 2010) prescribers should continue to follow the existing NICE guideline for the management of AF. Dronedarone could be considered as an option, within its licensed indications, by specialists for those patients for whom amiodarone is indicated, but not appropriate, e.g. if there are intolerable adverse effects. Clinicians will need to balance whether the use of dronedarone — a less efficacious but possibly safer antiarrhythmic drug than amiodarone — is justified for their patients with AF. For patients who are already receiving and tolerating amiodarone and have not developed unacceptable side effects, there would appear to be no good reason to switch to dronedarone.

Dronedarone is likely to be significantly more expensive than currently used anti‑arrhythmic drugs, which are mainly available generically. Local decision making bodies on medicines are advised to engage with stakeholders and agree a protocol for use when dronedarone is launched. This includes identifying those patients for whom the drug may be appropriate and planning for possible NICE guidance. It is important that steps are taken to inform prescribers of any contraindications and precautions, to ensure that dronedarone is used appropriately. 

What is the background to this?
On 24 September 2009, the EMEA Committee for Medicinal Products for Human Use (CHMP) adopted a positive opinion for dronedarone (Multaq®). It recommended granting a marketing authorisation for adult clinically stable patients with history of, or current non-permanent AF, to prevent recurrence of AF or to lower ventricular rate. A key study considered in providing this opinion was the ATHENA trial, which we have reviewed in a previous blog. In the ATHENA trial of 4,628 patients with AF or flutter, dronedarone was more effective than placebo (mean follow-up of 21 months) in reducing cardiovascular (CV) hospital admissions or death from any cause (31.9% vs. 39.4%; hazard ratio 0.76, 95% confidence interval (CI) 0.69 to 0.84, P<0.001), as well as other trials.

Because of the limited information available from studies that directly compare the efficacy and safety of dronedarone with amiodarone, Piccini and colleagues carried out a systematic review and indirect comparison meta-analysis using data from placebo-controlled trials of the two drugs in over 6000 people with AF.

Further information about AF can be found on the cardiovascular floor of NPCi. Dronedarone has been reviewed in an On the Horizon bulletin. Dronedarone is part of the 19th wave of technology appraisals from NICE, but a NICE clinical guideline on the management of AF is already available.

What does this study claim?
The study claims that dronedarone is less effective than amiodarone for the maintenance of sinus rhythm, but has fewer side effects.

The meta-analysis identified a statistically significant estimated reduction in recurrent AF with amiodarone versus placebo (odds ratio [OR] 0.12; 95%CI 0.08 to 0.19) but not for dronedarone versus placebo (OR 0.79; 95% CI 0.33 to 1.87). Using a logistic regression model incorporating all trial evidence, amiodarone was found to be superior to dronedarone (OR 0.49; 95% CI 0.37 to 0.63; P<0.001) for the prevention of recurrent AF, but was more likely to result in adverse events requiring drug discontinuation (OR 1.81; 95% CI 1.33 to 2.46; P<0.001).

The authors also suggest a ‘trend’ for reduced mortality in favour of dronedarone, although no statistically significant difference between treatments was identified (P=0.066).

How does this relate to other studies?
These results are consistent with the results of the DIONYSOS trial that directly compared dronedarone with amiodarone for the maintenance of sinus rhythm. However, results of DIONYSOS are only reported in a press release and are yet to be published in a peer-reviewed journal. DIONYSOS was a study of 504 patients with AF (mean follow-up 7 months). Dronedarone was less effective than amiodarone in preventing AF recurrence, or withdrawal due to intolerance or lack of efficacy (74% vs. 55%, P<0.001). Fewer thyroid and neurological events were reported in the dronedarone patients, but there were more reports of diarrhoea, vomiting and nausea. Amiodarone caused more bradycardia and QT prolongation. No cases of Torsade de Pointes were reported.

So what?
The present study found that dronedarone was significantly less effective in preventing recurrence of AF, but was associated with fewer side effects leading to discontinuation than with amiodarone. The indirect meta-analytical approach used in this study has many limitations (see accompanying Editorial) and the findings of this study can only be considered hypothesis generating and require confirmation from direct comparisons in adequately powered trials. Nevertheless, the reduction in efficacy and reduction in adverse effects seen in this study are consistent with the preliminary results from DIONYSOS.

Although the ATHENA study identified a significant benefit for preventing hospitalisation for CV events or death for dronedarone over placebo, no benefit over amiodarone has yet been demonstrated in this regard. Whether or not dronedarone offers any particular advantage over amiodarone for an individual with AF will require a value judgement of whether likely benefits from reduced side effects outweigh the disadvantage of a shorter time to recurrence of AF. At present there is no good quality clinical evidence from comparative studies measuring important patient-oriented outcomes (e.g. quality of life) demonstrating whether or not dronedarone offers any net clinical benefit over amiodarone at a population level.

NICE guidelines on the management of atrial fibrillation detail those situations where amiodarone might be considered. However, there are many other approaches that should be considered before, or as alternatives to, the use of amiodarone.

Full prescribing details (including dosage, contraindications, drug and food interactions, and monitoring requirements) for dronedarone have yet to be published. As discussed in a previous blog of the ATHENA trial, it may be advisable not to initiate therapy with dronedarone in patients with severe heart failure and left ventricular dysfunction.

Dronedarone is already licensed for use in the US. Contraindications in the US include patients with severe heart failure or those with NYHA 2 or 3 heart failure with a recent decompensation requiring hospitalisation or referral to a specialised heart failure clinic. Increases in serum creatinine have occurred in clinical trials with dronedarone, and there are potentially important drug interactions to consider (e.g. with strong CYP3A inhibitors such as voriconazole, and with drugs that prolong the QT interval, which might increase the risk of Torsade de Pointes). It is important that steps are taken to inform prescribers of any contraindications and precautions, to ensure that dronedarone is used and monitored appropriately.

Study details

Piccini JP, Hasselblad V, Peterson ED, et al. Comparative efficacy of dronedarone and amiodarone for the maintenance of sinus rhythm in patients with atrial fibrillation. J Am Coll Cardiol 2009;54:1089–95

Design: Systematic review and indirect comparison meta-analysis of RCTs of amiodarone (4 studies) and dronedarone (4 studies) versus placebo for the prevention of AF.

Patients: The dronedarone and amiodarone trials included 5,967 and 669 patients respectively. The mean age across all trials was 65 years. Studies of subjects age <18 years and subjects with acute cardioversion, catheter ablation, and post-operative AF were excluded. In all 4 dronedarone trials, patients with permanent AF were excluded. Additional exclusion criteria included advanced symptomatic heart failure, a corrected QT interval >500ms, and bradycardia with a heart rate <50 beats/min. In contrast to the dronedarone trials, the amiodarone trials predominantly included patients with persistent and permanent AF.

Interventions: Dronedarone or amiodarone versus placebo. All trials had a follow up of at least 6 months (means of 13 and 16 months, respectively).

Comparison: The effect of amiodarone versus dronedarone was summarised by the use of indirect comparison meta-analysis and normal logistic meta-regression models.

Outcomes and Results:
There was a significant estimated reduction in recurrent AF with amiodarone versus placebo (OR 0.12; 95%CI 0.08 to 0.19) but not dronedarone versus placebo (OR 0.79; 95%CI 0.33 to 1.87). A normal logistic regression model incorporating all trial evidence found amiodarone superior to dronedarone (OR 0.49; 95%CI 0.37 to 0.63; P<0.001) for the prevention of recurrent AF. There was no statistically significant difference between amiodarone and dronedarone identified with regard to all-cause mortality (OR 1.61; 95% CI 0.97 to 2.68; P=0.066). More patients discontinued treatment because of adverse effects with amiodarone than with dronedarone (OR 1.81; 95%CI 1.33 to 2.46; P<0.001). For every 1,000 patients treated with dronedarone instead of amiodarone, it was estimated that there would be approximately 228 more recurrences of AF in exchange for 62 fewer adverse events requiring discontinuation of drug.

Sponsorship: The lead author is supported by an American College of Cardiology Foundation/Merck award.

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6 November 2009

Introduction
The NPC has recently announced an ongoing programme of support for all NHS local decision-making (LDM) groups. The programme was commissioned from the NPC, by the Department of Health (DH), as a continuation of the support already provided to help the review and development of local decision-making processes around the funding of medicines and treatments. 

Action
Details of the support programme can be found on NPC’s website in the policy to practice section. The programme includes e-learning resources for LDM groups and a dedicated LDM website with a discussion group and sharing practice section.

Seven LDM facilitators, have also been recruited to work in SHA areas to encourage sharing of practice and to facilitate local activities. As part of the local focus to the support programme, the LDM facilitators are in the process of organising an LDM event specific to your area. Contact your facilitator to find out more.

Background
Earlier this year, the NHS Constitution¹ gave patients the right to expect decisions made about the funding of medicines and treatments to be made rationally following a proper consideration of the evidence and, in particular, where a decision is taken not to fund, that it can be explained.

PCTs have been encouraged to review their local decision making processes in-line with this NHS Constitution right and the high level Guiding Principles², issued by the DH and NPC, at the same time as the Constitution. The NPC also published a good practice Handbook³ to support PCTs in reviewing their processes in conjunction with other NHS stakeholders. 

Summary
Review the LDM pages on the NPC website to keep up to date with what support resources are available for your organisations and to find out who your LDM facilitators are. Join the LDM website to share practice or discuss the issues, that you are having to manage, with people working in the same area.

This is an ongoing support programme designed to respond to your needs. To give us feedback on what we have already developed, or to help inform the development of the programme moving forward,.get in touch with your LDM facilitator or email ian.pye@npc.nhs.uk at the NPC.

References

1. Department of Health (2009) The NHS Constitution for England http://www.dh.gov.uk/en/Publicationsandstatistics/Publications/
PublicationsPolicyAndGuidance/DH_0934190

2. National Prescribing Centre (2009) Defining Guiding Principles for Processes supporting Local Decision Making about Medicines http://www.dh.gov.uk/en/Publicationsandstatistics/Publications/Publications
PolicyAndGuidance/DH_093413

3. National Prescribing Centre (2009b) Supporting rational local decision-making about medicines (and treatments) http://www.npc.co.uk/policy/local/constitution_handbook.htm

Feedback
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5 November 2009

NICE has issued a clinical guideline on the treatment and management of depression in adults. The guideline makes recommendations on the identification, treatment and management of depression in adults in both primary and secondary care, and partially updates and replaces previous NICE guidance (CG23) issued in 2004.

Action
Healthcare professionals involved in the treatment and management of patients with depression should familiarise themselves with the new guideline and base their management on this. The quick reference guide provides a summary of the recommendations and the key priorities for implementation. NICE has also issued a costing statement that discusses areas of possible costs and savings that should be considered locally.

What does the guideline cover?

Recommendations include:

• Case identification and recognition — Be alert to possible depression (particularly in people with a past history of depression or a chronic physical health problem). Note that NICE now recommends diagnosis according to DSM-IV criteria; this is different from previous guidance.

• Low-intensity psychosocial interventions — For people with persistent sub threshold depressive symptoms or mild to moderate depression, consider offering one or more of the following interventions, guided by the person’s preference:
  • individual guided self-help based on the principles of cognitive behavioural therapy (CBT)
  • computerised cognitive behavioural therapy
  • a structured group physical activity programme.

• Drug treatment — Do not use antidepressants routinely to treat persistent sub threshold depressive symptoms or mild depression, but consider them for people with:
  • a past history of moderate or severe depression, or
  • initial presentation of sub threshold depressive symptoms that have been present for a long period (typically at least 2 years), or
  • sub threshold depressive symptoms or mild depression that persist(s) after other interventions.

• Treatment for moderate or severe depression — For people with moderate or severe depression, provide a combination of antidepressant medication and a high-intensity psychological intervention, such as CBT.
• Continuation and relapse prevention — Support and encourage a person who has benefited from taking an antidepressant to continue medication for at least 6 months after remission of an episode of depression. Discuss with the person that this greatly reduces the risk of relapse and antidepressants are not associated with addiction.
• Counselling — This is now only recommended for people with persistent sub threshold depressive symptoms or mild-to-moderate depression who decline an antidepressant, CBT, behavioural activation, interpersonal psychotherapy and behavioural couples therapy.

Which antidepressants are recommended?
The review carried out for the NICE guideline considered escitalopram and duloxetine▼ for the first time. However, the overall conclusion (unchanged from the previous guideline) was that antidepressants have largely equal efficacy. Choice should,therefore, largely depend on side-effect profile, patient preference and previous experience of treatments, propensity to cause discontinuation symptoms and safety in overdose, as well as cost. Potential interactions with concomitant medications or physical illness are also important to consider when choosing an antidepressant.

A generic SSRI should normally be chosen. It is necessary to take into account that:

• Selective serotonin reuptake inhibitors (SSRIs) are associated with an increased risk of bleeding. Consider prescribing a gastroprotective drug in older people who are taking non-steroidal anti-inflammatory drugs or aspirin.
• fluoxetine, fluvoxamine and paroxetine have a higher propensity for drug interactions.
• for people who also have a chronic physical health problem, consider using citalopram or sertraline as these have a lower propensity for interactions.
• paroxetine is associated with a higher incidence of discontinuation symptoms.

Take into account toxicity in overdose for people at significant risk of suicide. Be aware that:

• compared with other equally effective antidepressants recommended in primary care, venlafaxine is associated with a greater risk of death from overdose.
• the greatest risk in overdose is with tricyclic antidepressants (TCAs), except for lofepramine.

When prescribing drugs other than SSRIs, take into account:

• the increased likelihood of the person stopping treatment because of side effects, and the consequent need to increase the dose gradually, with venlafaxine, duloxetine▼ and TCAs
• the specific cautions, contraindications and monitoring requirements for some drugs
• that non-reversible monoamine oxidase inhibitors (MAOIs, such as phenelzine), combined antidepressants and lithium augmentation of antidepressants should normally be prescribed only by specialist mental health professionals
• that dosulepin should not be prescribed.

When prescribing antidepressants for older adults prescribe at an age-appropriate dose, taking into account physical health and concomitant medication and monitor carefully for side effects.

Do not prescribe or advise use of St John’s wort for depression. Explain the different potencies of the preparations available and the potential serious interactions of St John’s wort with other drugs (including oral contraceptives, anticoagulants and anticonvulsants).

Switching of antidepressants. The evidence for the relative advantage of switching either within or between classes of antidepressants is weak. When this is considered appropriate, NICE recommends a different SSRI or a better tolerated newer-generation antidepressant. Subsequently, an antidepressant of a different pharmacological class that may be less well tolerated, should be considered, for example venlafaxine, a TCA (but not dosulepin) or an MAOI.

Other relevant guidance
Alongside this guidance, NICE has also published guidance on the treatment and management of depression in adults with chronic physical health problems.

Other relevant NICE guidelines should be consulted for depression occurring in the context of other disorders:

• Borderline personality disorder. NICE clinical guideline 78 (2009)
• Antenatal and postnatal mental health. NICE clinical guideline 45 (2007)
• Dementia. NICE clinical guideline 42 (2006)
• Bipolar disorder. NICE clinical guideline 38 (2006).
• Obsessive-compulsive disorder. NICE clinical guideline 31 (2005)
• Depression in children and young people. NICE clinical guideline 28 (2005)
• Post-traumatic stress disorder (PTSD). NICE clinical guideline 26 (2005)
• Anxiety (amended). NICE clinical guideline 22 (2004; amended 2007). 

Details of how the recommendations were developed, and reviews of the evidence they were based on, can be found in the NICE Full Guideline.

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4 November 2009

A short-term randomised controlled trial claims benefits for the addition of inhaled budesonide/formoterol to tiotropium (i.e. triple vs. single therapy) in patients with COPD. However, limitations of the study question its validity and relevance to clinical practice. 

Level of evidence:
Level 2 (limited quality patient-oriented evidence) according to the SORT criteria. 

Action
Healthcare professionals should not change practice on the basis of this study, and should continue to use inhaled therapy for symptom relief in patients with COPD in accordance with NICE guidance.

According to NICE guidance, breathlessness and exercise limitation should be treated initially with a short-acting bronchodilator (beta2-agonist or anticholinergic) as needed. If this does not control symptoms then a long-acting bronchodilator (tiotropium or long-acting beta2-agonist [LABA]) should be prescribed (a combination of a short-acting beta2-agonist and a short-acting anticholinergic before this step is an option in the guideline). A long-acting bronchodilator should also be prescribed if the patient has two or more exacerbations a year. An inhaled corticosteroid (ICS) should be prescribed in addition for patients with a forced expiratory volume in one second (FEV1) of 50% predicted or less, and who have two or more exacerbations needing treatment with antibiotics or oral corticosteroids a year.

If patients remain symptomatic on monotherapy, their treatment should be intensified by combining therapies from different drug classes. Effective combinations include: beta2-agonist and anticholinergic; beta2-agonist and theophylline; anticholinergic and theophylline; LABA and ICS. In patients with moderate or severe COPD who are still symptomatic a combination of LABA/ICS is suggested but should be discontinued if no benefit is seen after four weeks.

What is the background to this?
LABAs, tiotropium, and combination LABA/ICSs all reduce total exacerbations in patients with COPD, with absolute benefits likely to be greater in those patients who have frequent exacerbations. Few studies have investigated the effect of triple therapy with tiotropium, LABA and ICS compared with other therapies. A one-year study of 449 patients with moderate or severe COPD, which found that adding salmeterol or salmeterol/fluticasone to tiotropium did not reduce exacerbations in people with moderate to severe COPD. However, some statistically significant improvements in secondary outcomes (lung function, quality of life, and hospitalisation rates) were found. The present study aimed to assess the efficacy and tolerability of budesonide/formoterol added to tiotropium in patients eligible for LABA/ICS therapy. 

What does this study claim?
The authors claim, on the basis of this study, that budesonide/formoterol added to tiotropium provides rapid and sustained improvements with regard to lung function, improved morning symptoms and activities, and reduces severe exacerbations, compared with tiotropium alone.

With regard to the primary outcome, the study identified a statistically significant improvement in FEV1 of 65ml (1.25 vs. 1.08L; relative risk (RR) 1.06, 95% confidence interval [CI] 1.04 to 1.09; P<0.001) from pre-dose baseline over 12 weeks for patients receiving budesonide/formoterol compared with those receiving placebo (both added to tiotropium).

The study identified some other statistically significant improvements for triple therapy over monotherapy for some secondary outcomes. For example, there was a reduction in the in the rate of severe exacerbations (defined as worsening of COPD leading to treatment with systemic corticosteroids and/or hospitalisation/emergency room visit) from 18.5% to 7.6% (RR 0.38; 95%CI 0.25 to 0.57; P<0.001). Health related quality of life, assessed with the St. George’s Respiratory Questionnaire for COPD (SGRQ-C) was also improved more in the triple therapy group than in the monotherapy group (3.8 units vs. 1.5 units; difference 2.3, 95%CI 0.32 to 4.23; P=0.023). 

So what?
The study suggests possible benefits of adding budesonide/formoterol to tiotropium in patients with COPD. However, it is important to consider several limitations of the study that question its validity and relevance to currently recommended clinical practice in the UK.

The most obvious limitation in the study is its basic design. The study compared triple therapy to monotherapy therapy. It provides no useful information on the benefits of dual therapy (i.e. adding either of the individual components of budesonide/formoterol inhaler to tiotropium) and it is impossible to tell how much each of the components contributed to the benefits seen. The reason for not including the additional arm(s) into the study to provide this information is not clear. We do not know whether the patients who benefited from the added combination would have done better (or indeed worse) if budesonide or formoterol alone had been added to tiotropium. The earlier study of triple therapy using add-on fluticasone/salmeterol was much more robust, in terms of its duration (one year vs. 12 weeks) and the inclusion of a dual therapy arm with salmeterol and tiotropium. This earlier study found no difference in the exacerbation rate between triple therapy and either mono or dual therapy.

The study’s stated objective was to investigate the effect of adding budesonide/formoterol to tiotropium to patients eligible for ICS/LABA combination therapy. From a UK perspective, if we consider the NICE guidance, addition of long-acting inhaled bronchodilators (LABA and/or tiotropium) should be used to control symptoms and improve exercise capacity in patients who continue to experience problems despite the use of short-acting drugs. Addition of a LABA to tiotropium can also be considered if the patient is experiencing two or more exacerbations a year. An ICS should be added to long-acting bronchodilators to decrease exacerbation frequency in patients with an FEV1 less than or equal to 50% predicted who have had two or more exacerbations requiring treatment with antibiotics or oral corticosteroids per year. The inclusion criteria for exacerbations in the present study (at least one COPD exacerbation requiring antibiotics or systemic steroids) and the mean number of exacerbations in patients at baseline (1.4 per year) appears to fall short of NICE recommendations for addition of an ICS.

Examination of treatments used by patients at the time of study entry reveals a wide range of treatment regimens being used previously. About half were receiving a long-acting muscarinic (tiotropium) before entering the study, whereas two thirds were already receiving ICS and three-quarters were receiving a LABA; many were clearly already receiving combination therapy. It would seem that for most cases the window of opportunity for assessing the benefits of adding a LABA or an ICS to tiotropium had already been passed for most of the patients.

The design called for patients to be withdrawn from their ICS/LABA therapy prior to a two-week run-in period, when they were given tiotropium (and reliever therapy) only before randomisation. Perhaps it is not surprising that reintroduction of ICS and or LABA, which many patients had already been receiving to control their symptoms before entering the study, provided some benefit. Despite this limitation, the degree of improvement in lung function was small, and as pointed out in the Editorial, not sufficient to reach the level normally considered to be clinically significant. This also applies to the small degree of improvement in health-related quality of life.

The study can be criticised for use of some unvalidated scoring systems for evaluating exacerbations. The Editorial identified that the definition of severe exacerbation used for this study differed from that of other studies because it included hospital/emergency room visits (regardless of whether or not they required antibiotic/systemic corticosteroid treatment). It points out that there was no significant difference between triple and monotherapy regarding antibiotic-treated exacerbations and the rate of corticosteroid-treated exacerbations was not reported. The results can not therefore be compared directly with other studies in this respect.

The study was of too short a duration (only 12 weeks) to provide meaningful information on long-term clinical outcomes; longer term studies are required to substantiate the apparent benefits in outcomes and adverse effects. The EMEA recommends that pivotal clinical studies in COPD should be longer than six months in duration. Although this study was only of 12 weeks duration, it took place over an entire year, and many of the subjects would have been treated and evaluated outside of the winter period when exacerbations and pneumonia are more likely. The potential of the study to demonstrate clinically meaningful improvements in these parameters was, therefore, diluted considerably.

Another limitation of the study is the failure to provide the reasoning behind the estimation of the sample numbers for the study (power calculation). No justification is given for why a 6% reduction in FEV1 (the actual difference shown in the study) was chosen as being a clinically meaningful level on which to power a study to show superiority of one therapy over another. Furthermore, no explanation of the choice of expected variation in response (i.e. standard deviation) used in the power calculation is provided. We have discussed inadequate sample size calculation and reporting in clinical trials in a previous Blog. 

The large number of centres used in the study, with an average of only about 6 subjects per centre might indicate a seeding trial (see previous Blog).

More information on COPD can be found in a recent MeReC Bulletin and on the COPD floor of NPCi. 

Study details

Welte T, Miravitlles M, Hernandez P, et al. Efficacy and tolerability of budesonide/formoterol added to tiotropium in patients with chronic obstructive pulmonary disease. Am J Resp Crit Care Med 2009;180:741–50 

Design: Multicentre (102 centres, 9 countries), double-blind, randomised controlled trial. Enrollment started May 2007 and the last subject completed in June 2008.

Patients: 660 patients (75% male); mean age 62 years; mean FEV1 38% predicted normal (25% FEV1 50 to 80%, 11% FEV1 less than 30% predicted); mean exacerbations during the last year 1.4.

Intervention and comparison: Previous treatments with LABA and/or ICS were withdrawn 2 and 4 weeks, respectively, before a 2 week run-in phase with tiotropium only. Patients continued to receive tiotropium (18 micrograms daily), and were randomised to receive either combination budesonide/formoterol 320/9 microgram or placebo twice daily for 12 weeks. 

Outcomes/results:

The primary outcome was the change in pre-dose FEV1 from baseline. There was a statistically significant improvement in FEV1 of 65ml (1.15 vs. 1.08L; RR 1.06, 95%CI 1.04 to 1.09; P<0.001) from pre-dose baseline over 12 weeks for patients receiving tiotropium plus budesonide/formoterol compared with those receiving tiotropium plus placebo.

Secondary outcomes:

Budesonide/formoterol reduced the rate of severe exacerbations (defined as worsening of COPD leading to treatment with systemic corticosteroids and/or hospitalisation/emergency room visit) compared with placebo from 18.5% to 7.6% (RR 0.38; 95%CI 0.25 to 0.57; P=<0.001).

Health related quality of life, assessed with the St. George’s Respiratory Questionnaire for COPD, was also improved more in the triple therapy group than in the monotherapy group (3.8 units vs. 1.5 units; difference 2.3, 95%CI 0.32 to 4.23).

Compared with placebo, statistically significant treatment differences in favour of triple therapy were seen for all COPD symptoms (including breathlessness, night-time awakening, chest tightness and cough), total morning activity scores, and reliever use, from run-in to last week of treatment (week 12) (all P<0.001).

Adverse events were reported in 25% of patients in both groups, with no apparent difference in adverse event profiles between the groups. There were three cases of pneumonia reported in each treatment group.

Sponsorship:  AstraZeneca

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27 October 2009

This updated Cochrane review found that, although the evidence is of limited quality, hygiene and physical barriers can be effective in reducing or preventing the spread of respiratory viruses such as influenza.

Level of evidence:
Level 2 (limited-quality patient-oriented evidence) according to the SORT criteria.

Action
Health professionals should be advocating (and following themselves) the clear public health messages issued by the Department of Health, NHS and Health Protection Agency (HPA) in: “catch it, bin it, kill it” (use of tissues when sneezing and their prompt disposal afterwards, followed by hand washing), and staying away from crowded places and public transport if one has probable swine ‘flu. The HPA recommends that healthcare workers wear a facemask if they come into close contact with a person with symptoms, to reduce their risk of catching the virus from patients. However, its does not recommend that healthy people wear facemasks in their everyday life.

What is the background to this?
Much popular media attention in conjunction with the current swine ‘flu pandemic has focussed on the pros and cons of antivirals (see our blogs for the evidence on antiviral use in adults and children). Respiratory viral infections, including influenza, are transmitted by droplet infection. This systematic review examined the available evidence for physical interventions to interrupt or reduce the spread of these kinds of infections.

What does this study claim?
The systematic review included 58 reports looking at 59 studies. The four randomised controlled trials (RCTs) of individuals and most of the cluster-randomised controlled trials were of poor quality; the observational studies were of mixed quality. The large quantity of data from very disparate studies, which could not be combined in meta-analyses, makes summarising the results difficult.

Most of the case control studies these looked at the effect of measures to reduce the spread of Severe Acute Respiratory Syndrome (SARS) in 2003. Results from these could be combined and show broadly similar results as in other studies. Compared with no intervention (“doing nothing”), disinfection of living quarters was highly effective in preventing the spread of SARS (odds ratio [OR] 0.30, 95% confidence interval [95%CI] 0.23 to 0.39) and handwashing for a minimum of 11 times a day prevented most cases (OR 0.45, 95%CI 0.36 to 0.57, number needed to treat [NNT] 4), Wearing simple masks was highly effective (OR 0.32, 95%CI 0.25 to 0.40, NNT 6) and wearing N95 masks (respirators with 95% filtration capability) was even more effective (OR 0.09, 95%CI 0.03 to 0.30, NNT 3). Wearing gloves was effective (OR 0.43, 95%CI 0.29 to 0.65, NNT 5) as was wearing gowns (OR 0.23, 95%CI 0.14 to 0.37, NNT 5). Handwashing, gloves, gowns and masks together achieved high effectiveness (OR 0.09, 95%CI 0.02 to 0.35, NNT 3).

The authors conclude that most effect on preventing the spread of respiratory viruses can be expected from hygienic measures in younger children and household members of index cases. Implementing barriers to transmission, isolation, and hygienic measures are effective with the use of relatively cheap interventions to contain epidemics of respiratory viruses, they say.

So what?
The NHS Choices website provides extensive advice about swine ‘flu. The question and answer section advises people with swine ‘flu against travelling on public transport or visiting crowded places so that they are less likely to spread the illness. It also advises everyone always to cover one’s nose and mouth with a tissue when coughing or sneezing, to dispose of dirty tissues promptly and carefully, to maintain good basic hygiene, for example frequently washing hands, and to clean hard surfaces, such as door handles, often and thoroughly using a normal cleaning product. Alcohol handrubs can be used on visibly clean hands if there is no easy access to soap and water.

NHS Choices says that the Health Protection Agency (HPA) recommends that healthcare workers wear a facemask if they come into close contact with a person with symptoms (within one metre), to reduce their risk of catching the virus from patients. However, the HPA does not recommend that healthy people wear facemasks in their everyday life, as there is no evidence to suggest that this is a useful preventative measure and there are concerns about the risks of not using facemasks correctly. They must be changed regularly as they are not so effective when dampened by a person’s breath. People may infect themselves if they touch the outside of their mask, or may infect others by not throwing away old masks safely.

Study details –
Jefferson T, et al. Physical interventions to interrupt or reduce the spread of respiratory viruses: systematic review. BMJ 2009;339:b3675

Sponsorship
NHS research and development programme and National Health and Medical Research Council of Australia.

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27 October 2009

A large systematic review found that compared with LABA monotherapy, combined LABA/ICS did not statistically significantly reduce severe exacerbations, all-cause mortality, respiratory mortality or CV mortality, in patients with moderate to very severe COPD. Although combined LABA/ICS did provide some statistically significant benefits (e.g. reduction in moderate exacerbations, improvement in FEV1 measures and quality of life scores), the magnitude of these benefits were not considered clinically important. Furthermore, combined LABA/ICS was associated with serious adverse effects, particularly pneumonia.

Level of evidence:
Level 1 (good quality patient-oriented evidence) according to the SORT criteria.

Action
Health professionals should continue to follow NICE guidance on COPD, which recommends that inhaled corticosteroids (ICSs) are only prescribed for specific patients. An ICS should be added in to treatment with a long-acting bronchodilator (salmeterol, formoterol or tiotropium) only in patients with moderate or severe COPD (forced expiratory volume in one second [FEV1] <50% predicted) who have had two or more exacerbations requiring treatment with antibiotics or oral corticosteroids in a 12-month period. Adding an ICS could also be considered in patients with moderate or severe COPD who are still breathless despite monotherapy with a long-acting bronchodilator, but the ICS should be discontinued if there is no benefit after four weeks.

What is the background to this?
As we discussed in a MeReC Bulletin on recent safety issues with inhaled treatments for COPD, there is no good evidence that ICSs improve survival in people with COPD, or reduce the rate of FEV1 decline. However, there is evidence to suggest that ICSs may reduce the frequency of COPD exacerbations, and may improve quality of life.

The potential risks of ICSs range from unpleasant local side effects, such as oral candidiasis and dysphonia, to less common systemic effects, such as adrenal suppression and osteoporosis. Recently, ICS treatment in patients with COPD has also been associated with an increased risk of pneumonia.

Current NICE guidance on COPD recommends that ICSs should be added to long-acting bronchodilators only in patients with moderate to severe COPD, and in specific circumstances as outlined above. The aim of treatment is to reduce exacerbation rates and slow the decline in health status, and not to improve lung function per se. This recent meta-analysis and systematic review of 18 RCTs (n=12,446) aimed to determine the risks of adding in an ICS to a long-acting beta agonist (LABA), compared with LABA monotherapy, and whether combined LABA/ICS provides any significant clinical benefits over LABA monotherapy in COPD.

What does this review claim?
Compared with LABA monotherapy, combination therapy with LABA/ICS did not statistically significantly decrease the risk of severe COPD exacerbations requiring hospitalisation or withdrawal (relative risk (RR) 0.91, 95% confidence interval [CI] 0.82 to 1.01), all-cause mortality (RR 0.90, 95%CI 0.76 to 1.06, P=0.77), respiratory mortality (RR 0.80, 0.61 to 1.05, P=0.58) or cardiovascular (CV) mortality (RR 1.22, 95%CI 0.88 to 1.71, P=0.46). There was a significant reduction in moderate exacerbations requiring oral corticosteroids or antibiotic use (RR 0.84, 95%CI 0.74 to 0.96, P=0.008. For further details of the analysis of primary outcomes, see Table 1 below.

Therapy with a LABA/ICS was also associated with improvements in measures of lung function, St George respiratory questionnaire (SGRQ) scores and end of treatment dyspnoea score, compared with LABA alone. However, LABA/ICS was found to increase the risk of pneumonia, oropharyngeal candidiasis and viral respiratory infections. For more details of secondary outcomes, see Table 2 below.

The authors concluded that compared with LABA monotherapy, the magnitude of the benefits of LABA/ICS therapy did not reach that of the predefined criteria for clinically important effects and were associated with serious adverse effects.

So what?
In this large study, treatment with combined LABA/ICS did not reduce severe COPD exacerbations (requiring hospitalisations or withdrawal), all-cause mortality, respiratory mortality or CV mortality. Only one of the primary outcomes reached statistical significance (moderate COPD exacerbations requiring oral corticosteroids or antibiotic use), although the authors question the clinical significance of this result. The relative risk reduction of moderate exacerbations with combined LABA/ICS was 16%, which is lower than the suggested threshold value of 22% for clinical significance.1 These findings appear to be consistent with other large studies. For example, in a Cochrane review of LABA/ICS combinations, combined LABA/ICS reduced total exacerbations, compared with LABA alone, but there was no reduction in all-cause mortality.

Other benefits were observed with combined LABA/ICS in some secondary outcomes e.g. mean change in pre- and post-bronchodilator FEV1, mean change in SGRQ scores, end of treatment dyspnoea scores, compared with LABA alone. However, the authors of the review also question the relevance of these improvements, as the magnitude of benefit did not reach the suggested clinically important minimal differences (FEV1 0.10 to 0.14L; SGRQ score 4 units).

The relative benefits of treatment with combined LABA/ICS must also be weighed against the risks. This review found a relative risk increase of 63% for pneumonia and 59% for oropharyngeal candidiasis for LABA/ICS compared with LABA. As we have previously blogged, other large RCTs and meta-analyses have demonstrated an increased risk of pneumonia with ICSs in people with COPD. A recent meta-analysis suggests that budesonide does not increase the risk of pneumonia, although further research is necessary to establish if budesonide does offer any long-term safety advantage over other ICSs (e.g. fluticasone) in COPD.

There are also other potential risks which are important and were not considered in this review e.g. osteoporosis (especially in the presence of other risk factors). When considering adding an ICS to treatment regimens for people with COPD, prescribers should consider, and discuss with patients, the potential increased risk of pneumonia, as well as osteoporosis and other side effects.

This review was well conducted but it is important to consider some potential limitations, which are particularly relevant to all COPD studies. The included studies did not consistently use similar definitions for COPD exacerbations or pneumonia, which may have affected the results. No studies were specifically designed or powered to detect differences between the two treatment groups for all-cause, respiratory or CV mortality. Furthermore, allocation concealment was unclear in 13 studies.

Further information on the management of COPD can be found on the COPD floor of NPCi

Reference
1. Cazzola M, MacNee W, Martinez FJ, et al. Outcomes for COPD pharmacological trials: from lung function to biomarkers. Eur Respir J 2008;31:416–68

Study details
Rodrigo GJ, Castro-Rodriguez JA, Plaza V. Safety and efficacy of combined long-acting β-agonists and inhaled corticosteroids vs long-acting β-agonists monotherapy for stable COPD. Chest 2009;136:1029–38

Design: Meta-analysis and systematic review of 18 RCTs (n=12,446). Fourteen studies used salmeterol/fluticasone and four studies used formoterol/budesonide. Eleven of the studies were long term (>52 weeks). Allocation concealment was adequate in only 5 studies, and was unclear in the remaining 13 studies.

Patients: Stable adults (>40 years) with moderate to very severe COPD (<80% predicted FEV1), according to the GOLD classification. Mean age of patients was 64 years with an average baseline FEV1 of 40% of predicted normal values. Eleven studies reported that a mean of 31% (range 0–55%) of patients had received ICSs before enrollment in the study.

Intervention & comparison: Inhaled combined LABA/ICS as the intervention arm compared with LABA monotherapy for more than 1 month.

Outcomes: Primary outcomes were severe COPD exacerbations (requiring hospitalisation or withdrawals), moderate COPD exacerbations (requiring oral corticosteroids or antibiotic use), all-cause mortality, respiratory death (due to a respiratory event e.g. COPD exacerbation, pneumonia) and cardiovascular mortality, during the treatment period. Secondary outcomes included measures of lung function, health-related quality of life (using SGRQ) and adverse effects.

Results:

Table 1: Primary outcomes ― LABA/ICS vs. LABA

^a The I² statistic measures heterogeneity in a meta-analysis. A value of 0% indicates no observed heterogeneity, and larger values show increasing heterogeneity.

Table 2: Secondary outcomes ― LABA/ICS vs. LABA

^b The number of participants in the study arm

Post publication amendment (4/11/09)

In the first publication of this blog (27 October 2009), we included the numbers needed to treat (NNTs) and numbers needed to harm (NNHs), which had been calculated by the authors of the meta-analysis from pooled effect estimates. Following feedback and further consideration, these have now been removed due to the heterogeneity of different durations of treatment in the included studies. 

Sponsorship: No sponsorship from institutions or pharmaceutical industry was provided.

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27 October 2009,

The RE-LY study found that, in patients with atrial fibrillation with at least one other risk factor for stroke, dabigatran▼ was non-inferior to adjustable dose warfarin in preventing strokes, and reduced the incidence of major bleeding. Further studies are required to establish long-term safety.

Level of evidence:
Level 2 (limited quality, patient-orientated evidence) according to the SORT criteria

Action
Should dabigatran receive a license for use in AF it may offer an effective alternative for those patients who have difficulty maintaining anticoagulation control or who cannot take warfarin for other reasons. The advantages demonstrated in this study for efficacy (high dose only) and for reduction of bleeding (low dose only) are small in absolute terms. Questions remain regarding dabigatran’s long-term safety and how it would compare in patients who are well controlled on warfarin. It is likely to have a considerably higher drug cost than warfarin.

A NICE appraisal of dabigatran in AF is expected to begin during early March 2010, in order to be available at or around the expected launch of dabigatran later in the year, should its licence be approved. Cost-effectiveness relative to warfarin should be an important consideration. Local decision making bodies on medicines are advised to engage with stakeholders and agree a protocol for its use if/when dabigatran is licensed for this indication. This includes identifying those patients for whom the drug may be appropriate and planning for possible NICE guidance.

What is the background to this?
NICE recommends thromboprophylaxis for people with AF with either warfarin or aspirin depending on their level of risk, and after consideration of individual patient factors. Dose-adjusted warfarin is the most effective and preferred option for people who are at high risk of stroke. However, it is associated with a higher bleeding risk than aspirin, and is not appropriate for those at low risk of stroke.

For more information on the background and treatment options for AF, including the evidence supporting the use of warfarin and aspirin, please refer to the Cardiovascular floor of NPCi.

Dabigatran (more correctly called dabigatran etexilate – a prodrug of dabigatran) is an orally active antithrombotic agent. It is a direct thrombin inhibitor, which has the potential advantage over warfarin of not requiring blood monitoring, and may have fewer clinically important drug interactions. It is currently licensed for short-term use (maximum 35 days) in the primary prevention of venous thromboembolism in adults undergoing elective total hip or knee surgery, and is recommended by NICE as one of the options to consider in this indication.

Dabigatran is also being considered for the prevention of strokes in people with AF. The RE-LY study was a Phase III clinical study. It had a prospective, randomized, open-label, blinded endpoint (PROBE) design. It evaluated the non-inferiority of two doses of dabigatran compared with warfarin in people with AF who were at moderate to high risk of stroke. The primary efficacy endpoint of the trial was incidence of stroke (including haemorrhagic) and systemic embolism. The primary safety endpoint was major bleeding.

What does this study claim?
Over a median two-year follow-up, the mean rates of the primary end point were 1.53%/year for low-dose dabigatran (110mg twice daily), 1.11% per year for the high-dose dabigatran (150mg twice daily) and 1.69% per year for warfarin. The study found that the lower dose of dabigatran was non-inferior to warfarin at reducing the risk of stroke and systemic embolism in people with AF (relative risk [RR] 0.91; 95% confidence interval [CI] 0.74 to 1.11; P<0.001 for non-inferiority). The higher dose was found to be statistically significantly more effective than warfarin (RR 0.66; 95%CI 0.53 to 0.82; P<0.001; number needed to treat [NNT] 172 over one year).

The mean rates for major bleeding were 2.71% per year for low dose dabigatran, 3.11% per year for high dose dabigatran and 3.36%/year for warfarin. Whereas low-dose dabigatran was associated with a reduced risk of major bleeding (P=0.003; NNT 154 over one year), there were no significant differences between the high-dose dabigatran and warfarin in this respect.

How does this relate to other studies?
To reduce the risk of stroke in people with AF, the NICE guideline on the management of AF recommends thromboprophylaxis with either adjusted-dose warfarin (target international normalised ratio [INR] 2.5, range 2.0 to 3.0) or aspirin depending on the level of stroke risk. A stroke risk stratification algorithm is provided in the NICE guideline for this purpose. For those at high risk, warfarin is recommended, although aspirin can be considered where warfarin is contraindicated. For those at moderate risk of stroke either warfarin or aspirin can be considered, and for people at low risk of stroke (i.e. not at moderate or high risk) aspirin is recommended. However, owing to lack of sufficient clear-cut evidence, treatment may be decided on an individual basis, and the physician must balance the risks and benefits of warfarin versus aspirin. The potential bleeding risks of long-term anticoagulation are an important consideration.

Clopidogrel has also been considered for stroke prevention in people with AF. However it is not licensed, or recommended for use, alone or with aspirin for this indication. Studies to date in people with AF, have not demonstrated any significant benefits over existing treatments. The ACTIVE W demonstrated clear superiority of warfarin over clopidogrel in preventing vascular events. In the ACTIVE A study (see Blog) clopidogrel plus aspirin reduced the risk of a vascular composite end point compared with aspirin alone in people with AF who were at increased risk of stroke, and for whom warfarin-like drugs were unsuitable. However, this benefit has to be balanced against a significant increased risk of major bleeding where the NNT to cause a major bleed was similar to that to prevent a major vascular event – around 42 over 3.6 years.

So what?
The RE-LY study aimed to demonstrate non-inferiority for dabigatran compared with adjustable dosed warfarin. The design allowed for superiority to be tested once non-inferiority was identified, which it was for the primary endpoint.

Dabigatran was shown to be at least as effective as warfarin in preventing strokes, particularly haemorrhagic strokes, in people with AF who are at moderate or high risk of strokes. This finding, taken together with no greater risk of major bleeding, suggests a possible role as an alternative to warfarin in such patients.

However, there are a number of issues raised by the study which need to be considered when putting the results in the context of normal clinical practice. These relate to the level of anticoagulant control in the warfarin group, the long-term safety and tolerability of dabigatran, and limitations in the study methodology.

In the study, the INR was within the therapeutic range for 64% of the time. Although, this seems low, this is similar to other contemporary trials of warfarin and, in this trial, may reflect the high proportion of people in the study who had not received warfarin previously. Nevertheless, some patients will have been more controlled than others, and the study does not address the issue of whether dabigatran would be as effective as warfarin in those people who were well controlled on warfarin.

More patients discontinued treatment with dabigatran than warfarin during the study, which might be due to poorer tolerability. A higher incidence of discontinuations that were a result of serious side effects supports this view. However, as patients and physicians knew which treatment (dabigatran or warfarin) were being received this may have raised their perception of possible side effects from the newer drug, and decisions to discontinue may have been taken more readily.

Although, major bleeding was no more frequent between groups overall, the higher risk of GI side effects (both doses) and GI bleeding with dabigatran at the 150mg dose compared with warfarin raises questions about its use in people who are at high risk of these effects.

The study only considered dabigatran treatment for a median period of two years, and thus long-term safety is unclear. Serious hepatic side-effects were the reason for the withdrawal of the license for ximelegatran (another thrombin inhibitor) for a similar indication. Although there were no indications of a difference between treatments with regard to hepatic side effects in the present study, patients with a creatinine clearance of less than 30ml/min were excluded. It is not known whether monitoring of liver enzymes will be required with long-term use of dabigatran.

The significantly greater rate of MIs with high-dose dabigatran serves as a signal of potential long-term safety which will need to be considered. The absolute differences in this study were small; results suggest that 476 patients, like those in this study, would need to be treated with dabigatran for one year for one of them to have a myocardial infarction who would not have done if they had received warfarin. Nevertheless, this raises particular concerns about the use of dabigatran in people who are at high risk of coronary heart disease.

The studies main limitation, in terms of design, is its open-label nature. Both patients in the study and the physicians allocating treatment were aware of the treatment allocated (although allocation of dabigatran doses was blinded); this has potential to introduce considerable bias into the study. We have already mentioned how this might affect discontinuation. The independent blinded assessment of outcomes mitigates this effect to some degree, at least for the objective outcomes.

The results of this study are not directly applicable to those patient groups who were excluded from the study (e.g. those with recent strokes). However, in general, the patients included, who were at moderate to high risk of stroke, are the types of patients for which warfarin can be considered according to the NICE guideline.

All statistical analyses were conducted according to intention-to-treat principles. A per-protocol analysis, which includes patients who dropped out of the study, may have provided support to the non-inferiority status (as per EMEA recommendations).

In conclusion, recognising the limitation above, what does this study tell us about dabigatran’s place in therapy for the management of atrial fibrillation?

Any advantages in efficacy and safety were small in absolute terms. However, dabigatran has the considerable advantage that, unlike warfarin, it does not require regular anticoagulant monitoring, and there would be reductions in non-drug costs associated with provision of this service to people prescribed dabigatran instead of warfarin. Dabigatran may, therefore, be an appropriate option for those patients who cannot take warfarin, or undergo the monitoring required, or where control of anticoagulant status is poor, despite best efforts. However, may of the costs associated with current warfarin services will be fixed due to the need to maintain the existing infrastructure for patients well-established on warfarin. Therefore it seems unlikely that there will be real cost savings associated with the development of alternatives to warfarin, should the evidence for their wider use become more established.

Offset against the advantages for dabigatran, are questions about its long-term safety, and cost could be an issue. The drug’s acquisition cost is likely to be considerably higher than warfarin. According to the BNF, the current costs for dabigatran 110mg is £2.10 per capsule; this equates to about £1500 for a year’s course when given twice daily. The cost of warfarin is about 1000-times less; a year’s supply of warfarin 5mg costs about £16. NICE is due to review the use of dabigatran for AF in 2010, and cost-effectiveness should be an important consideration.

The increased drug cost may be offset by avoiding additional non-drug costs associated with anticoagulant monitoring. 

Although dabigatran interacts with a number of medicines (see SPC), it has fewer clinically important food and drug interactions than warfarin. However, unlike warfarin its antithrombotic effect is not rapidly reversible, and there is no antidote. This may be of particular concern in patients who are at high risk of bleeding.

Study details –

Connolly SJ, Ezekowitz MD, Yusuf S, et al. Dabigatran versus warfarin in patients with atrial fibrillation. N Engl J Med 2009;361:1139-51.

Design
Multicentre, international, clinical study with PROBE design

Patients
The study included 18,113 patients with AF and at least one other risk factor for stroke. Exclusion criteria included the presence of severe heart-valve disorder, stroke with 14 days or severe stroke with six months before screening, a creatinine clearance of less than 30ml/min, or active liver disease. The mean age was 71 and 64% were men. At baseline, the mean CHAD score was 2.1; 20% had had a previous stroke or TIA, 16–17% a previous MI, and 32% had heart failure. Half were receiving vitamin K antagonists and 39–41% were receiving aspirin.

Intervention and comparison
Patients were randomised to one of three groups. Dabigatran 110mg or 150mg (blinded) twice daily or warfarin (unblinded) adjusted to an INR of 2.0 to 3.0. The INR was within the therapeutic range for 64% of the study period. Aspirin was used continuously during the treatment period in 20–21% of patients in all three groups.

Outcomes and results
After a median of 2 years, complete follow-up was achieved in 99.9% of patients. The rates of discontinuation at two years were 17% for warfarin and 21% for both dabigatran groups (P<0.001 for both dabigatran doses vs. warfarin).

The primary outcome of stroke or systemic embolism occurred at a rate of 1.53% 1.11% per year, and 1.69% per year, for dabigatran 110mg, dabigatran 150mg, and warfarin, respectively. The 110mg dabigatran dose was non-inferior to warfarin but not superior (RR 0.91; 95%CI 0.74 to 1.11; P<0.001 for non-inferiority, P=0.34 for superiority). The 150mg dose was superior to warfarin in relation to the primary outcome (RR 0.66; 95%CI 0.53 to 0.82; P<0.001; NNT172). The primary outcome events were mainly strokes — pulmonary emboli occurred at rates of 0.12% per year, 0.15% per year, and 0.09% per year for dabigatran 110mg, dabigatran 150mg, and warfarin, respectively (no significant difference between groups).

Rates of haemorrhagic stroke were 0.12% per year, 0.10% per year and 0.38% per year, for dabigatran 110mg, dabigatran 150mg and warfarin, respectively. The differences were statistically significant from warfarin for both doses of dabigatran 110mg (RR 0.31, 95%CI 0.17 to 0.56; P<0.001; NNT 384) and 150mg (RR 0.26; 95%CI 0.14 to 0.49; P<0.001; NNT 357).

The rate of MI was higher but not significantly different in the dabigatran 110mg group (0.72% per year) than in the warfarin group (0.53% per year) (RR 1.35; 95%CI 0.98 to 1.87; P=0.07) but significantly higher in the dabigatran 150mg group (0.74% per year) (RR 1.38, 95% CI, 1.00 to 1.91; P=0.048; number needed to harm (NNH) 476).

Rates of death from any cause were 4.13% per year with warfarin, as compared with 3.75% per year with dabigatran 110mg (RR 0.91; 95%CI 0.80 to 1.03; P=0.13) and 3.64% per year dabigatran 150mg (RR 0.88; 95%CI, 0.77 to 1.00; P=0.051). Death from vascular causes was significantly lower with dabigatran 150mg compared with warfarin (2.28% vs. 2.69% per year; RR 0.85; 95%CI 0.72 to 0.99; P=0.04).

The rate of major bleeding was significantly lower in the dabigatran 110 mg group (2.71% per year) compared with the warfarin group (3.36%) (RR 0.80; 95%CI 0.69 to 0.93; P=0.003; NNT 154). There was no significant difference in major bleeding between the dabigatran 150mg group (3.11% per year) and the warfarin group (RR 0.93; 95%CI, 0.81 to 1.07; P=0.31).

Rates of life-threatening bleeding, intracranial bleeding, and major or minor bleeding were significantly higher with warfarin (1.80% per year, 0.74% per year, and 18.15% per year, respectively) than with either the 110mg dose of Dabigatran (1.22% per year, 0.23% per year, and 14.62% per year, respectively) or the 150mg dose of Dabigatran (1.45% per year, 0.30% per year, and 16.42% per year, respectively); RR and CIs for comparisons are available in the full article; all P-values were less than 0.05. Rates of major GI bleeding were higher with dabigatran 150mg (1.51% per year) compared with warfarin (1.02% per year, RR 1.50, 95%CI 1.19 to 1.89; P<0.001, NNH 204), but not dabigatran 110mg (1.12% per year). There were no significant differences between groups with regard to non-threatening major bleeding or extracranial bleeding.

Serious adverse events leading to discontinuation occurred more frequently with both doses of dabigatran (both 2.7%) than with warfarin (1.7%; P<0.001; NNH 100) Gastrointestinal symptoms (which included pain, vomiting and diarrhoea) were given as the reason for discontinuation more often with dabigatran 110mg (2.2%) and dabigatran 150mg (2.1%) than with warfarin (0.6%).

Dyspepsia occurred in 5.8% of patients in the warfarin group, 11.8% in the 110mg dabigatran group and 11.3% in the 150mg dabigatran group (P<0.001 for both dabigatran doses vs. warfarin, NNHs 17 and 19, respectively).

Sponsorship
The study was funded by Boehringer Ingelheim

More information on atrial fibrillation can be found on the cardiovascular floor of NPCi

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27 October 2009

The MHRA has established a safety monitoring programme for swine flu vaccines to capture, evaluate, and monitor suspected adverse drug reactions.

Action
Members of the public and healthcare professionals should report any suspected adverse reactions to pandemic swine flu vaccines (Celvapan▼ and Pandemrix▼) or antiviral medicines used for the treatment or prevention of swine flu (Tamiflu▼ and Relenza▼) through the dedicated online reporting website that has been set up by the Medicines and Healthcare products Regulatory Agency (MHRA).

Details
In a press release on the 22nd October, the MHRA announced that it has extended its dedicated Adverse Drug Reaction (ADR) website for reporting suspected side effects to H1N1 (swine flu) antivirals to now include separate reports about the recently introduced H1N1 vaccines.

Most people who receive the vaccine are not expected to experience any significant side effects. As with all new vaccines, the MHRA is keen to evaluate ADR reports and encourages both members of the public and healthcare professionals to inform them of any suspected reactions.

The MHRA has an established safety monitoring programme to ensure the reports linked to the swine flu vaccines are promptly captured, evaluated and monitored against background or ‘expected’ rates.

A dedicated team of drug safety scientists are responsible for reviewing ADR reports submitted to the MHRA through the Swine Flu Portal allowing fast, real-time surveillance of possible side effects.

Further information on swine flu vaccines, including product information (patient information leaflets and Summaries of Product Characteristics is available on a dedicated webpage of the MHRA website.

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20th October 2009

Introduction
In October 2009 the results from the Care homes’ use of medicines study: prevalence, causes and potential harm of medication errors in care homes for older people¹ were published. The objective of the study was to determine the prevalence and potential harm of prescribing, monitoring, dispensing and administration errors in UK care homes, and to identify their causes. The results of the study have generated much interest as the authors call for action from all concerned to address the need for improvement.

The results found that 69.5% of residents involved in the study had experienced one or more medication errors. Contributing factors to the findings included:

• Doctors who were not accessible, did not know the residents and lacked information in homes when prescribing
• Home staff’s high workload, lack of medicines training and drug round interruptions
• Lack of team work among home, practice and pharmacy
• Inefficient ordering systems
• Inaccurate medicines records and prevalence of verbal communication
• Difficult to fill medication administration systems

Action
In it’s discussion section, the authors of Care homes’ use of medicines study: prevalence, causes and potential harm of medication errors in care homes for older people¹ make several suggestions that could contribute to improved patient safety in care homes.

These include:

• Exploring the suggestion of a lead GP for each home; ensuring appropriate monitoring of patients on riskier medicines and that all patient’s medication is reviewed by a pharmacist
• Consideration of one person, perhaps a pharmacist, having overall responsibility for medicines use in one or more care homes
• Constant review of the use and accuracy of medication administration records. (The authors noted that lack of protocols and adequate staff training is an issue)
• Prescribing medicines for different times to ease busy morning drug rounds which can often be interrupted
• Monitoring of omitted doses and ordering systems , particularly of “as required” medicines, to reduce administration errors from omissions when a drug is not available

Everyone involved in medicines management systems and processes in care homes, including care home managers, healthcare professionals and staff, and commissioners who have a lead role in ensuring safe medication practices are embedded in patient care, should read this document and take action.

Background
Medication errors can occur at any stage of the medicines management process, from prescribing and dispensing through to administration and monitoring.²

As reported in Care homes’ use of medicines study: prevalence, causes and potential harm of medication errors in care homes for older people¹, prescribing has been found to be suboptimal in UK care homes, although the prevalence of medication errors in this setting in the UK is not known.  

The Department of Health released the report Building a safer NHS for patients: Implementing an organisation with a memory in 2001, ³ which set out the Government’s commitment to reducing medication errors, as well as the agenda for improving care by reporting and learning from adverse events. This was followed by a further report Building a safer NHS for patients: Improving Medication Safety in 2004.⁴ As well as other recommendations, the 2004 report highlighted that errors in prescribing may occur in the care home environment due to prescribing decisions being inadequately recorded, and that decisions made by GPs during care home visits must be incorporated into the patient’s records in a timely manner. The report also stressed that the application of procedures, checks and defences is especially important in care home settings if safer administration of medicines is to be achieved.

What does this mean to medicines management?
Older patients in care homes (residential, nursing or combination) are a frail and vulnerable population at particular risk of medication errors. Medicines Management in care homes needs to focus on improving the systems designed to support prescribing, dispensing, administration and monitoring. This can be achieved by reducing the likelihood of human error through effective training that takes into account the knowledge of how medicines are used, how to recognise and deal with problems as they occur, and encourage staff to report and learn from medication errors (through the National Reporting and Learning System (NRLS)) that have occurred previously. 

How does this relate to other publications or evidence?
The article National Minimum Standards in care homes: what roles do pharmacists have?, published in the Pharmaceutical Journal in 2002, identified the important role suitably qualified pharmacists could have in supporting care homes to improve medicines management by, amongst other things, acting as an important source of medicines information to carers; providing assistance with medicines controls by keeping patient medication records; and providing computer generated Medicines Administration Record (MAR) charts and monitored dosage systems.

The NPC currently has a number of medicines management resources that support improved practice in all care settings. Some of these resources are particularly relevant to medicines management in care homes and should be signposted to by organisations wishing to respond to the call for action. 

These resources include the following NPCi floors:

• Medicines Management in Care Homes (Focus includes: Understanding current regulations and standards for medicines use in care homes; the principles of good practice in handling of medicines in care homes; and the benefits of robust policies and procedures for medicines handling in care home)
• Reducing Medication Errors (Focussing on enabling people to: use tools for assessing and reducing medication errors; identify steps in the medication process where errors can and do occur; understand and contribute actively to the reporting of medication errors; develop practice to improve the detection and management of medication errors; and contribute to reducing medication errors through a range of actions and interventions
• An Introduction to Medicines Management (Focus includes: Understanding what ‘medicines management’ is, and how it is used in different situations; the benefits of good medicines management ; barriers and potential solutions to improving medicines management)
• Medicines Management in Long Term Conditions (Focus includes: understanding the problems commonly faced by people who have to take medicines as part of the management of their condition; problems facing people with specific common long term conditions; and potential solutions to medicines-related problems)

And the documents:

• A Guide to Medication Review, 2008 (Providing advice for those providing and commissioning medication reviews in a wide range of care settings – with the needs of vulnerable groups, such as the elderly and people with long term conditions particularly in mind. Supporting NPCi floor also available)
• Medicines Reconciliation: A Guide to Implementation, 2008 (Helping people to understand the importance of obtaining accurate and timely information about patients’ medicines, and the part that each of us has to play in ensuring that every patient receives a personalised service as far as their medicines are concerned. Supporting NPCi floor also available)

Readers wishing to share initiatives which have improved medicines management in care homes can complete and submit an NPC Medicines Management example of improvement form . All examples of improvement would appear in the Medicines Management examples of improvement section of the NPC website.  

References
1. Barber, ND, Alldred, DP, Raynor, DK, Dickinson, R, Garfield, S, Jesson, B, Lim R, Savage I, Standage, C, Buckle, P, Carpenter, J, Franklin B, Woloshynowych, M, Zermansky, AG, (2009). Care homes’ use of medicines study: prevalence, causes and potential harm of medication errors in care homes for older people.

2. Department of Health (2008) The Pharmacy White Paper: Building on strengths and delivering the future.

3. Department of Health (2001). Building a safer NHS for Patients: Implementing an organisation with a memory.

4. Department of Health (2004). Building a safer NHS for patients: Improving Medication Safety.

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15 October 2009

We have added and updated some new resources on the therapeutics section of NPCi recently — why not take a look?

The therapeutics section of the NPCi virtual building contains materials arranged in floors (for example, asthma) which are grouped into categories (for example, respiratory tract). For each theme, some or all of the following materials are available:

• A <60 minute eLearning event, where you can watch and listen to an NPC trainer present a series of short workshops on the theme – generally all in less than 60 minutes.
• A key slide set for the theme, with extensive notes, to use in discussion with others.
• A data focussed commentary, where you can read a commentary which compares recent prescribing data with the evidence base for that theme. There are questions for reflection.
• A patient decision aid which you can download to help explain therapeutic choices to patients so that they can come to an informed decision.
• One or more quizzes where you can test your knowledge of the theme. The quizzes are formative — getting answers wrong is a valuable way of learning as fully referenced answers are provided.
• One or more case studies, which are fictional but represent “real world” scenarios where you can apply your understanding and compare your answers with fully referenced suggested model answers.

The NPC are still in the process of developing materials for the NPCi Website, and are continually updating material. The following list shows the most recent updates.

New patient decision aids are now available on the following topics:

• Acute coronary syndrome
• Atrial fibrillation
• Common infections – UTI
• Dementia
• Schizophrenia
• Contraception
• HRT – Combined & Oestrogen-only
• Oseltamivir (Tamiflu▼)

Common Infections – UTI floor 2009 update

• <60 minutes eLearning
• Key slides and notes
• Data focussed commentary
• Case study
• Quiz
• Common infections – UTI

Other updated material includes:

• Hypertension — 2009 update to <60 minutes eLearning
• Mental Health Overview — Data focussed commentary
• Bipolar disorder — <60 minutes eLearning

Please comment on this blog in the NPCi discussion rooms, or using our feedback form.

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15 October 2009

The MHRA and CHM have published the October edition of Drug Safety Update. There is a first-year safety review of the human papillomavirus immunisation programme, based on Yellow Card reports, which reports that the balance of risks and benefits remains positive. Important new drug safety advice for ceftriaxone and high-dose cyproterone acetate is included, and some potentially clinically important interactions between medicines and smoking status are considered. There is also a review of two recent studies of aspirin, which do not give support to its use for primary prevention of vascular events (currently an unlicensed indication). A ‘Stop Press’ summarises the results of a recent cohort study that found no clear evidence of an increased risk of fatal or non-fatal self-harm with the use of varenicline▼.

Action
Drug Safety Update (DSU) is an essential read for everyone whose professional practice involves medicines. It is published every month in electronic format only. In light of recent media attention, the section on the adverse event picture seen with HPV vaccine is of particular note.

First-year safety review of the human papillomavirus (HPV) immunisation programme
At least 1.4 million doses of Cervarix▼ HPV vaccine have now been administered across the UK. As at the end of July 2009, the MHRA had received 2,195 Yellow Cards, reporting 4,830 suspected adverse reactions, in association with the vaccine. According to the MHRA, the total number and nature of suspected side effects reported was much as expected. Most reports related to the signs and symptoms of recognised side effects, which are generally not serious. The most commonly reported suspected adverse reactions were dizziness, headache and nausea.

A quarter of the reported suspected reactions were classified as “psychogenic reactions”. These include vasovagal syncope, faints, panic attacks, and associated symptoms. These can occur with any injection procedure, not only vaccination, and can be common in adolescents. Such events can be associated with a wide range of temporary signs and symptoms, including: loss of consciousness; vision disturbance; injury; limb jerking (often misinterpreted as a seizure or convulsion); limb numbness or tingling; and difficulty in breathing or hyperventilation. These are due to fear or anticipation of the needle injection and are not side effects of HPV vaccine as such.

No new risks were identified, and the balance of risks and benefits remains positive. The MHRA and CHM encourage health professionals and members of the public to report all suspected adverse reactions to HPV vaccine, via the Yellow Card system. As with all vaccines, the MHRA and CHM will continue to monitor closely the safety of Cervarixq during continued use in the UK.

Updated safety advice: Ceftriaxone (Rocephin®) — interaction with calcium containing solutions
Ceftriaxone should not be given simultaneously with calcium-containing solutions (other than total parenteral nutrition solutions given via a different infusion line at a different site) for intravenous administration because of a risk of calcium precipitation. Ceftriaxone is contraindicated in newborns up to age 28days who need intravenous treatment with any calcium-containing solution. Calcium and ceftriaxone may be infused sequentially in patients aged 28days or older provided that either a) the infusion line is rinsed or flushed between solutions, or b) the infusions are given via different infusion lines at different sites.

Updated safety advice: High-dose cyproterone acetate — potential risk of (multiple) meningiomas
Patients with existing meningioma or a history of meningioma must not be prescribed high-dose (greater than or equal to 25mg per day) cyproterone acetate (i.e. Cyprostat-50®, Cyprostat-100®, or Androcur-50®). This advice does not apply to low-dose cyproterone acetate products such as co-cyprindiol (Dianette®).

Smoking and smoking cessation: clinically significant interactions with commonly used medicines
Smoking induces the drug-metabolising enzyme CYP1A2 and thus in patients who smoke, or who are cutting down or stopping smoking (with or without the aid of drug treatment), the doses of any concomitant medication metabolised by CYP1A2 may need to be adjusted accordingly. The most important medicines to consider in those who smoke, or who are trying to quit, include theophylline, olanzapine, clozapine, caffeine, and warfarin.

In addition to this pharmacokinetic interaction, it is important to consider pharmacodynamic interactions. The most clinically significant interacting drugs include: hormonal contraceptives (increased risk of cardiovascular disease); inhaled corticosteroids (efficacy may be reduced in smokers with asthma); and betablockers (nicotine activation of sympathetic nervous system may counteract effect).

Although clear guidelines for clinical practice are not available, it is suggested that the following general approach should be taken:

On starting CYP1A2 substrates:

- Obtain smoking status

- Determine clinical significance of any potential interaction

- Monitor efficacy and side effects

- Adjust dose if necessary

- Monitor smoking status and advise patients to seek advice from doctor if smoking status is to change

During smoking cessation:

- Find out what medicines the patient is taking

- Determine clinical significance of any potential interaction

 - Monitor for side effects

- Adjust dose if necessary

Aspirin: not licensed for primary prevention of thrombotic vascular disease
A recent randomised controlled trial (AAA, available as a congress report only) and a meta-analysis (ATT) have looked at the use of low-dose aspirin in the prevention of heart attacks and strokes in people without a history of vascular disease — i.e. primary prevention. Both studies found that the risk of having a major bleed outweighed any vascular benefit. In the UK, low-dose aspirin is licensed for prevention of thrombotic cerebrovascular or cardiovascular disease only in those who already have vascular disease — i.e. secondary prevention. Although aspirin is used in primary prevention, this is not a licensed indication. This issue is discussed further in a MeReC Rapid Review Blog of the ATT meta-analysis.

Varenicline▼ and suicidal behaviour — cohort study provides some reassurance
A Stop Press reports the results of a recently published observational study of 80,660 people, which did not identify a statistically significant increased risk of fatal or non-fatal self-harm for varenicline▼ compared with nicotine replacement therapy (NRT) or bupropion. However, a two-fold increased risk cannot be ruled out on the basis of the upper 95% confidence interval (CI). Compared with NRT, the hazard ratio for self-harm in people prescribed varenicline▼ was 1·12 (95%CI 0·67 to 1·88), and was 1·17 (95%CI 0·59 to 2·32) for those prescribed bupropion. 

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14 October 2009

The British Thoracic Society (BTS) has published updated guidance on management of community acquired pneumonia (CAP) in adults. This updates the 2004 guidance.

What’s new in the area of CAP?
The guidelines note the following developments:

• There are ever-increasing concerns about health-care associated infections, especially MRSA and C difficile. We should take steps to ensure their prudent and careful use, and, in particular, limit the use of levofloxacin and moxifloxacin in favour of other classes of antibiotics where appropriate.
• A reversal in the trend for increasing resistance of S pneumoniae, with rates of penicillin-resistance in the UK remaining below 4%.
• Increases in admissions to hospital and intensive care units.
• Changes in processes for managing acutely ill patients in hospitals.
• Enlarged priorities regarding timeliness of treatment, including the 4-hour admission target.
• Changes in practice regarding microbiological investigations.

These are reflected in the guidance, where most of the changes relate to hospital care.

Key messages for community-based health professionals

• Clinical judgement, supported by the CRB65 score, should be used to decide whether to treat patients at home or in hospital. When deciding on home treatment, the patient’s social circumstances and wishes must be taken into account in all instances.
• Patients in the community should be reviewed after 48 hours, or earlier if clinically indicated.
• Patients with suspected CAP should be advised to rest, drink plenty of fluids and not to smoke.
• Pleuritic pain should be managed with simple analgesia such as paracetamol.
• Pulse oximetry, should be considered, and should be available in the out-of-hours setting and in all locations where emergency oxygen is used.
• Amoxicillin 500mg three times daily is the preferred antibiotic, with doxycycline or clarithromycin as alternatives, for example in those patients hypersensitive to penicillins.
• Microbiological investigations are not recommended routinely but may be appropriate in certain circumstances. For example Examination of sputum should be considered for patients who do not respond to empirical antibiotic therapy.
• In patients with suspected severe, life-threatening CAP referred to hospital, GPs should administer antibiotics in the community: either benzylpenicillin 1.2g intravenously or amoxicillin 1g orally.

More information on CAP and bronchitis can be found on the common infections — respiratory tract floor of NPCi.

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6 October 2009

Ticagrelor plus aspirin was significantly more effective than clopidogrel plus aspirin in preventing vascular events in patients with acute coronary syndrome in the PLATO trial (NNT=53). There was no significant difference in the rates of major bleeding between the two groups, although more patients taking ticagrelor withdrew from the study, mainly due to adverse effects. Patients taking ticagrelor were significantly more likely to suffer from non-procedure related bleeding (NNH=143) and breathlessness than those taking clopidogrel.

Level of evidence:
Level 2 (limited quality, patient-orientated evidence) according to the SORT criteria

Action
Patients with ACS require careful risk assessment, whichever dual antiplatelet regimen is being considered. It is important to balance the benefits of treatment (i.e. reduced risk of CV events) against any adverse effects (e.g. increased risk of bleeding).

Ticagrelor’s place in therapy is unclear at present. This study suggests that ticagrelor may reduce the risk of CV events, and its rapid reversibility may give it advantages for acute treatment of patients who require surgery. However the greater risk of non-procedural major bleeding and other treatment-related side-effects (dyspnoea, bradyarrhythmia, increased serum levels of uric acid and creatinine) compared with clopidogrel, raise questions about its safety, particularly over the longer term. As yet there is no clinical evidence for any advantage/disadvantage compared with prasugrel▼.

 As the effects of ticagrelor reverse rapidly, compliance may be particularly important for effective treatment, and patients may need additional counselling and surveillance in this respect.

AstraZeneca is hoping to file ticagrelor with the regulatory authorities in the fourth quarter of 2009. If ticagrelor is granted a marketing authorisation, local decision makers will need to agree a protocol for its use.

What is the background to this?
Dual antiplatelet therapy is commonly used in patients with acute coronary syndromes (ACS). Clopidogrel in combination with aspirin is licensed, and recommended by NICE for, non-ST-segment elevation ACS. Clopidogrel is also licensed for patients with ST-segment-elevation ACS, in combination with aspirin, in medically treated patients eligible for thrombolytic therapy.

Prasugrel is licensed for patients with both non-ST and ST-segment-elevated ACS who are undergoing primary or delayed percutaneous coronary intervention (PCI). The current NICE FAD recommends prasugrel only when immediate primary PCI is necessary is necessary or when stent thrombosis has occurred with clopidogrel or for patients with diabetes mellitus.

Both clopidogrel and prasugrel, are irreversible inhibitors of adenosine diphosphate receptor P2Y₁₂ on platelets. Unlike clopidogrel and prasugrel, ticagrelor does not require metabolic activation, and its effects are more rapidly reversible. As pointed out in the accompanying Editorial, this provides potential advantages for ticagrelor where a patient with ACS needs non-deferrable surgery, such as urgent CABG. The PLATO study compared the effects of ticagrelor and clopidogrel, both in combination with aspirin, on CV events in patients admitted to hospital with an ACS.

What does this study claim?
In patients who have had an ACS, with or without ST-segment elevation, treatment with ticagrelor plus aspirin significantly reduced the risk of death from vascular causes, myocardial infarction [MI] or stroke (primary composite outcome) compared with clopidogrel plus aspirin. The primary composite outcome occurred in 9.8% of the ticagrelor patients and 11.7% of those on clopidogrel at 12 months (hazard ratio [HR] 0.84, 95% confidence interval [CI] 0.77 to 0.92, P<0.001. This gives an absolute risk reduction of 1.9% and a number needed to treat (NNT) of 53 over 12 months. The rate of death from any cause was also reduced by ticagrelor (4.5% vs. 5.9%, P<0.001; NNT 72).

No significant difference in major bleeding (the primary safety variable) was found between groups (ticagrelor 11.6%, clopidogrel 11.2%, P=0.43). However, ticagrelor was associated with a significantly increased risk of major bleeding not related to CABG (4.5% vs. 3.8%, P=0.03; number needed to harm [NNH] 143).

Discontinuation of the study drug due to adverse events occurred more frequently with ticagrelor than with clopidogrel (7.4% vs. 6.0%, P<0.001; NNH 72)

How does this relate to other studies?
In 2004, NICE recommended use of clopidogrel in combination with low-dose aspirin for up to 12 months in the management of non-ST-segment-elevation ACS in people who are at moderate to high risk of MI or death. This recommendation was largely based on the results of the CURE study, which demonstrated a significant reduction in the incidence of death from CV causes with clopidogrel plus aspirin compared with aspirin alone. The number of patients who would need to be treated (NNT) with clopidogrel in combination with aspirin to prevent one additional CV death, non-fatal MI or stroke was 48. However, there was a significantly increased risk of major bleeding (NNH 100).

Key clinical evidence for prasugrel in ACS comes from the TRITON-TIMI 38 study. This demonstrated improved efficacy for prasugrel over clopidogrel, both given with aspirin, in reducing CV death or non-fatal MI or stroke (NNT 46), but there was an increased major bleeds (NNH 125). Guidance on prasugrel is due from NICE in October 2009.

A NICE technology appraisal on ticagrelor is anticipated in May 2011 and a clinical guideline on the management of patients with ACS is due in February 2010. Further information on the management of ACS can be found on the ACS floor of NPCi.

So what?
The place of therapy for ticagrelor is currently unclear. The study suggests a possible advantage of ticagrelor over clopidogrel when used with aspirin in the treatment of patients with ACS. However, any benefit in the reduction of CV events has to be balanced against the increased risk of adverse effects. Although the reduced risk of CV deaths compared with clopidogrel without any apparent increased risk of major bleeding (overall) is encouraging for ticagralor, the increased risk of non-CABG-related bleeding and other treatment-related adverse effects, raises concerns about it safety and may limit its use, especially over the long-term. At present there is no clinical evidence with which to directly compare the benefits and risks of ticagrelor with those of prasugrel.

As the Editorial points out, it is possible that by considering the advantages and disadvantages of each antiplatelet agent, it may be possible to individualise treatment for patients with ACS. However, further trials, including a comparison with prasugrel would be useful for guiding ticagrelor’s place in therapy.

There are a number of other limitations to the PLATO study, which also need to be considered when interpreting the results of this study:

• It is uncertain whether the allocation of patients to the randomised treatment groups was concealed.
• Not all patients received the same duration of treatment, with some patients discontinuing treatment at six or nine months, if the pre-specified number of events had been reached.
• The loading dose of clopidogrel was different among patients, depending on whether or not they had already received open-label clopidogrel.
• The higher rate of major bleeding seen in PLATO in both treatment groups (11–12%) is very much higher than that seen in CURE (3–4%) and TRITON-TIMI 38 (2–3%), questions the comparability of results between PLATO and the other studies, whether or not the difference arises due to the methods used for assessing bleeding or due to difference in baseline risk of bleeding between patients.

Caution is also needed when interpreting the results that relate to secondary outcomes, for which the study was not powered. For example, although the PLATO trial found that the rate of death from any cause was statistically significantly reduced with ticagrelor, the trial was not powered to detect differences in this outcome, and as such this could just be a chance finding.

Although the rapid reversibility of ticagrelor may give advantages in some clinical situations (e.g. prior to CABG), it also means that compliance with treatment may be more of an issue in its efficacy compared with clopidogrel or prasugrel. Ticagrelor requires twice-daily dosing.

Study details
Wallentin L, Becker RC, Budaj A et al for the PLATO Investigators. Ticagrelor versus clopidogrel in patients with acute coronary syndromes. N Engl J Med 2009;361:1045–57

Design: Randomised, multicentre, double-blind, phase III trial.

Patients: 18,624 patients hospitalised because of ACS with (38%) or without (43%) ST-segment elevation (17% unstable angina). Patients were eligible if onset of symptoms had been within the previous 24 hours. Patients had a median age of 62 years.

Intervention and comparison: Ticagrelor or clopidogrel were given in a double-dummy fashion to maintain blinding. Ticagrelor patients (n=9,333) received 180mg loading dose followed by 90mg twice a day. In the clopidogrel group (n=9,291), patients who had not received an open-label loading dose and had not been taking clopidogrel for at least 5 days before randomisation received 300mg as a loading dose then 75mg thereafter. Otherwise patients in this group received 75mg daily. All patients received aspirin 75–100mg daily, unless intolerant.

Outcomes and results: The primary outcome was a composite of death from vascular causes, MI, or stroke. At 12 months, 9.8% of ticagrelor patients and 11.7% of those receiving clopidogrel had a primary outcome (HR 0.84; 95% CI 0.77 to 0.92; P<0.001).

The rate of death from any cause was reduced in the ticagrelor group (4.5% vs. 5.9%; HR 0.78 (95% CI 0.69 to 0.89, P<0.001). Although statistically significant fewer MIs were identified in the ticagrelor group (5.8% vs. 6.9%; HR 0.84 (95%CI 0.75 to 0.95, P=0.005), the rate of stroke did not differ significantly between the two treatment groups. Definite stent thrombosis was seen in 1.3% of the ticagrelor patients and 1.9% of those on clopidogrel (HR 0.67, 95% CI 0.50 to 0.91, P=0.009).

No significant difference in major bleeding (the primary safety variable) was found between groups (ticagrelor 11.6%, clopidogrel 11.2%; HR 1.04 (95%CI 0.95 to 1.13, P=0.43). Ticagrelor was associated with an increased risk of major bleeding not related to CABG (4.5% vs. 3.8%; HR 1.19 (95%CI 1.02 to 1.38, P=0.03).

23.4% and 21.5% of ticagrelor and clopidogrel patients, respectively, stopped treatment early (P=0.002). 7.4% and 6.0% stopped due to adverse events (P<0.001).

Dyspnoea was reported by 13.8% of ticagrelor patients compared to 7.8% of clopidogrel patients (P<0.001). Discontinuation because of dyspnoea occurred in 0.9% of patients in the ticagrelor group. Greater increases in both serum uric acid and creatinine from baseline were seen in the ticagrelor group than in the clopidogrel group at both one and 12 months (all P<0.001). Holter monitor detected more ventricular pauses (greater than or equal to 3 sec) during the first week in the ticagrelor group than in the clopidogrel group (P=0.01).

Sponsorship: AstraZeneca

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2nd October 2009

The Chief Medical Officer’s Venous Thromboembolism (VTE) Implementation Working Group and eLearning for Healthcare have published a web-based education resource (e-VTE) designed to help raise awareness and improve understanding of VTE.

Action
Healthcare professional, both in primary and secondary care should be aware of the importance of preventing VTE. e-VTE provides pragmatic information on assessing the risk of VTE for an individual and advising appropriate preventative measures. It complements the NPCi educational materials, which provide a detailed summary of the evidence base for the prevention and treatment of VTE.

What is the background to this?
VTE is a significant patient safety issue because it is estimated to cause 25,000 potentially avoidable deaths each year in hospitals in England. The VTE eLearning resource was designed to support the national VTE prevention strategy and aims to improve understanding of VTE within the clinical community in both the hospital setting and in primary care. The interactive learning materials include a pre-learning questionnaire and a post-learning assessment together with four sessions of eLearning. These cover the demographics, epidemiology and risk profile of VTE, and include an overview of methods of thromboprophylaxis (mechanical and pharmacological) and risk assessment and implementation of thromboprophylaxis in hospitals and in primary care.

This resource is likely to be useful in conjunction with the NPC’s suite of educational materials on VTE, available on NPCi. This includes a <60 minute eLearning event, which considers the prevention and treatment of VTE and looks in more detail at the evidence base for pharmacological interventions. A case study, a quiz, and key slides are also available.

NICE is currently producing a clinical guideline on reducing the risk of VTE, which is due for publication in January 2010. 

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2nd October 2009

This meta-analysis of individual patient data found that budesonide treatment for 12-months does not increase the risk of pneumonia in people with COPD. However, other studies which considered all inhaled corticosteroids, including budesonide, have shown a significantly increased risk of pneumonia. Further research is necessary to establish if budesonide offers any long-term safety advantage over other inhaled steroids (e.g. fluticasone) in COPD.

Level of evidence:
Level 1 (good quality patient-oriented evidence) according to the SORT criteria.

Action
Although this study suggests that budesonide is not associated with an increased risk of pneumonia in people with COPD, clinicians should not change their practice on the basis of these new data. When considering adding an inhaled steroid to treatment regimens for people with COPD, prescribers should still consider, and discuss with patients, the potential increased risk of pneumonia, as well as osteoporosis and other side effects.

Health professionals should continue to follow NICE guidance on COPD , which recommends that ICSs are only prescribed for certain patients with moderate or severe COPD (forced expiratory volume in one second [FEV1] <50% predicted). An inhaled steroid should be added in to treatment with a long-acting bronchodilator (salmeterol, formoterol or tiotropium) only in patients with moderate or severe COPD who have had two or more exacerbations requiring treatment with antibiotics or oral corticosteroids in a 12-month period. Adding an inhaled steroid could also be considered in patients with moderate or severe COPD who are still breathless despite monotherapy with a long-acting beta-agonist, but the steroid should be discontinued if there is no benefit after four weeks.

What is the background to this?
As we discussed in a MeReC Bulletin on recent safety issues with inhaled treatments for COPD, there is no good evidence that inhaled corticosteroids ICSs improve survival in people with COPD, or reduce the rate of FEV1 decline. However, there is evidence to suggest that ICSs may reduce the frequency of COPD exacerbations, and may improve quality of life.

The potential risks of ICSs range from unpleasant local side effects, such as oral candidiasis and dysphonia, to less common systemic effects, such as adrenal suppression and osteoporosis. Recently, ICS treatment in patients with COPD has also been associated with an increased risk of pneumonia.

The TORCH study found that pneumonia occurred more frequently in the fluticasone and combination fluticasone/salmeterol groups, than in the salmeterol alone and placebo groups (19% vs. 13%). For every 17 people treated for three years with an inhaler containing fluticasone instead of salmeterol alone or placebo, one suffered from pneumonia. Similarly, the INSPIRE study found the risk of pneumonia was almost doubled in the fluticasone/salmeterol group, compared with the tiotropium group (8% vs. 4%, hazard ratio (HR) for time to pneumonia 1.94, 95%CI 1.19 to 3.17, P=0.008). A subsequent systematic review and meta-analysis by Drummond, et al, also found that patients receiving an ICS had a significantly higher incidence of pneumonia; 14.4% vs. 10.4%, relative risk 1.34, 95%CI 1.03 to 1.75, P=0.03, I2=72%^a, number needed to harm (NNH) = 25.

Both TORCH and INSPIRE specifically studied the ICS fluticasone, and the Drummond meta-analysis was heavily weighted (approximately 70%) by fluticasone studies. This new meta-analysis of individual patient data from 7 RCTs (n=7,042) aimed to establish the effects of the inhaled ICS budesonide on the risk of pneumonia in patients with COPD.

^a The I2 statistic measures heterogeneity in a meta-analysis. A value of 0% indicates no observed heterogeneity, and larger values show increasing heterogeneity.

What does this study claim?
There was no statistically significant difference between the inhaled budesonide and placebo groups for the occurrence of pneumonia as an adverse event (3% [n=122 patients] vs. 3% [n=103] adjusted HR 1.05, 95%CI 0.81 to 1.37) or a serious adverse event (1% [n=53] vs. 2% [n=50], adjusted HR 0.92, 95%CI 0.62 to 1.35), or for time to pneumonia as an adverse event (log-rank test 0.94) or a serious adverse event (log-rank test 0.61). Increasing age and decreasing % FEV1 were the only two variables that were significantly associated with the occurrence of pneumonia as an adverse event or a serious adverse event. The authors claim that 12 months treatment with inhaled budesonide is safe for clinical use in COPD patients during that time.

So what?
This meta-analysis did not show an increased risk of pneumonia in COPD patients treated with inhaled budesonide for 12 months. Other large RCTs and meta-analyses have demonstrated an increased risk of pneumonia with ICSs, although these were heavily weighted with studies of fluticasone. On the basis of this new study, budesonide could be considered a safer option than fluticasone with respect to the risk of pneumonia, but this should not change current practice. As pointed out in an accompanying Comment, health professionals should continue to follow current guideline recommendations on the management of COPD.

There are some important limitations to these new findings and further long-term research is needed that directly compares budesonide with other ICSs at comparative doses. Furthermore, the risk of pneumonia is only one of a number of important factors to consider when assessing the risks of prescribing an ICS for an individual patient with COPD e.g. local side-effects, adrenal suppression, osteoporosis.

The authors of this meta-analysis had access to individual patient data, so they were able to assess and adjust for potential confounders e.g. age, symptoms, lung function. However, they did not appear to consider the dose of inhaled budesonide as a potential confounder. The Drummond meta-analysis found that the risk of pneumonia was significantly higher in the ‘highest ICS dose’ (>1000 micrograms beclometasone equivalent) subgroup. All the RCTs included in this meta-analysis had a maximum observation period of 12 months, so we don’t know if any differences between the treatment groups would have been observed over a longer duration.

None of the studies in this meta-analysis were specifically designed or powered to detect pneumonia. The diagnosis of pneumonia was identified from adverse event reports submitted by the investigators, and not validated by chest radiograph. This is a particular concern as the differentiation between pneumonia and acute exacerbation of COPD is often difficult.

More information on COPD can be found in a recent MeReC Bulletin and on the COPD floor of NPCi.

Study details
Sin DD, Tashkin D, Zhang X, et al. Budesonide and the risk of pneumonia: a meta-analysis of individual patient data. Lancet 2009;374:712–9

Design: Meta-analysis of individual patient data from 7 double-blind RCTs of at least 6 months follow-up. All studies were of high quality (Jadad score >4, range 0–5). Intention to treat analysis was conducted.

Patients: 7,042 patients (mean age 61.6 years) with stable COPD ― defined as either a clinical diagnosis of COPD, or a current/former smoker (>10 pack-years) with a FEV1:FVC (forced vital capacity) ratio of <0.7 from postbronchodilator spirometry. According to the GOLD classification, 22% had very severe COPD (<30% predicted FEV1), 52% had severe COPD (30–49% predicted FEV1), 16% had moderate COPD (50–79% predicted FEV1), and 10% had mild COPD (>80% of predicted FEV1).

Intervention and comparison: Inhaled budesonide (320–1280 micrograms/day, n=3,801), with or without formoterol, versus control regimen (formoterol alone or placebo, n=3,242).

Outcomes: The primary outcome was the risk of pneumonia as an adverse event, or serious adverse event during the trial or within 15 days of the trial end. An adverse event was defined as the development of an undesirable disorder, or deterioration of a pre-existing disorder, irrespective of severity, and was assessed by study investigators. A serious adverse event was defined as an adverse event that resulted in death or hospital admission, or fulfilled any other criteria described in an appendix.

Results: There was no statistically significant difference between treatment groups for the occurrence of pneumonia as an adverse event (3% [n=122 patients] vs. 3% [n=103], adjusted HR 1.05, 95%CI 0.81 to 1.37) or a serious adverse event (1% [n=53] vs. 2% [n=50], 0.92, 95%CI 0.62 to 1.35), or for time to pneumonia as an adverse event (log-rank test 0.94) or a serious adverse event (0.61). Adjustments for potential confounders such as age, baseline lung function, and smoking status did not affect the overall results related to both treatment selection and outcome. Increasing age and decreasing % predicted FEV1 were the only two variables that were significantly associated with an increased risk of pneumonia as an adverse event or a serious adverse event. The proportion of patients who withdrew from the study for any reason was higher in the control group, compared with the budesonide group (30% [n=961] vs. 23% [n=877]).

Sponsorship: Michael Smith Foundation for Health Research. Original data was provided by AstraZeneca, but no funding for the study was supplied.

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2nd October 2009,

The phase III RECORD-1 study compared oral everolimus to placebo in 410 patients with metastatic renal cell carcinoma whose disease had progressed despite treatment. The trial was stopped early after a pre-specified interim analysis indicated a benefit in progression-free survival for everolimus. 

Level of evidence:
Level 2 (limited quality patient-oriented evidence) according to the SORT criteria. 

Action
Recent NICE guidance recommends the VEGF (vascular endothelial growth factor) inhibitor sunitinib as a first-line option for people with advanced and/or metastatic renal cell carcinoma (RCC) who are suitable for immunotherapy. As everolimus is licensed for use in patients with advanced cancer whose disease has progressed after treatment with VEGF inhibitors, the number of patients in this category is likely to be small initially. Results from the RECORD study have shown an extension in progression-free survival of two to three months over best standard care. NICE guidance on everolimus is anticipated in June 2010 and therefore, in the interim, local decision making bodies will need to identify the likely eligible patients for the drug and plan accordingly.

What is the background to this?
RCC is a highly vascular disease. Advanced or metastatic disease is known to be resistant to chemotherapy. Rates of response to chemotherapy alone are in the region of 5%. New drugs have been developed which target angiogenesis and tumour growth. These include sunitinib and sorafenib (VEGF receptor tyrosine kinase [TK] inhibitors); bevacizumab (a monoclonal antibody to VEGF) and temsirolimus which is directed at the mammalian target of rapamycin (mTOR) signal transduction pathway.

Everolimus is also an inhibitor of mTOR. Everolimus tablets (Afinitor®) were launched on 21st September 2009 for the treatment of patients with advanced RCC, whose disease has progressed on or after treatment with VEGF-targeted therapy. Further information can be found in the Summary of Product Characteristics. The cost for thirty days treatment with everolimus 10mg daily will be £2,970 (NHS List price).

What does this study claim?
Median progression free survival was 4.0 months (95% confidence interval [CI] 3.7 to 5.5) in the everolimus group and 1.9 months (1.8 to 1.9) for placebo patients.

How does this relate to other studies?
NICE guidance issued in March 2009 recommends sunitinib as a first-line option for people with advanced and/or metastatic RCC who are suitable for immunotherapy and have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1. However, more recently NICE has stated that bevacizumab, sorafenib and temsirolimus are not recommended as first-line treatment options for people with this condition. In addition, sorafenib and sunitinib are not recommended as second-line options.

A technology appraisal of everolimus for the second-line treatment of advanced and/or metastatic RCC is in progress and due to be published in June 2010.

So what?
RCC usually originates in the lining of the tubules of the kidney and accounts for approximately 3% of all adult cancers. Kidney cancer is becoming more common. In the UK, male kidney cancer incidence rates increased from 7.1 per 100,000 in 1975 to 13.9 per 100,000 in 2006. In women the rates more than doubled over the same period from 3.2 to 7.0 per 100,000. Some of the increase is believed to be due to wider use of diagnostic imaging techniques resulting in more kidney tumours being found by chance. 

In England and Wales in 2004, there were 5,745 cases of newly diagnosed kidney cancer. The estimated overall 5-year survival rate for RCC is 44%, but this depends on the stage of disease at the time of diagnosis. The 5-year survival rate for metastatic RCC is approximately 10%.

Recent NICE guidance states that there are currently no interventions that reliably cure advanced and/or metastatic RCC. The primary objectives of treatment are relief of physical symptoms and maintenance of function. Advanced and/or metastatic RCC is usually treated with either interferon alfa-2a or interleukin-2 (aldesleukin), or a combination of the two. Approximately 14% of cases of metastatic RCC respond to interferon alfa when used alone. The median duration of response is six months. Interleukin-2 (aldesleukin) can result in a median duration of response of about 54 months, but it is not always tolerated.

Everolimus is in clinical trials for other types of cancer and for transplantation.

Study details
Motzer RJ, Escudier B, Oudard S et al for the RECORD-1 Study Group. Efficacy of everolimus in advanced renal cell carcinoma: a double-blind, randomised, placebo-controlled phase III trial. Lancet 2008; 372:449-56

Design: Randomised, double-blind, placebo-controlled, phase III trial. 

Patients: Adults with metastatic RCC, with a clear-cell component, which had progressed on or within six months of stopping sunitinib or sorafenib, or both. Patients previously treated with interferon alfa, interleukin 2 (aldesleukin) or bevacizumab were also included, but patients previously on temsirolimus were excluded. Patients were stratified according to the Memorial Sloan-Kettering Cancer Center (MSKCC) score (favourable, intermediate and poor risk groups) and number of previous VEGF TK inhibitors.

Intervention and comparison: Oral everolimus 10mg once daily (n=272) or placebo (n=138) were combined with best supportive care. These were continued until death, disease progression, unacceptable toxicity or discontinuation for other reasons. Patients initially randomised to placebo could cross-over to open-label everolimus on disease progression.

Outcomes and results: Assessment of patient response was by blinded, independent review and reported as an intention to treat (ITT) analysis. The primary outcome was progression free survival, defined as time from randomisation to first documented sign of disease progression or death from any cause.

The trial was terminated early because the predefined stop criteria were met. The median duration of therapy was 95 days (range 12 to 315) in the everolimus group and 57 (21 to 237) in the placebo group. Compared to placebo, progression free survival was significantly prolonged in the everolimus group with 37% of events vs. 65% in the placebo group; hazard ratio [HR] 0.30, 95% CI 0.22 to 0.40, P<0.0001.

Median progression free survival was 4.0 months (95% CI 3.7 to 5.5) in the everolimus group and 1.9 (1.8 to 1.9) for placebo. Baseline MSKCC risk classification had no effect on the outcome (a pre-defined sub-group analysis). Adequate assessment of overall survival (a secondary endpoint) was not possible as placebo patients had been able to cross-over to everolimus treatment.

Adverse events were mainly classified according to the Common Terminology Criteria for Adverse Events as grade 1 or 2. The safety analysis involved all patients who had received at least one dose of study drug and were followed-up. The most common adverse events in the everolimus group (n=269) were stomatitis (40% of patients), rash, fatigue, asthenia and diarrhoea. 3% of the everolimus patients experienced grade 3 stomatitis compared to no patients in the placebo group (n=135). There were no cases of grade 3 or 4 infection in the placebo group compared to 2% and 1%, respectively, of patients in the everolimus group. Non-infectious pneumonitis was seen in 22 patients (8%) in the everolimus group, 8 of which were classified as grade 3 (6 of whom stopped therapy). There were statistically significant differences in the results of certain laboratory tests, such as hypercholesterolaemia and hyperglycaemia (more common in everolimus patients, probably as a result of the role of mTOR in glucose and lipid metabolism). Drug toxicity resulted in treatment being stopped in 10% of everolimus patients and 4% of the placebo group.

Sponsorship: Novartis Oncology

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