Dangers with inappropriate use of long-acting beta agonists

Around 5.4 million adults and children in the UK have asthma, a common respiratory condition involving inflammation of the airways. On average, three people die each day from this disease^[1]
. The death rate is now at the highest level in the past decade. In 2015, 1,468 people died from an asthma attack^[2]
,[3]
.

In the UK, the cornerstone of the management of chronic asthma is guidelines first published by the British Thoracic Society (BTS) in 1990. Since 2008, this has been collaborative work with the Scottish Intercollegiate Guideline Network (SIGN). It features a stepwise plan that begins with short-acting beta-2 agonists (SABAs, e.g. salbutamol), and adds in agents such as inhaled corticosteroids (ICSs, e.g. beclometasone) and long-acting beta-2 agonists (LABAs, e.g. salmeterol) as the condition worsens. It provides clinicians with a useful toolkit for diagnosing asthma in the initial phases of symptoms, prescribing medicines and altering them as the disease progresses, and recommending some non-pharmacological interventions that are centred on lifestyle changes.

Unsurprisingly, the introduction of LABAs in the early 1990s coincided with a large number of prescriptions for salmeterol. The NHS Business Services Authority prescription cost analysis, which provides community pharmacy dispensing data from across England, reported that 1.8 million salmeterol inhalers were dispensed in 1998 (earliest data available). However, it is not known how many of these inhalers were prescribed alongside an ICS^[4]
.

Although there are caveats with all medicines, LABAs have been the subject of controversy since their arrival on the market in the early 1990s. There are several documented safety concerns associated with the use of LABAs, such as severe asthma exacerbations, and prescribers and pharmacists are reminded to use the drugs with care to reduce patient harm and hospital admissions.

Safety concerns

According to the BTS/SIGN guideline, LABAs should not be used in monotherapy for the prevention of asthma without an ICS because of safety concerns. This UK recommendation is in line with guidelines published by the US Institute for Clinical Systems Improvement^[5],[6]
.

The associated risks with all beta agonists, but particularly LABAs, have long been established and include aggravation of hypoxaemia (abnormally low concentration of oxygen in the blood); cardiotoxicity secondary to hypoxaemia and hypokalaemia, increased amount of antigen in an unprotected airway; tolerance to the bronchodilatory effects of beta-agonists; and toxicity of propellants, such as chlorofluorocarbons, in certain devices, causing bronchospasm themselves^[7]
.

On account of the risks, LABAs were placed under increased scrutiny as monotherapy. The seeds of doubt were first sewn in 1993, with the publication of the Serevent nationwide surveillance study (SNS). This was a double-blind, randomised clinical trial of 25,180 patients monitored over 16 weeks that compared salmeterol 50µg twice a day with salbutamol 200µg four times a day (pre-existing therapy for the patients was unchanged). The main endpoint was any serious medical or non-medical reason for withdrawal from the trial whether it involved the medicines in question or not. On the surface, the results of the trial looked favourable for the LABA. There were fewer medical withdrawals on account of asthma in the patients taking salmeterol over salbutamol (2.91% versus 3.79%; P =0.0002). However, there was a “small but non-significant” (P =0.1) three-fold increase in asthma events, including deaths, in the salmeterol arm. Although the authors of the study said this was statistically non-significant, the fact that increased death rates were in any way implicated was enough to raise concerns with regulatory authorities^[8]
.

In 1996, GlaxoSmithKline (GSK), the British pharmaceutical company that holds the licence for Serevent, conducted a large randomised, double-blind-controlled trial — the Salmeterol Multicenter Asthma Research Trial (SMART) — after considerable pressure from the US Food and Drug Administration (FDA). SMART compared the long-term effects (over 28 weeks) of the addition of salmeterol 42µg twice daily versus placebo to established asthma treatment in 26,355 sufferers aged over 12 years. The study had two endpoints: the outcome in combined respiratory-related deaths or life-threatening experiences, or asthma-related deaths or life-threatening experiences. The study had to be terminated early, with only about half of the intended uptake, on account of negative outcomes. Upon evaluation of the data provided at the early suspension of the trial, the researchers concluded that salmeterol was not significantly better than placebo when added to existing treatment. In fact, there was a statistically significant difference in asthma-related deaths in the African-American arm of the study^[9]
.

Two meta-analyses in 2006 and 2008 compared the risks of LABA versus non-LABA asthma treatment. The first meta-analysis was weighted heavily on the SMART study and suggested that up to 80% of asthma deaths in the United States could be directly attributed to salmeterol toxicity^[10]
. The second meta-analysis was prompted by pressure from the FDA, which requested that all pharmaceutical companies marketing LABAs in the United States (AstraZeneca with Oxis [formoterol], GSK with Serevent, and Novartis with Foradil [formoterol]) collate all data from all trials using their products. It used data from a range of randomised, controlled trials conducted between 1966 and 2005, and calculated the “risk differences” (RD) of LABAs versus non-LABAs when looking at three outcomes: asthma-related death; asthma-related death or intubation; or asthma-related hospital admission.

The RD was 2.80 (95% confidence interval [CI] 1.11 to 4.49). The study went even further and calculated the risk of LABAs alone versus LABAs/ICS. For patients receiving LABAs alone, the RD was 3.63 (95% CI 1.51 to 5.75), whereas in LABAs/ICS (either taken separately or in a combined device) the RD was a non-significant 0.25 (95% CI -1.69 to 2.18 per 1,000 subjects). In other words, 43 of 44 deaths and intubations occurred in 22,286 individuals receiving LABAs alone, compared with just 1 in 7,862 individuals in trials that allowed concomitant ICS and LABA use ^[11]
. Furthermore, there were no deaths or intubations associated with combination LABA/ICS device users (22,600 individuals)^[12]
.

A shift in usage pattern

The studies outlined formed the basis of the paradigm shift from using LABAs as monotherapy to only recommending their use alongside an ICS. Studies had shown early on that the addition of LABAs to an ICS could have a positive synergistic effect, and that it improved outcomes for those receiving combination products so that the dose of steroid was not high enough to cause unwanted side effects, such as stunted growth in children and adolescents^[13]
.

The use of LABAs only in addition to an ICS was finally made mandatory by the FDA and the Medicines and Healthcare products Regulatory Agency (MHRA) in the UK in 2014^[14],[15]
, with single-device combinations (such as Seretide 50 Evohaler (salmeterol 25µg with fluticasone 50µg) recommended for children and adolescents with the perceived adherence benefits in mind. Before this, the regulatory bodies had only advised caution.

Since the recommendation and shift in guidelines to avoid using LABAs as monotherapy, there have been consistent reductions in salmeterol prescribing from GPs. According to Open Prescribing, a search interface for UK raw prescribing data files published by the Health and Social Care Information Centre, NHS GP monthly prescribing of salmeterol in England decreased by 45% between June 2011 and June 2016 (97,341 prescriptions in 2011 versus 53,447 prescriptions in June 2016)^[16]
. Although it is not possible to determine how many of these prescriptions included an ICS, the reduction is reassuring in terms of guideline adherence and consequential patient safety.

The FDA has suggested a personalised asthma action plan since 2010, something the UK only caught up with in the latest BTS/SIGN guidelines in 2016^[6]
. In light of all the evidence against standalone LABAs in the management of asthma, despite the issue being investigated extensively over the past three decades, it would appear that their time as monotherapy has come to an end, ultimately to the benefit of asthma sufferers globally. Unfortunately, there is still anecdotal evidence of inappropriate prescribing of LABAs as monotherapy. This must stop and it is up to all prescribers and pharmacists to follow national guidelines and ensure LABAs are used only when appropriate.