Old doc, new data: Mild asthma strategies

Casey Parker

20/06/2019 3:21:25 PM

GPs will manage patients with mild asthma almost every day, guided by National Asthma Council recommendations.

Long-acting beta-2 adrenoreceptor agonists have become popular in treating asthma. But do the data support it?

For many patients experiencing asthma, the use of intermittent short-acting bronchodilators is the easiest and usually an adequate strategy. Some with more frequent symptoms will require some form of maintenance therapy – in most cases, this is a low-dose inhaled corticosteroid.
In recent years, however, we have seen the emergence of new strategies to manage mild asthma. Specifically, the use of long-acting beta-2 agonists such as formoterol has become popular.
So, which is the best strategy – short acting or long acting?
The National Asthma Council still recommends a stepped approach to limit the use of unnecessary medications and side effects, and that is how most of us practice. (Fun fact: The pyramidal diagram in the previous link is called a ziggurat after the ancient Mesopotamian temples.)
But just last month, a new study published in the New England Journal of Medicine claimed that another strategy – using an ‘as required’ combination budesonide–formoterol (Symbicort) – may be superior to the status quo.
The study, based on the Novel START trial, compared three strategies, so let us take a dive into this paper and see if the claims are justified.
Patients in the trial were adults aged 18–75 from Australia, New Zealand, Italy or the UK – 675 patients were randomised, and 668 were included in the analyses.
Patients had mild asthma, with only 7.3% reporting a severe exacerbation in the previous 12 months and 54% reporting using a SABA (short-acting beta-2 agonists) on two or fewer occasions per week in the previous four weeks.
Patients were excluded if they had been admitted in the year prior or had any sort of long-term smoking history, ie they tried to exclude patients with chronic obstructive pulmonary disease (COPD) rather than primary asthma diagnosis.
Patients were randomised to follow one of three strategies for their asthma over a 52-week period. These were:

  • albuterol (sold as Ventolin), 100 μg, with two inhalations from a metered-dose inhaler as needed for symptom relief
  • budesonide (sold as Pulmicort), 200 μg, one inhalation twice daily, plus albuterol (sold as Ventolin), 100 μg, two inhalations from as needed for symptom relief
  • budesonide–formoterol (sold as Symbicort), 200 μg of budesonide+ 6 μg of formoterol, one inhalation as needed for symptom relief. No regular preventer used. 
Patients were given an asthma action plan to follow and their usage of the medication was monitored using an electronic monitor. They were required to keep a log of visits for urgent/emergent care, and any other steroid use, such as prednisolone for exacerbations.
The primary outcome measured was the annualised rate of asthma exacerbations per patient. This was defined as worsening asthma that resulted in one or more of:
  • an urgent medical care consultation (eg a primary care visit, emergency department [ED] visit, or hospital admission)
  • a prescription of systemic glucocorticoids for any duration
  • an episode of high beta-2 agonist use (more than 16 doses of albuterol or eight actuations of budesonide–formoterol over the course of 24 hours).
This seems like a sensible, patient-oriented outcome. It is also quite objective and easy to measure accurately.
There was also a pile of secondary outcomes, but those are tiger territory. There can be only one outcome in the power calculations.
So what happened? Which strategy reigned supreme?
Well, before we get to that there are a few technical factors and confounders to consider with this trial.
Firstly, it was sponsored by Astra-Zeneca, the makers of Symbicort. So this is a pharma paper. Having said that, there does seem to be a good separation of church and state when it comes to the actual conduct of the trial. It was run independently by New Zealand’s Medical Research Institute.
Secondly, this is an open-label trial. The patients knew what they were taking and that may induce bias. The researchers went to some length to discuss the rationale and the practical considerations behind this design choice. It is certainly very tricky to do a double-blind, double-dummy placebo trial with three arms. However, bias remains inescapable in this design.
Finally, the power calculation required 225 patients in each group to make the numbers work, but they didn’t quite make it, as 13 patients were lost to follow up. So it was not mathematically pleasing to the stats nerds out there.
Okay, enough nerdiness. Onto the bottom line.
What worked?
It looks like strategies 2 (budesonide) and 3 (budesonide–formoterol) are significantly better than strategy 1 (albuterol as required) for the primary outcome. The write-up shows a 50% relative risk reduction. This sounds very impressive, until you look at the scale on the vertical axis.
In absolute terms, we are seeing well under a half of an ‘exacerbation per patient, per year’.
Another way to state that outcome is that patients receiving PRN albuterol had an exacerbation roughly every 2.5 years, while patients in the other groups had one roughly every five years. These exacerbations were largely on the mild end of the spectrum.
In sum, these are overall very well people and really did not need much treatment at all.
I am not sure if I would want to take either a regular inhaled steroid or a PRN combination agent for that long to prevent a single exacerbation. It seems like overkill.
Whenever I see a drug company-sponsored trial I have a simple method to assess the validity of the data in the real world.
I think to myself, ‘What is the most common side effect of this drug?’ and ‘How often would I expect to see it in this population?’
Then I scroll to the side-effects/adverse events section and check whether the figure seems to be in that ballpark.
For this trial I thought to myself, ‘Inhaled steroids can cause oral thrush’. The company’s own patient information leaflet specifies it occurs in 1–10% of patients.
However, in this trial, the rate of oral thrush was not reported. This means it was either not seen or not counted. This makes me less confident in the external validity of this data.
So, for me, the bottom line for this data is: patients with very mild asthma probably will do great with whatever strategy you like.
I plan to keep it simple and use a single agent without many side effects. Ventolin PRN would be what I would use. If there is evidence of ongoing inflammation, I’ll add in a steroid to treat the underlying issue.
What did I take away from this trial? Beware the use of relative risk numbers to make a drug look good.
Always look at the absolute figures and ask yourself, ‘Is it enough bang for the buck?’

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Dr Armando Reyes Sta.Ana   21/06/2019 4:44:52 PM

In regards to some Asthma management trial, is there any evidence based trials dealing with magnesium supplement in asthma control or maintenance?
Since magnesium is a mineral that relaxes the smooth muscles of the body, it also controls Ht and improves constipation.
It seems that daily supplement of magnesium tab 300 to 500mg, reduces the symptoms of asthma and lessens the usage of these anti asthma inhalers in the long term.
As myself is mildly asthmatic, after taking mag supplement daily basis for some months now, I was less reliant now using these steroid and B2 agonist inhalers lately.

Alex   21/06/2019 9:54:18 PM

I like your analysis and the importance of the relative value vs absolute value of benefit. In this study, symbicort as reliever actually shown to have similar benefit as budesonide preventer in reducing asthma exacerbation. At the same time, it delivers less budesonide (ie less steroid intake) which can be a concern for a lot of patients. This sounds like a win to me for those who currently needs both a SABA reliever and a steroid preventer. Who needs two when you only need one!