NPC Archive Item: Comparative safety of ICS/LABA combinations in chronic asthma

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3 June 2010

A Cochrane review found no significant difference in serious adverse events when different combinations of inhaled corticosteroids and long-acting beta2 agonists were compared in people with chronic asthma. However, these events were rare, so there was insufficient evidence to know for certain whether regular formoterol and budesonide (or formoterol and beclometasone) has an equivalent, or different, safety profile to salmeterol and fluticasone. There were little comparative safety data on formoterol and beclometasone (Fostair▼), and no data available in children.

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

Health professionals should follow the British guideline on the management of asthma. For adults, adolescents and children aged >5 years, who are not adequately controlled on an inhaled corticosteroid (ICS) alone (step 2), the addition of a long-acting beta2 agonist (LABA) should be considered on an individual trial basis (step 3). However, before starting a new drug or stepping up treatment, the patient’s understanding of the role of treatment, adherence to treatment, inhaler technique, and appropriate elimination of trigger factors should be confirmed. Control of asthma should be assessed after an agreed duration, depending on the desired outcome, and the LABA discontinued in the absence of benefit. CHM advice on the use of formoterol and salmeterol in asthma should be followed.

If treatment with an ICS and LABA is considered appropriate, NICE recommends that the decision to use a combination device or separate devices should be made on an individual basis, taking into consideration therapeutic need and the likelihood of treatment adherence. If a combination device is chosen, then the least costly device that is suitable for the individual is recommended. Switching patients from one combination device to another, for example on cost-grounds, is not a simple switch programme. Many patients with asthma are over-treated, and clinicians should focus on ensuring that patients are reviewed regularly, with a view to stepping down therapy when asthma control has been achieved.

What is the background to this?
The British asthma guideline, published jointly by BTS and SIGN, advocates a stepwise approach for the treatment of adults and children with asthma. ICS are the first-choice regular preventer therapy for adults and children for achieving overall treatment goals.

A proportion of patients with asthma may not be adequately controlled on an ICS alone at step 2 and add-on therapy may be required (step 3). For adults, adolescents and children aged >5 years, the addition of a LABA (formoterol or salmeterol) to an ICS should be considered. For children under five years, the first choice add-on therapy to an ICS is a leukotriene receptor antagonist. However, before adding or changing treatment, practitioners should check compliance with existing therapy, check the patient’s inhaler technique and eliminate trigger factors.

Addition of a LABA to an ICS can lead to improvements in lung function, symptoms and decreased exacerbations. However, current evidence and guideline recommendations do not support using an ICS plus a LABA without a prior trial of ICS alone. As we discussed in a MeReC Bulletin on asthma, a small but significant increase in serious adverse events and asthma mortality has been observed with both formoterol and salmeterol in some meta-analyses. This appears to be substantially reduced, but perhaps not abolished when LABAs are used concurrently with an ICS. Monotherapy with salmeterol or formoterol alone has been associated with significant adverse events, and therefore LABAs should only be used in conjunction with an ICS (step 3). To ensure safe use, the Commission on Human Medicines (CHM) has advised that for the management of chronic asthma, LABAs should:

  • be added only if regular use of standard-dose ICSs has failed to control asthma adequately
  • not be initiated in patients with rapidly deteriorating asthma
  • be introduced at a low dose and the effect properly monitored before considering dose increase
  • be discontinued in the absence of benefit
  • be reviewed as clinically appropriate: stepping down therapy should be considered when good long-term asthma control has been achieved.

Existing Cochrane reviews have examined the safety of regular formoterol or salmeterol separately (with or without ICS), compared with placebo, short-acting beta2 agonists, or ICS alone. Formoterol and salmeterol are known to have differences in their speed of onset and receptor activity. Therefore, this Cochrane review directly compared the safety of regular formoterol and salmeterol, when each was used in combination with a randomised ICS (budesonide, fluticasone or beclometasone), either in a single device or as separate inhalers.

What does this study claim?
This review of 8 randomised controlled trials (RCTs) of 6,163 adults and adolescents with chronic asthma found no statistically significant difference in serious adverse events between different combinations of ICS and LABA treatments. Seven studies (n=5,935) compared formoterol and budesonide with salmeterol and fluticasone, with all but one study administering these as the combined products (Symbicort® vs. Seretide™). There was no difference between groups in all-cause mortality, all-cause non-fatal serious adverse events, or in asthma-related non-fatal serious adverse events (see study details [LP1] below for results). One study of 228 adults (see ‘How does this relate to other studies’ below) compared formoterol and extra-fine beclometasone (Fostair▼) with salmeterol and fluticasone, but there were no deaths or hospital admissions, so the safety of this comparison could not be assessed.

Although no significant differences were found between the ICS and LABA combinations, the authors conclude that the confidence intervals are too wide to claim equivalence in safety, and the studies were underpowered to detect possible important differences in serious adverse events.

How does this relate to other studies?
Another recent Cochrane review (5 RCTs, n=5,537 adults) assessed the relative effects of combination formoterol/budesonide (Symbicort) and salmeterol/fluticasone (Seretide) in a single inhaler, in terms of asthma control, safety and lung function. It found that the odds of an exacerbation requiring oral steroids, an exacerbation leading to hospital admission, or serious adverse events did not differ significantly between the two treatments.

Two RCTs have compared the formoterol/extra-fine beclometasone combination (Fostair) with formoterol/budesonide (Papi A, et al. Eur Respir J 2007;29:682–9) and salmeterol/fluticasone (Papi A, et al. Allergy 2007;62:1182–8). These found no differences between the two groups in asthma exacerbations and adverse events. However, these 12-week studies involved only small numbers of participants (n=219 and n=228, respectively) and it is likely that possible important clinical differences in, for example, serious adverse events would not have been detected given their design.

So what?
For many patients with chronic asthma who are uncontrolled on ICS alone, the addition of a LABA can provide significant benefits in terms of improvements in lung function, symptoms and decreased exacerbations. However, these benefits must be weighed against a possible, small absolute increased risk of serious adverse events and asthma mortality, even when an ICS is used concurrently. BTS/SIGN recommend that the addition of a LABA to an ICS should be treated as a therapeutic trial. Control of asthma should be assessed after an agreed duration, depending on the desired outcome. Not all patients will respond to a LABA, some may obtain greater benefit from increasing the dose of ICS. So, if there is no response to treatment, the LABA should be discontinued. If there has been partial benefit, the LABA should be continued, and the dose of ICS increased (up to 800 micrograms/day for adults and adolescents, 400 micrograms/day for children aged 5 to 12 yearsa).

There has been a substantial increase in the prescribing of ICS/LABA combination inhalers in England over recent years — see Figure 1 below. A significant proportion, but by no means all, of this prescribing will be for patients with COPD, but it would appear that increasing numbers of patients with asthma are being treated at BTS/SIGN step 3 or above. This apparent increase in ICS/LABA prescribing may reflect better treatment for previously under-treated patients. Alternatively, it may reflect patients being stepped up from step 2 to achieve control of their asthma, but not being stepped back down again, or steroid-naïve patients being treated with ICS/LABA, and missing step 2 out completely. In either case, this could potentially  represent inappropriate management of these patients. BTS/SIGN guidance recommends stepping down therapy once asthma is controlled, but this recommendation appears to be sub-optimally implemented, leaving some patients over-treated. Advice on stepping down treatment can be found in the British asthma guideline (section 4.6) and in the GINA guidelines 2009 (page 62). Local audits, repeated at regular intervals, are required to determine whether practice is concordant with these important recommendations.

Figure 1. Trends in costs  of treatments for asthma and COPD in general practice in England (Quarter to June 2004 – Quarter to December 2009).


©NHSBSA 2009

Choice of combination agent — the role of Fostair?
If treatment with an ICS and LABA is considered necessary, and is appropriate based on BTS/SIGN recommendations and CHM advice —  how does the evidence help inform decisions about which choice of combination treatment (either as single or separate devices) may be most appropriate? This Cochrane review found no significant difference between the different combinations in measures of serious adverse effects (although there was insufficient comparative data on the safety of Fostair). However, due to the small numbers of patients who experienced these events, and the wide confidence intervals, we cannot be certain that the products are equivalent or one is superior in terms of safety. Another large Cochrane review found similar rates of asthma exacerbations and serious adverse events when Symbicort and Seretide were directly compared with each other, but this level of evidence is not currently available for Fostair.

The British asthma guideline states that “there is no difference in efficacy in giving an ICS and LABA in combination or in separate inhalers”. In general, CKS recommends that combination inhalers are reserved for people who are stabilised on the component drugs in the same dose ratio, and who have difficulty using separate inhalers. If a combination product (Symbicort, Seretide or Fostair) is initiated, it may be more difficult to titrate treatments to individual patient response, although combination inhalers do ensure that LABAs are not taken without an ICS. See Part 4 of the NPCi e-learning event on asthma and CKS asthma guidelines, which discuss the risks and benefits of single and combination ICS/LABA inhalers in more detail.

NICE guidance on the use of ICS in adults (>12 years) and in children (<12 years) recommends that “the decision to use a combination device or the two agents in separate devices should be made on an individual basis, taking into consideration therapeutic need and the likelihood of treatment adherence. If a combination device is chosen then the least costly device that is suitable for the individual is recommended”. The least costly device is currently Fostair 100/6 micrograms metered dose inhaler (MDI) — £29.32, compared with £35.00 for Seretide 125/25 micrograms MDI and £38.00 for Symbicort 200/6 micrograms dry powder inhaler (all 120-dose inhalers).

Given the lower acquisition cost of Fostair, some prescribers and prescribing managers may favour the use of this combination, in preference to either Symbicort or Seretide, when an ICS/LABA product is appropriate. However, switching existing patients from Symbicort or Seretide to Fostair may involve switching the ICS, switching the LABA, adjusting the dose, changing the inhaler device, or any combination of these, including all of them. It appears that this would not be a simple switch programme and, as NICE recommends, the choice of combination product should be considered on an individual basis. Clinicians should also focus on reviewing patients on ICS and LABAs and stepping down their treatment (were appropriate) to ICS alone, rather than solely focusing on switching to a cheaper combination inhaler. Better management with regular clinical review and stepping down as appropriate may provide greater cost-savings and better quality care.

In addition to the data described above, there are also a number of other considerations:

  • There is only one fixed-dose combination of Fostair, which potentially means there is less flexibility of dosing
  • MHRA/CHM has advised that Fostair is more potent than traditional beclometasone CFC-containing inhalers. Each ‘puff’ of Fostair contains 100 micrograms of ‘extra-fine’ beclometasone — equivalent to 250 micrograms of standard CFC-free beclometasone. The need for adjusting the dose of beclometasone due to the particle size in Fostair could potentially cause additional confusion, particularly if a large switch programme was activated
  • There is less experience of the use of Fostair compared with Symbicort and Seretide, and it is under intensive surveillance by the MHRA. All adverse reactions that are thought to occur as a result of treatment with Fostair should be reported via the Yellow Card Scheme
  • Fostair is not licensed for use in children and adolescents under 18 years, although data on all ICS/LABA combinations are lacking in children

It is likely that the choice of combination inhaler will depend largely on individual patient factors, for example: the availability of the drug and dose in the specific device, the ability to develop and maintain an effective technique with the specific device, suitability of the device to the person’s lifestyles, preference for and willingness to use a particular device. Where more than one product is suitable and acceptable to the individual, the least costly should be chosen.

a Beclometasone equivalent doses.

Study details
Cates CJ, Lasserson TJ. Regular treatment with formoterol and an inhaled corticosteroid versus regular treatment with salmeterol and an inhaled corticosteroid for chronic asthma: serious adverse events. Cochrane Database of Systematic Reviews 2010, Issue 1. Art. No.: CD007694. DOI: 10.1002/14651858.CD007694.pub2

Systematic review and meta-analysis of 8 RCTs.

6,163 adults and adolescents with chronic asthma, unrestricted by disease severity, previous, or current treatment. No studies in children were found.

Intervention and comparison
Patients were randomised to regular formoterol and an ICS vs. regular salmeterol and an ICS. Any fixed dose was allowed, by any single or separate devices for at least 12 weeks. Most studies compared formoterol 12 micrograms twice daily with salmeterol 50 micrograms twice daily, and ICS doses were judged to be equivalent in each arm (except for two studies — one used higher dose budesonide [n=428], one used higher dose fluticasone [n=248]). Seven studies (n=5,935) compared formoterol and budesonide with salmeterol and fluticasone. Only one study (n=228 adults) compared formoterol and extra-fine beclometasone (Fostair) with salmeterol and fluticasone.

Outcomes and results
Primary outcomes — all-cause mortality and all-cause non-fatal serious adverse events. A ‘serious adverse event’ was defined as any untoward medical occurrence that at any dose: results in death, is life-threatening, requires in-patient hospitalisation or prolongation of existing hospitalisation, results in persistent or significant disability/incapacity, or is a congenital anomaly. Secondary outcomes included asthma-related non-fatal serious adverse events.

Formoterol/ICS vs. salmeterol/fluticasone Peto odds ratio (95%CI) I2 a
all-cause mortality 1.03 (0.06 to 16.44) 50%
all-cause non-fatal serious adverse events 1.14 (0.82 to 1.59) 26%
asthma-related non-fatal serious adverse events 0.69 (0.37 to 1.26) 33%

a Heterogeneity is described here. The higher the I2 value, the greater the heterogeneity

The review was conducted by Cochrane authors. All included studies were sponsored by the manufacturers of ICS/LABA combination inhalers.

More information on asthma can be found on the respiratory section of NPC.

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