23 August 2019

Evidence, risk, patient context and asthma: moving forward

Clinical Respiratory

Ask 10 different asthma patients what their logic is for how they use relievers versus preventers (if they even use preventers) and you’re likely to get 10 quite different stories. 

That’s because asthma protocols, despite great work by experts over the years in terms of developing evidence-based guidelines, are still very complex. Based on lots of variables, such as frequency, dose, device type, risk and affordability,  many patients have found it difficult to adhere to their recommended regimes over any length of time.

Now there are major changes in the wind for Australian asthma guidelines, which are being described by some global experts as the most significant since we first published local guidelines for management back in 1989. 

But will the underlying issues that exist with patient behaviour towards cost, risk and adherence persist through such changes, no matter how significant those changes are?

In April this year, the Global Initiative for Asthma (GINA) published new recommendations for asthma management1,2 which represent significant potential for changes to be made to the current Australian guidelines.3

GINA, taking into consideration long-standing evidence on the risks and consequences of treating asthma with short acting  beta-2 agonists (SABAs) alone, together with two large studies published in the New England Journal of Medicine in May 2018 about as-needed preventer treatment that provided a feasible alternative for mild asthma,4 is no longer recommending treatment of asthma in adolescents and adults with SABAs alone.

“Instead, to reduce their risk of serious exacerbations, all adults and adolescents with asthma should receive either symptom-driven (in mild asthma) or daily inhaled corticosteroid (ICS)-containing treatment,” the GINA authors say.

Less than a month later, another paper also published in the NEJM provided a little more fuel for the GINA positioning, with a study that again compared SABA-only treatment with low-dose ICS plus as-needed SABA, and with combined ICS (budesonide) plus long acting beta-2 agonist (LABA; formoterol), in patients with mild asthma. The study concluded the budesonide-formoterol (b-f) combination to be superior to either of the other approaches to preventing severe attacks.5

The GINA report, although a global evidence-based strategy that is used as the basis for many national asthma guidelines, is not that well known in Australia.  These studies passed with little fanfare in the Australian media, until  an inflammatory editorial piece was published in the Lancet Respiratory Medicine last month by a UK- based respiratory paediatrician, Professor Andrew Bush.6

Professor Bush cites the GINA positioning and the NEJM paper, and then refers to the long-trusted “blue” preventer inhaler as a “killer”, saying that “it should be considered negligent to prescribe SABA to adults in any other context” other than where ICS is not indicated in “some airway diseases at the extremes of age, namely non-atopic wheeze in children younger than five years, and chronic pulmonary disease.”

It was the stuff of pharmaceutical company corporate communication nightmares. Within the week, one piece in the medical media in Australia had published a selection of Professor Bush’s comments with a headline that included the term “killer blue inhalers”.

Local experts contacted to comment on the editorial were of the view that there was a certain amount of overreach in the Lancet Respiratory Medicine  comment piece, in particular, any suggestion that SABAs be removed entirely from asthma management. All were at pains to point out that SABAs still have a role, especially given they can save the life of a patient who is experiencing a severe exacerbation. 

In Australia, the SABA positioning in the Lancet Respiratory Medicine editorial is in even more stark relief to the situation in the UK, because here, SABAs have been available inexpensively over the counter for many years. It is estimated that up to 30% of adults with asthma rely on this medication alone for relief of symptoms, without any other preventer treatment.

Inhaler manufacturer GSK issued a statement to The Medical Republic on the report and sent letters to all GPs, respiratory specialists and pharmacists in Australia, such was the company’s concern about the reverberations of the Lancet editorial.

“We are particularly concerned that these reports could result in patients stopping the use of reliever therapy (also known as SABAs, such as salbutamol). In fact, there are many situations in which it is entirely appropriate for people with asthma to continue to use reliever therapy including for the treatment of potentially life-threatening asthma flare-ups and as part of an asthma management plan,” the company said.

It is important to note that the “killer” inhaler tag has not been picked up by  consumer media, so potential patient confusion isn’t likely at this stage.

Contacted for comment on the Lancet editorial and the likely impact of the changes in the GINA recommendations, Professor Helen Reddel, Chair of the GINA Science Committee and Research Leader at the Woolcock Institute of Medical Research in Sydney, said that while the piece was raising important issues, and Professor Bush was a well-respected international researcher, some of the positions put in his article “did not reflect what GINA was calling for in their recent changes to recommendations around SABAs”.

In Australia, starting mild asthma treatment with SABAs alone was part of the very first set of asthma guidelines published some 30 years ago.

This strategy was based on an underlying assumption about the mechanisms of asthma that dated back to the 1960s and 70s, that it was a disease of bronchoconstriction. At the time, there was also substantial concern about the risk of corticosteroids, based on experience with oral corticosteroids. 

ICS use was restricted largely to people whose symptoms weren’t easily controlled with a short-acting bronchodilator alone. 

Although guidelines subsequently recommended that most asthma patients should receive at least a low-dose ICS preventer, few of these basics were challenged until about 12 years ago, when researchers such as Professor Reddel began to study alternative approaches.2

Possibly because of concern around not wanting to encourage anything that might degrade patient adherence, there wasn’t a great deal of commercial interest in pursuing such studies at the time. The push and the research largely came from clinicians, although some commercial funding did help in the end.

Research on alternatives started in earnest about five years ago, but it is only in the last couple of years that evidence has started to emerge around the efficacy of other approaches in mild asthma, in particular, for patients to receive a fast-onset long-acting reliever combined with an ICS on an as-needed basis.2,4

This strategy reduces the risk of severe exacerbations by between one half  and two-thirds, compared with SABA-only treatment.5

“Any changes to guideline recommendations during the resultant update will be carefully and widely communicated to health professional and patient communities.” –

 National Asthma Council statement

It is the results of these studies (and some others) that form much of the underlying logic of the new GINA recommendations and have prompted an application by AstraZeneca to the TGA and PBAC for approval of a new indication for budesonide–formoterol. Budesonide-formoterol (Symbicort) has been approved for as-needed use in Australia and many other countries for more than a decade, as part of maintenance and reliever treatment . The new applications are for as-needed-only use in patients with mild asthma to reduce the risk of severe exacerbations.

Late last month, the TGA approved budesonide–formoterol for “as-needed” therapy in mild asthma, and last month PBAC considered an application for PBS funding for the indication. The outcome of the PBAC meeting is not yet known, but there is much evidence and logic to support an approval.  

Putting together the mounting clinical evidence, the TGA approval and likely PBAC approval, the GINA changes to recommendations, and even the Lancet editorial drawing the attention of the world to these changes, and you have a runway for potentially significant changes in asthma management.

The timing of the GINA changes hasn’t synchronised well with the Australian cycle of review for asthma guideline recommendations, however. Currently the Australian National Asthma Council (NAC) recommends SABA-only treatment for a small number of patients and separate preventer and reliever therapy for most. The last update of the NAC guidelines was in March,3 one month before the GINA recommendations were released, but it is understood those are now are under review now by the NAC. A PBAC approval for budesonide–formoterol would also presumably prompt some form of review. 

After being asked to comment on the GINA changes, the NAC sent The Medical Republic a media release welcoming the TGA approval of the new budesonide-formoterol indication and quoting NAC CEO Siobhan Brophy as follows:

“NAC has been following recent studies and international recommendations around as-needed budesonide/formoterol and treatment options for mild asthma with great interest. The TGA approval is an essential first step in considering whether the international developments could be implemented locally.

“The NAC is currently working on how this treatment fits in the Australian context for the next Australian Asthma Handbook update for the treatment of mild asthma in adults and adolescents. 

“As always, the Australian Asthma Handbook deliberations utilise well-established and rigorous protocols to determine recommendations for inclusion, and TGA approval provides a sure footing for these deliberations.

“Any changes to guideline recommendations during the resultant update will be carefully and widely communicated to health professional and patient communities…”

A key issue if the guidelines do change is likely to be familiarity with, and trust in, SABA inhalers, and a lack of perceived need for a preventer treatment for mild asthma. 

Many patients currently using a SABA alone are happy with how they manage their asthma, even if they have needed urgent healthcare for asthma in the last 12 months .7  

A further issue with uptake of any new strategy in mild asthma treatment is that the conversation with a patient about risk. This conversation will almost always further muddy the waters on the benefit of potential new ways to use asthma medication and new indications for use.

“The challenging thing in all these new changes is going to be the conversation with a patient about reducing risk when for a person with mild asthma, risk is just not prominent in their thinking,” Professor Reddel said.

“If you had a headache once or twice a week and it went away within five minutes of taking a paracetamol tablet, you probably wouldn’t think of that as being something serious enough to kill you one day,” she said.

“The speed of the resolution of symptoms with something you can buy over the counter at a pharmacy argues against it being something that is a serious enough problem in the minds of most patients.”

A lack of perceived need for a preventer treatment for mild asthma will be a key issue

Although the absolute risk of serious exacerbations or asthma-related deaths is low, around 400 people still die of asthma each year in Australia. 

Professor Reddel points out that the evidence for reducing this risk even with regular low dose ICSs is overwhelming, both for death (some 50% reduction) and hospitalisation (a 30% reduction) even in patients with mild asthma. So these conversations with patients should be undertaken. 

“We are used to having conversations with patients about anti-hypertensives and statins to reduce the risk of heart attack or stroke, but in mild asthma, the conversation is has mainly been about symptom control,” she said. 

In terms of the new GINA recommendations, she says this makes the approach in mild asthma firmly a “population-level recommendation”.

“For an individual patient, you will not necessarily know if they have dodged a bullet,” she said. 

And therein is the problem for many patients. They have relied on the blue inhaler for so long, and the risk is so far at the back of their minds, they are not easy targets for substantive behavioural change.

The key messages for GPs at this point of time, according to Professor Reddel, are:

There is now a lot of evidence around  the risk associated with SABA-only treatment which is prompting changes.

 For patients needing regular preventer treatment, adherence and cost issues will likely persist, even with the potential changes. 

“Stay tuned and watch this space closely” over the next few months as the evidence, TGA changes and GINA recommendations start to resonate through the ystem.

“We are particularly concerned that these reports could result in patients stopping the use of reliever therapy (also known as SABAs, such as salbutamol).” –

 GSK statement

On the specialist side, there remain quite a few gaps in evidence about mild asthma that need work, especially with respect to:

Management of asthma in the emergency department.

Prevention of exercise-induced asthma.

Treatment of asthma in childhood, where reliance on SABAs is often established.

The underlying mechanisms of asthma and how this might further improve our understanding of management. 

References:

1. Global Initiative for Asthma. Global Strategy for Asthma Management and Prevention, 2019. Available from www.ginasthma.org

2. HK Reddel, et al. GINA 2019: a fundamental change in asthma management. Treatment of asthma with short-acting bronchodilators alone is no longer recommended for adults and adolescents , Eur Respir J; 53: 1901046

3. National Asthma Council Australia. Australian Asthma Handbook, V2.0. National Asthma Council Australia, Melbourne, 2019.

4. Bateman, E, et al. As-Needed Budesonide–Formoterol versus Maintenance Budesonide in Mild Asthma, N Eng J Med, 2018; 378:1877-1887

5. Beasley R, et al. Controlled trial of budesonide–formoterol as needed for mild asthma. N Eng J Med 2019; 380: 2020-30

6. Bush, A. Preventing asthma deaths: above all, do no harm. Lancet Respiratory Medicine, June 25 online. http://dx.doi.org/10.106/s2213-2600(19)30197-3

7. Reddel HK et al. Risks associated with managing asthma without a preventer: urgent healthcare, poor asthma control and over-the-counter reliever use in a cross-sectional population survey. BMJ open 2017; 7: e016688.

8. Bateman, E, et al. As-Needed Budesonide–Formoterol versus Maintenance Budesonide in Mild Asthma, N Eng J Med, 2018; 378:1877-1887

9. O’Byrne PM, FitzGerald JM, Bateman ED, Barnes PJ, Zhong N, Keen C, Jorup C, Lamarca R, Ivanov S, Reddel HK. Inhaled combined budesonide-formoterol as needed in mild asthma. N Engl J Med 2018; 378: 1865-1876.