19 December 2019

Down the rabbit hole of initiation for mild asthma

Patients Respiratory

Within weeks of the Global Initiative for Asthma (GINA) releasing revised guidelines stipulating that “all adults and adolescents with asthma should receive either symptom-driven (in mild asthma) or daily inhaled corticosteroid (ICS)-containing treatment”, contradictory opinions saw divisions start to appear in the position of experts across the world.

The old stalwart of asthma treatment, the Ventolin puffer was branded the “killer blue inhaler”, with GINA proponents pushing the treatment of mild asthmatics to be focused on  the combo therapy of budesonide-formoterol.

Most recently at a session of the European Respiratory Society Congress in Madrid in September, Professor Sebastian Johnson of respiratory medicine at Imperial College London’s National Heart and Lung Institute, closed his session by saying: “Using a LABA without ICS in asthma is clearly unsafe … overusing a SABA without ICS is also clearly unsafe, and I suspect that that kills people with asthma …”

This was, to put it mildly, somewhat controversial.

In Australia, there is some high-level support for us going down the GINA path.

According to allergist and immunologist Professor Pete Smith, from Griffith University and Bond University in Queensland, if you set aside limitations placed on the system by registration and TGA limitations, “SABAs-only” are now the wrong message.

“This does not treat the disease, it helps mask that you have an inflammatory process in the lung, but the bronchospasm can be relieved enough so that you might be able to breathe,” Professor Smith tells Allergy and Respiratory Republic.

“If some medication is good, the patient may think more is better. This is incorrect, it is a warning sign of more severe asthma. The 2019 GINA guidelines address this and SABA-only is not first line. You treat inflammation plus [use a] bronchodilator,” he says.

Professor Smith supports the updating on the Australian guidelines to include the GINA recommendations sooner rather than later.

“I would argue the only role for SABAs are for testing airway reversibility and for ED treatment of asthma,” he says.

But some experts are worried that things might be moving too fast, and there is not enough real-world Australian data to confidently make such a change.

Most GPs will initiate a mild asthmatic on a SABA, not only to relieve the symptoms but also to help establish a diagnosis, as Professor Smith is suggesting.

If a patient needs to use a SABA more than three times a week, most doctors will get the patient to start preventive treatment, commonly an ICS.

All this is as per the current Australian Asthma Handbook, which is the bible for most GPs when it comes to asthma protocols.

But Dr Greg King, a respiratory physician with the Woolcock Institute of Medical Research, is cautious about embracing the GINA guidelines too quickly.

“There are potentially major implications for a change [in protocol] like this which we shouldn’t be rushing into yet,” he tells Allergy and Respiratory Republic.

Supporters of the GINA approach concede that although some studies indicated that more than 50% of mild asthma sufferers are non-eosinophilic, and therefore won’t respond to an ICS anyway, they say it is worth using nonetheless as there is no downside to the combo. This is unlike what can happen when a patient is on SABA-only treatment and the underlying condition gets worse.

But Dr King feels there isn’t enough data to make the change yet.

“Over reliance on SABA is an issue and something we need to fix, but using a combo as a solution to SABA-only use has potential scenarios where things can go wrong,” he says.

He says that using a LABA/ICS combination on an “as needed” basis is not appropriate at this stage.  GINA is basing its decisions on research findings that are very new. We need “real world” data that takes into account all the various factors that can affect this very patient-driven management to feel confident about safety and effectiveness, he says.

The controversy has led to a considerable amount of confusion. Within a few weeks of the GINA recommendations being published, the organisation was forced to clarify a number of details as there was already evidence that the guidelines had been misinterpreted at various centres across Europe.

If you visit the GINA website today you should get a prominent pop up box as your first communication stating: “We have become aware that the GINA 2019 recommendation for ‘Preferred reliever’ in Steps 3-5 is sometimes being misinterpreted. Please note the following important information …”

The note goes on to say that GINA does not recommend use of ICS-formoterol as the reliever for patients taking combination ICS-LABA medications with a different LABA. For these patients, their as-needed reliever inhaler should be a short-acting b2-agonist (SABA).

The National Asthma Council of Australia, which regularly reviews and sets local guidelines and authors the Asthma Handbook, reacted to the GINA change  in a predictably cautious manner by saying that it would be considering the changes as it considered all new evidence.

Then council told Allergy and Respiratory Republic that it would, in part, be guided by how the Therapeutic Goods Administration (TGA) viewed the evidence surrounding a submission by Astra Zeneca to extend the current authority on budesonide-formoterol combination (Symbicort) to include use as an anti-inflammatory reliever therapy administered, as needed, for adolescent and adult patients with mild asthma who are uncontrolled on SABA, as needed, or controlled on a regimen of inhaled corticosteroid (ICS) maintenance plus a SABA as needed.

In late September the TGA announced it had approved budesonide-formoterol for this indication. So it’s now indicated for this purpose, but the next hurdle is to get in on the PBS.

However, last week PBAC released the findings of its July meeting. It had rejected Astra Zeneca’s application to have the indication subsidised. It rejected the application on grounds of evidence and value for money.

Astra Zeneca has resubmitted its PBAC application for review in November as a “minor resubmission” and PBAC will report on that decision on December 20.

Budesonide-formoterol taken as needed is already approved on the PBS in combination with budesonide-formoterol maintenance treatment in moderate-to-severe asthma, but the new indication means GPs can prescribe the combination prn for patients with mild asthma, without daily maintenance treatment.

But that is unlikely to happen without PBAC approval, because without the subsidy the protocol is too expensive for most patients.

Adding to the intrigue in this story a little, Asthma Australia appears to have come out in support of the Astra Zeneca’s PBAC resubmission. At least in part.

“Asthma Australia supports the listing of Symbicort (budesonide-formoterol) as needed on the PBS for adults, given the evidence that this treatment regime will reduce the risk of exacerbation for people with mild to moderate asthma who are at risk of exacerbation,” Asthma Australia CEO Michele Goldman tells Allergy and Respiratory Republic.

However, there is a caveat. “We do not support the listing for adolescents, given concerns from paediatric experts about systemic effects of inhaled corticosteroids,” she says, citing insufficient evidence to support a strong case for adolescents at this time.

“In order to realise the potential benefits explored in the research, and address the potential areas of risk and concern, there needs to be a strong focus on education for both health professionals and patients,” Ms Goldman says.

Should the PBS approve the combination on a prn basis for mild asthma, the potential for confusion in how such a change in practice might be implemented is not insignificant.

Dr King predicts that given the different views, prescribing doctors will be looking for clear and definitive guidance on the issue, and he suggests a  deliberate education campaign should accompany any significant change should.

A lot seems to hang now on what PBAC makes of the resubmitted Astra Zeneca application as to which way Australia might turn in the near future.

The Asthma Council says it will be guided by the TGA, but the TGA has approved the budesonide-formoterol combo for mild asthmatics on an as-needed basis already, and the council remains in lock-down mode on the matter.

Asked for an official position, the council. provided the following statement to Allergy and Respiratory Republic: “This is currently a work in progress and both the [Asthma] Handbook working group and guidelines committee are engaged in robust deliberations while considering all the evidence and deciding upon recommendations in the context of evidence-based guidelines for Australian primary care.”

Pressed for a timeframe in which it might make a decision and change the guidelines, a NAC spokesperson said possibly in the first quarter of 2020.

That will be interesting if PBAC announces an approval for the revised Astra Zeneca submission on budesonide-formoterol, as the regulatory and pricing authorities will then be out of step with the peak guidelines body.

And while, in Australia there is disagreement on how to address the issues with SABA-only initiation, there is generally strong agreement that there are some big holes with the current regimen which need to be urgently solved.

Outside of the complexities which surround a potential change to how and when we initiate treatment at the mild end of the asthma spectrum, the fact that SABAs are over the counter in Australia, adds to the issues faced by the peak bodies.

Most experts believe that over-the-counter SABAs has created a population of mild to moderate asthmatics who are virtually “in the wild”, because they have decided that the blue inhaler is easy to access and all they need.

Some SABA-using asthma patients may have never actually have seen a GP. But that’s a whole other story.

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