Using Controllers PRN for Mild Persistent Asthma – An Oxymoron?

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O’Byrne PM, et al. Inhaled combined budesonide-formoterol as needed in mild asthma. N Engl J Med. 2018; 378: 1865-76. AND Bateman ED, et al. As-needed budesonide-formoterol versus maintenance budesonide in mild asthma. N Engl J Med. 2018; 378: 1877-87.

Two recent studies challenge our current approach to managing patients with mild persistent asthma. When patients with asthma are prescribed inhaled corticosteroids (ICSs), we instruct them to use the medication daily. The US and global guidelines for asthma management recommend escalating and deescalating asthma treatment based on the patient’s symptom frequency, risk for asthma exacerbations, and the impact of asthma symptoms on daily activities.1,2 Treatment should not only reduce asthma symptoms but reduce asthma exacerbations and prevent loss of lung function. In patients with persistent asthma, including patients with mild asthma, guidelines recommend maintenance therapy, with either an ICS or a combination ICS/long-acting beta-agonist (LABA), in addition to the use of a short-acting beta-agonist (SABA) as needed for rescue treatment.1

 

One problem in asthma management is that many patients have difficulty adhering to their maintenance therapy, increasing the risk of an asthma exacerbation.2-5 Poor adherence to controller medications in patients with asthma can be due to a number of factors including: a lack of perceived need for therapy as symptoms improve; concerns about side effects, particularly from ICSs; complicated medication regimens; and cost.3-5 The Symbicort Given as Needed in Mild Asthma (SYGMA) 1 and SYGMA 2 trials challenge the traditional approach of maintenance plus rescue therapy for patients with mild persistent asthma. These trials compared combination ICS/LABA (budesonide-formoterol) as needed to traditional ICS maintenance with SABA rescue therapy. SYGMA 1 also compared combination ICS/LABA as needed to SABA monotherapy as needed.  Using an ICS/LABA as needed could help reduce healthcare providers’ concerns about adherence to maintenance therapy and reduce patient concerns about side effects from daily steroid use.6,7

 

SYGMA 1 and SYGMA 2 were similar in several ways.  Both were randomized, double-blind trials that followed patients for 12 months. Both enrolled patients 12 years of age or older with mild asthma requiring the use of maintenance therapy. In both studies, mild asthma was defined as patients whose symptoms were uncontrolled with SABAs as needed alone or asthma that was previously well controlled on low-dose ICS therapy or leukotriene receptor antagonist therapy. SYGMA 1 and SYGMA 2 each had a run-in phase prior to randomization to ensure that patients truly had mild asthma. In both trials, all medications were delivered with the Turbuhaler® device and the devices tracked how frequently the patient used the inhalers.6,7

 

There were some notable differences between the two trials. See Table 1. SYGMA 1 included three treatment arms whereas SYGMA 2 had only two.6,7 In SYGMA 1, patients used electronic diaries to record their symptoms daily which prompted them to use their maintenance inhalers (budesonide or placebo) daily.6  These reminders did not occur in SYGMA 2, giving it a more pragmatic study design.7 SYGMA 1 and SYGMA 2 also had slightly different study endpoints.6,7

 

Table 1: Notable Methodological Differences Between SYGMA 1 and SYGMA 26,7

 

SYGMA 1

(n = 3849)

SYGMA 2

(n = 4215)

Treatment Groups

  1. Budesonide group: budesonide (200 mcg) twice daily plus terbutaline (0.5 mg) as needed
  2. Terbutaline group: placebo twice daily plus terbutaline (0.5 mg) as needed
  3. Budesonide-formoterol group: placebo twice daily plus budesonide-formoterol (200 mcg-6 mcg) as needed
  1. Budesonide group: budesonide (200 mcg) twice daily plus terbutaline (0.5 mg) as needed
  2. Budesonide-formoterol group: placebo twice daily plus budesonide-formoterol (200 mcg-6 mcg) as needed

Primary Endpoint

Asthma symptom control assessed by patient-reported symptoms in an electronic diary

Annual rate of severe exacerbations

Key Secondary Endpoints

  • Rate of exacerbations
  • Time to exacerbation
  • Use of ICSs
  • Asthma-Control Questionnaire (ACQ-5) scores
  • Asthma Quality of Life Questionnaire (AQLQ) scores

 

  • Time to severe exacerbation
  • Use of ICSs
  • Asthma-Control Questionnaire (ACQ-5) scores
  • Asthma Quality of Life Questionnaire (AQLQ) scores

 

 

In SYGMA 1, budesonide-formoterol was superior to terbutaline in terms of asthma symptom control as assessed by patient-reported symptoms in an electronic diary (34.4% of recorded weeks with well-controlled asthma per patient vs. 31.1%; p = 0.046).  Additionally, patients in the budesonide-formoterol group had a lower rate of exacerbations compared to the terbutaline group (annualized severe exacerbation rate 0.07 vs. 0.20; RR = 0.36; 95% CI, 0.27 to 0.49). These two findings demonstrate budesonide-formoterol as needed is superior to SABA monotherapy as needed.6

 

However, when comparing the budesonide-formoterol group to the budesonide group in SYGMA 1, budesonide-formoterol was inferior at controlling asthma symptoms (34.4% of recorded weeks with well-controlled asthma per patient vs. 44.4%; OR = 0.64; 95% CI, 0.57 to 0.73). The budesonide-formoterol group had a similar rate of exacerbations compared to the budesonide group (annualized severe exacerbation rate 0.07 vs. 0.09; RR = 0.83; 95% CI 0.59 to 1.16). Over the yearlong trial, patients in the budesonide-formoterol group were exposed to less ICS than the budesonide group (83% lower median daily dose of ICS).6

 

Similar to the results in SYGMA 1, in SYGMA 2, budesonide-formoterol was noninferior to budesonide with regard to the annual rate of severe exacerbations (0.11 vs. 0.12). However, the daily use of budesonide was better at controlling symptoms (44.3% of patients achieved a decrease in Asthma Control Questionnaire-5 score of at least 0.5 units from baseline vs. 40.3%; OR = 0.86; 95% CI, 0.75 to 0.99). Patients in SYGMA 2 who used budesonide-formoterol as needed were exposed to less ICS than those in the budesonide group (75% lower median daily dose of ICS).7

 

The results in both trials were surprisingly consistent. As needed use of budesonide-formoterol prevented exacerbations as well as daily budesonide use but was not as effective at controlling asthma symptoms. Patients in the budesonide group were exposed to substantially more ICS. Adverse effects were similar across treatment groups in both trials.6,7

 

Strengths of both trials include the large sample size, randomization, study duration, balanced baseline characteristics, and use of the same inhaler device across treatment groups. Another strength was inhaler use was monitored electronically through the device rather than relying on self-report which is subject to both social desirability and recall bias.6,7

 

There are notable study limitations, including patient adherence.6,7 Adherence in SYGMA 1 was high likely due to daily prompting through the electronic diary. Adherence was approximately 80% across all treatment groups.6 In SYGMA 2, adherence was lower (approximately 65%) than SYGMA 1, but still higher than many of us see in clinical practice.7 Higher than expected adherence to daily inhalers would potentially overestimate the benefits of daily budesonide use. Both SYGMA 1 and SYGMA 2 were double-blind, so patients in the budesonide-formoterol groups were instructed to use (unbeknownst to them) a placebo inhaler twice daily and this may have influenced adherence rates. While both trials enrolled patients aged 12 and older, the average age of participants in both trials was approximately 40 years old; so these results may not truly represent the effects in an adolescent population.6,7 Moreover, the Turbuhaler® device used in these studies is not available in the United States.

 

Daily low-dose ICSs as maintenance therapy combined with SABAs as needed for symptoms is currently the standard of care for patients with mild asthma.1 SYGMA 1 and SYGMA 2 demonstrated this regimen (low dose budesonide twice daily) was better than budesonide-formoterol as needed at controlling asthma symptoms when adherence to the maintenance regimen was high. However, budesonide-formoterol as needed was as good as the standard of care at preventing exacerbations.6,7

 

In patients with mild asthma who can commit to using a maintenance medication every day, low dose ICSs are the best option for symptom control.2 Healthcare providers should reinforce continued adherence to therapy even when symptoms improve.4  However, in patients with mild asthma who aren’t able (or don’t wish) to take a medication every day or who are worried about adverse effects from long-term ICS use, it is reasonable to use budesonide-formoterol as needed.  This approach will still reduce the risk of exacerbations and could reduce costs.

 

If you are considering recommending budesonide-formoterol as needed, you will want to note that Turbuhaler®, a dry powder inhaler device, does not expire after opening and is good until the expiration date on the package.8 In the United States, budesonide-formoterol is only available in a metered-dose inhaler device that expires three months after opening.If patients are using budesonide-formoterol as needed, they will need to be counseled to replace the device every three months regardless of whether there are still inhalations in the device.9

 

The FDA has not approved any ICS/LABA combinations for as needed use, but as needed use has been approved in other countries and is recommended in the global asthma guidelines.2,8 No longer can we assume budesonide-formoterol therapy necessitates daily use.  Indeed, you may have already started to see ICS/LABA combination products being used or prescribed as rescue therapy. Do your patients with mild asthma have problems adhering to ICS maintenance therapy? Would you recommend budesonide-formoterol as needed instead?