What do the SYGMA 1 & 2 papers mean for asthma management?

The SYGMA 1 and SYGMA 2 asthma trials have led to significant changes to the GINA guidelines for asthma management.

Asthma deaths are still a problem worldwide and continue to occur in patients across the spectrum of disease severity, including those with mild asthma. Asthma management guidelines provided by international respiratory societies e.g. GINA (Global Initiative for Asthma) provide recommendations for appropriate treatment based on an assessment of asthma severity and frequency of symptoms. These guidelines use a stepwise system from step 1 to 5.

Step 1 involves the use of a reliever medication only and is indicated for patients who require their reliever therapy twice a month or less. At the initial diagnosis of asthma, this step also advises consideration of low dose ICS with close follow up over 4-6 weeks. Step 2 treatment requires regular preventer therapy with low dose regular inhaled corticosteroids (ICS) to treat airway inflammation plus as-needed short-acting beta-agonist (SABA) therapy to relieve acute airway constriction. However, adherence to daily inhaled therapy can be problematic for many patients with mild asthma leading to many patients relying on as needed SABA therapy only. Up to 70% of asthmatics have mild persistent asthma which requires step 2 GINA asthma management (2018 guidelines).

The SYGMA studies examined asthma control of as required ICS/Long-acting Beta agonist (LABA) therapy against standard Step 1 ( PRN SABA)  and Step 2 (Regular ICS + PRN SABA) therapies. The ICS/LABA used was Symbicort (Budesonide + Formoterol), the SABA was Terbutaline and regular ICS was Budesonide.

Who were the patients?

Participants had asthma that required step 2 GINA asthma management (2018 guidelines)^*. Participants mean age was 39.6 years (SD 16.6) in SYGMA 1 and 41 years (SD 17.0) in SYGMA 2. Patients were recruited from > 300 sites around the world.

^{*regular preventer therapy with low/med dose regular ICS or leukotriene receptor antagonist}

What was the intervention?

In SYGMA 1 participants were randomly assigned to one of 3 groups ^{(A, B, C)} in a double-blind fashion. In SYGMA 2 participants were randomly assigned to one of 2 groups ^{(B, C)}. Both studies took place over a 52 week period and involved over 3000 patients in each study. Electronic monitoring of inhaler use was conducted during both studies.

A = Placebo BD + Terbutaline PRN

B = Placebo BD + Symbicort® PRN

C = Budesonide BD + Terbutaline PRN

SYGMA 2 built upon the findings of SYMGA 1 and used a more pragmatic study design. There were no daily reminders to take medications and the participant’s clinicians were blinded as to their patient’s adherence to treatment.

What were the main outcomes?

The primary outcome in SYGMA 1 was the long term efficacy of PRN Symbicort® vs PRN Terbutaline. This was measured by the weeks of well-controlled asthma.

The primary outcome in SYGMA 2 was the rate of severe exacerbations.

What did the authors conclude?

SYGMA 1

• PRN Symbicort® is superior to PRN Terbutaline in achieving asthma control (4% of weeks with well-controlled asthma vs 31.1% of weeks)
• PRN Symbicort is superior to PRN Terbutaline in reducing severe asthma exacerbation rate (64%) and in reducing moderate to severe exacerbation’s (60%)
• PRN Symbicort® was inferior to Budesonide maintenance therapy in achieving asthma control (34.4% of weeks with well-controlled asthma vs 44.4% of weeks).
• PRN Symbicort® was similar to Budesonide maintenance therapy in reducing asthma exacerbation rates, but less total steroid dose was used and patients did not need to remember to take a medication every day.

Participants had reminders to take medications and it was felt that the high level of adherence (79%) recorded in the low dose maintenance budesonide group was unlikely to reflect real-world experience. This good adherence was hypothesized as the reason for the better findings in the budesonide group. SYGMA 2 was designed as a more pragmatic study to represent real-world adherence levels and evaluate this hypothesis.

SYGMA 2

• PRN Symbicort® was non-inferior to low-dose budesonide maintenance treatment in preventing severe asthma exacerbations.
• PRN Symbicort® prevented a similar rate of severe exacerbation with less than 25% of the total exposure to inhaled glucocorticoid received with budesonide maintenance therapy.
• When adherence is at the level seen in the trial (63%); budesonide maintenance therapy is more effective in addressing symptoms, with larger improvements in FEV1 and ACQ-5 and Quality of life (AQLQ) scores seen in the regular ICS arm. However, it should be noted that the magnitude of the difference in scores, which though statistically significant, would not be considered clinically significant.

What has been the impact of these papers so far?

These studies have hit the mainstream press with headlines such as “the blue inhaler is a killer” based on the outcome of a higher exacerbation rate in the mild asthmatics who received PRN terbutaline only, which occurred in the SYGMA 1 trial.

The GINA guidelines have been updated referencing the SYGMA studies as the evidence behind such significant changes that there is now conflicting/confusing advice depending on which resource you refer to. The GINA guidelines now recommend that at step 1, which includes people with asthma who only require their reliever medication twice a month or less, patients use a combined ICS/LABA therapy on an as-needed basis.

The BTS guidelines (July 2019) and Australian Asthma Handbook (March 2019) both conflict with the updated GINA guidelines (April 2019). 

Applying trial results to the right patients

Whilst patients aged 12-18 years were included in the SYGMA trials, the mean ages of participants were 39 and 41 years, indicating the majority of participants were adults. No subgroup analysis of patients based on age was presented in the papers or in the published supplementary material. GINA guidelines group adults together with adolescents and applies the same management advice to all asthma patients aged 12 and over.

The new GINA guidelines advise using Symbicort® as step 1 in mild asthmatics. However, participants in these trials had to require step 2 therapy to be eligible.

Inconvenient results – the change in FEV1 and ACQ scores

Whilst Symbicort® achieved the same efficacy in term of preventing exacerbations as budesonide maintenance using significantly less steroid doses, it was inferior in terms of weeks with well controlled asthma, FEV1 and ACQ outcome measures. The lungs of a 12 year old are still achieving their potential best volume. Is it appropriate to discount the long term effects of persistent symptoms and poorer FEV1 results on this adolescent group’s long term lung health?

Once-daily ICS options and alternative ICS+LABA combination inhalers

There are various options when it comes to selecting ICS and ICS+LABA combinations for a patient aged 12 or over. One option is ciclesonide, a prodrug that is converted to its active metabolite when inhaled into the lungs and has negligible systemic corticosteroid absorption. It’s also only required to be taken once daily. At the 64% adherence rate seen in SYGMA 2, the average daily dose of steroid would be similar to the budesonide dose in the Symbicort arm, it should be noted though that the active metabolite des-ciclesonide is more potent than budesonide in its affinity to bind glucocorticoid receptors by a factor of approximately 1.3.

Symbicort® is suitable for reliever use as is contains formoterol, a LABA with a short onset of action similar to SABAs onset of action. Formoterol is also available for twice-daily administration with fluticasone propionate as Flutiform, however, Symbicort® and Duo Resp® (both contain Budesonide + Formoterol) are the only ICS+LABA inhalers licenced for use as a reliever.

Will these papers change my practice?

These 2 papers demonstrate reproducible findings, were large, blinded, randomised controlled trials with significant and important results. However, I am conflicted about applying their findings to patients aged 12-18 years, as recommended by the updated GINA guidelines.