AMAZES: Effect of azithromycin on asthma exacerbations

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Gibson PG, et al. "Effect of azithromycin on asthma exacerbations and quality of life in adults with persistent uncontrolled asthma (AMAZES): a randomised, double-blind, placebo-controlled trial". Lancet. 2017. 390(10095):659-668.
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Clinical Question

In adult patients with symptomatic asthma who are currently using an inhaled corticosteroid and a long acting bronchodilator, does oral azithromycin decrease the frequency of asthma exacerbations?

Bottom Line

Adults with persistent symptomatic asthma experience fewer asthma exacerbations and improved quality of life when treated with oral azithromycin for 48 weeks. Azithromycin might be a useful add-on therapy in persistent asthma

Major Points

Asthma is a chronic illness that millions of people suffer from globally. Some adults who suffer from severe or uncontrolled asthma may need some kind of additive or more persistent therapy. Asthma is characterized by chronic airway inflammation that often leaves the patient at risk for infection and other illnesses. Although an inhaled corticosteroid is often used as treatment for the condition, different patients have different reactions to this therapy so the goal of the study was to assess the safety and efficacy of azithromycin as a potential add on treatment for the disease1. The clinical question on which the study was based around was “In adult patients with symptomatic asthma who are currently using an inhaled corticosteroid and a long acting bronchodilator, does oral azithromycin decrease the frequency of asthma exacerbations?” 420 patients were randomly assigned (213 in the azithromycin group and 207 in the placebo group). It was a randomized, double blinded, placebo controlled parallel group trial. Patients were followed from June 13, 2009 to January 31, 2015. Over the course of therapy, patients were analyzed across eight sites at weeks 6, 12, 24, 36, 48 and 52 of their treatment[1]. Overall, moderate and severe asthma exacerbations were reduced to 61% in the placebo group and 44% in the azithromycin group (p=0.001) showing significant clinical data in favor of using azithromycin to decrease the amount of exacerbations in asthma patients[1]. Overall, the results indicated that azithromycin could have a clinical benefit when used in combination with an inhaled corticosteroid and a long acting bronchodilator. In analyzing the study for validity, there are a few criticisms of this study that would make us as pharmacists question whether or not to use it. The sample size of 420 people was considerably small for such a disease state that affects millions, and the adherence to treatment in the study was observed to be only 80%[1]. In addition, this is an off label use of azithromycin, so we would need to see many future studies in which the positive effect of the medication was confirmed. There are counter arguments that argue against the findings of this study, and the medical community needs to come to a consensus before azithromycin can be recommended. In addition, using azithromycin for such a long period could increase resistance to the medication. Finally, smokers and people with a prolonged QT interval were excluded from this study. Prolonged QT is a side effect of azithromycin, and the study does not discuss what to do for this group of patients. Smokers have a huge risk of developing asthma, and there are millions of individuals who partake in this habit, so by excluding these patients the study excluded a large number of individuals at risk for the very disease that they were studying.

Guidelines

Patients with uncontrolled persistent asthma may be treated with a medium-to-high dose inhaled corticosteroids plus a long-acting bronchodilator. Asthma is usually treated as a step by step regimen according to the severity of the condition. These guidelines are from the National Heart, Blood and Lung Institute[2]

1. SABA as needed

2. SABA AND daily low dose ICS (Evidence level A)

3. SABA AND daily medium dose ICS (level A) or sustained-release theophylline (requires serum level monitoring b/c of tachycardia and GERD), consider subcutaneous allergen immunotherapy

4. SABA AND medium dose ICS+LABA (Evidence level B), consider subcutaneous allergen immunotherapy

5. SABA AND high dose ICS+LABA (Evidence level B), consider omalizumab for allergies

6. SABA AND high dose ICS+LABA+oral corticosteroid, consider omalizumab for allergies

SABA- Short Acting Beta Agonist

ICS- Inhaled CorticoSteroid

LABA- Long Acting Beta Agonist

Design

  • The study was done as a multicenter study. It was a randomized, double-blind, placebo controlled parallel group trial.
  • N= 420 adult patients
  • Experimental arm (azithromycin group): n=213
  • Standard (placebo group): n=207
  • Setting: The study took place in Australia. Stenlake *Compounding Pharmacy in Sydney, Australia provided the study drug and the placebo for the patients. Data was collected at eight sites.
  • Enrollment: June 12, 2009-January 21, 2015
  • Mean follow up: 52 weeks
  • Analysis: Data was analyzed on an intention-to-treat basis.
  • Primary outcome: The primary outcome was that azithromycin reduced the amount of exacerbations experienced


Population

Inclusion criteria

  • > 18 years of age
  • Asthma with documented objective evidence of variable airflow from bronchodilator response, airway hyperresponsiveness, or increased peak flow variability.
  • Currently symptomatic with at least partial loss of asthma control despite treatment with maintenance inhaled corticosteroids or long-acting bronchodilators
  • Clinically stable with no recent infections, exacerbations, or changes in maintenance medications in the past 4 weeks
  • Non-smoker

Exclusion Criteria

  • Prior smoking more than 10 pack-years of smoking if carbon monoxide diffusing capacity was less than 70% of predicted value.
  • Hearing impairment
  • Abnormally prolonged QTc interval

Baseline Characteristics

  • Age
    • Placebo (49.58-67.98 years old)
    • Treatment (50.62-68.74)
  • Male
    • Placebo (42%)
    • Treatment (37%)
  • Ex-smoker
    • Placebo (81)
    • Treatment (80)
  • BMI
    • Placebo (28-81)
    • Treatment (29-90)
  • Asthma history
    • Age asthma symptoms began
      • Placebo 13 (4–40)
      • Treatment 17 (5–40)
    • Age asthma diagnosed
      • Placebo 20 (5–44)
      • Treatment 21 (5–42)


Interventions

  • Patients on an inhaled corticosteroid and long acting bronchodilator were assigned to two groups for 48 weeks of treatment
    • Azithromycin 500 mg (213)
    • Placebo (207)
  • Assessments took place at a clinic on weeks 6,12,24,36,48,and 52 where medication use, asthma exacerbations, spirometry, adherence, adverse events and symptoms were reviewed.


Outcomes

Primary Outcomes

(These numbers are presented as placebo vs. azithromycin)

  • Total number of asthma exacerbations (severe and moderate)
  • Severe exacerbation categorized: hospitalization due to asthma, ER visit requiring systemic corticosteroid, or >3 days of systemic corticosteroids of >10 mg or temporary increase in > 10mg for > 3 days.
  • Moderate exacerbations categorized: ER visit not requiring systemic corticosteroids, increase in beta-2 agonist for at least 2 days, and increase in inhaled corticosteroids or antibiotics with a deterioration of asthma symptoms or both.
    • 1.86 vs. 1.07 (absolute difference -0.46; 95% CI 95% -0.79 to -0.14 P<0.0001) NNT=126
  • Asthma quality of life
    • 5.55 vs. 5.73 (absolute difference 0.36; 95% CI 0.21 to 0.52 P=0.001) NNT=555

Secondary Outcomes

  • ACQ6 Score
    • 1.31 vs. 1.21 (absolute difference -0.20; 95% CI -0.34 to -0.05) NNT=1000
  • Lung Function (pre-bronchodilator spirometry)
    • 2.18 vs. 2.06 (absolute difference -0.06; 95% CI -0.12 to -0.001) NNT=833
  • Induced sputum cell counts
    • 2.83 vs. 2.16 (absolute difference -0.62; 95% CI -1.23 to -0.002) NNT= 149

Adverse Events

  • Treatment related adverse events
    • Diarrhea
      • 39 (19%) to 72 (34%) (p=0.001) NNH=7

Criticisms

  • Small population group was observed for study when compared to the amount of people who were screened for the study
  • 20% of selected group withdrew from study
  • Mean Adherence to trial was 80%, 20% of the population study was not adherent
  • Study excluded patients who smoke, patients with hearing impairments and patients with a prolonged QT interval

Funding

National Health and Medical Research Council of Australia, John Hunter Hospital Charitable Trust

Further Reading

[1]
  1. 1.0 1.1 1.2 1.3 Gibson PG, Yang IA, Upham JW, Reynolds PN, Hodge S, James AL, et al. Effect of azithromycin on asthma exacerbations and quality of life in adults with persistent uncontrolled asthma (AMAZES): a randomised, double-blind, placebo-controlled trial. [Internet]. Advances in pediatrics. U.S. National Library of Medicine; 2017 [cited 2018May12]. Available from: https://www.ncbi.nlm.nih.gov/pubmed/28687413
  2. “Guidelines for the Diagnosis and Management of Asthma (EPR-3).” National Heart Lung and Blood Institute, U.S. Department of Health and Human Services, www.nhlbi.nih.gov/health-topics/guidelines-for-diagnosis-management-of-asthma.