BASALT

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Calhoun WJ, et al. "Comparison of physician-, biomarker-, and symptom-based strategies for adjustment of inhaled corticosteroid therapy in adults with asthma: The BASALT randomized controlled trial". Journal of the American Medical Association. 2012. 308(10):987-997.
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Clinical Question

Among patients with mild to moderate asthma, what is the comparative effect on disease outcomes when inhaled corticosteroids are adjusted based on physician assessment, biomarkers, or patient symptoms?

Bottom Line

Among patients with mild to moderate asthma, adjusting treatments based on physician assessment, biomarkers (exhaled nitric oxide or sputum eosinophils), or patient symptoms led to similar treatment failure rates.

Major Points

Physician assessment-based adjustment (PABA) strategies are the standard of care for controlling symptoms and exacerbations of asthma. Adjustment of medications based on objective data (eg, exhaled nitric oxide) or symptoms may be easier, although whether these approaches were as effective as PABA was unknown since large controlled trials were lacking. Symptom-based administration of inhaled corticosteroids (ICS) may provide benefit over traditional scheduled administration as it may improve patient adherence through increased motivation and reduce costs of care.[1]

Published in 2012, the Best Adjustment Strategy for Asthma in the Long Term (BASALT) trial randomized 342 adults with mild to moderate persistent asthma to one of three treatment algorithms: PABA, symptom-based adjustment (SBA), or biomarker-based adjustment (BBA) of inhaled corticosteroids, adjusted every 6 weeks for a period of 9 months. PABA was based upon published NHLBI guidelines, SBA was based upon patients' symptoms, and BBA was based on exhaled nitric oxide and sputum eosinophil measurements. The primary outcome was time to treatment failure, defined as asthma exacerbation, marked increase in asthma symptoms (based upon at-home peak expiratory flow measurements or increase in rescue albuterol inhaler use), or physician judgment (based upon forced expiratory volume or other in-clinic measurements). Asthma exacerbation rates, the proportion of treatment failures that progressed to an exacerbation, measures of lung function, or asthma symptoms did not differ significantly between groups. Time to treatment failure or multiple treatment failure rates did not differ significantly between the three treatment groups when evaluated by a 9-month Kaplan-Meier projection. Missed days of school or work was lower in the SBA group than the PABA group.

The BASALT results add to growing evidence that patient-directed medication adjustment may be appropriate in the majority of patients with mild to moderate persistent asthma. (This includes IMPACT,[2] BEST,[3] and a 2005 study by O'Byrne and colleagues.[4]) However, a 2013 Cochrane meta-analysis found no difference in rates of exacerbations when comparing these or similar strategies, though daily use of inhaled corticosteroids was associated with improved measurements of lung function, airway inflammation, overall asthma control, and reduced frequency of rescue inhaler use.[5] The most recent NHLBI asthma guidelines were published in 2007 and so this recommendation has not yet been addressed in asthma practice guidelines.

Of note, this trial was run in coordination with TALC (2010), which compared tiotropium to other treatment strategies in adult patients with asthma.[6]

Guidelines

As of March 2015, no guidelines have been published that reflect the results of this trial. The most recent NHLBI guidelines, which are from 2007 (supporting PABA), are mentioned below for reference.

National Health Lung and Blood Institute EPR-3 (2007, adapted)[7]

  • Mild to moderate persistent asthma:
    • Therapy should be monitored at 2-6 week intervals to ensure asthma control.
    • It is recommended to perform periodic (1-6 month) assessments of asthma control and the need for therapy adjustments.
    • Measurements of asthma control are the following: signs and symptoms of asthma, pulmonary function, quality of life, and history of exacerbations.
    • A written asthma action plan is recommended for all patients and can be symptom or peak-flow based.

Design

  • Multi-blinded, parallel-group, randomized, placebo-controlled trial
  • N=342 adults with mild to moderate asthma
    • Physician assessment-based adjustment (n=114)
    • Biomarker-based adjustment (n=115)
    • Symptom-based adjustment (n=113)
  • Setting: 10 US academic centers
  • Enrollment: 2007-2010
  • Analysis: Intention-to-treat
  • Primary outcome: Time to treatment failure (defined as exacerbation or treatment failure at home or clinic)

Population

Inclusion Criteria

  • Mild to moderate persistent asthma
  • Airway hyperreactivity defined as PFTs with either:
    • ≥12% improvement in FEV1 with albuterol or
    • ≥20% decrease in FEV1 with methacholine

Exclusion Criteria

  • Poorly controlled asthma

Baseline Characteristics

Based on the PABA group.

  • Age 34 years (mean)
  • Female: 63%
  • Race/ethnicity: white 67%, black 21%, Hispanic 2%
  • Asthma duration: 20 years (mean)
  • BMI: 28 kg/m2 (mean)

Interventions

Run-in
All patients were treated with inhaled corticosteroids (beclomethasone HFA 40 µg/puff, 2 puffs BID). Those with adequate control (score ≤1 on each of the 3 questions on the Asthma Evaluation Questionnaire and FEV1 >70%) were enrolled.
Pre-randomization
Patients were given four inhalers, one with beclomethasone, one with albuterol, and two with placebo. Participants were asked to use the inhalers daily or BID, those with ≥75% adherence as measured by a counting device were randomized to a group.
Physician assessment based approach (PABA)
Participants’ asthma control was assessed by physicians for symptoms, activity limitation, rescue albuterol use, lung function, and exacerbation rates at clinic visits every 6 weeks and inhaled corticosteroid dosing was adjusted in a step-wise fashion. Rescue algorithms are based on the recommendations provided by the NHLBI guidelines and severe acute episodes were managed by the medical judgment of the individual physician.
Symptom based approach (SBA)
Therapy was adjusted based on occurrence of symptoms on a day-to-day basis. One puff of inhaled corticosteroid was given for every puff of albuterol.
Biomarker based approach (BBA)
Therapy was adjusted based on biomarker of disease activity, including exhaled nitric oxide and sputum eosinophils measured every 6 weeks. If the exhaled NO was low (<22 ppb), the ICS dose was reduced by one step on the dosing table. If the exhaled NO was midrange (22-35 ppb), the current dose was continued. If exhaled NO was high (>35 ppb), the ICS was increased by one step.

Outcomes

HRs and P values are for comparisons to PABA.

Primary Outcomes

Treatment failure at 9 months
PABA: 22%
BBA: 20% (HR 1.2; 97.5% CI 0.6-2.3; P=0.68)
SBA: 15% (HR 1.6; 97.5% CI 0.8-3.3; P=0.18)

Secondary Outcomes

Days missed from school or work
PABA: 0.25 days/person-year
BBA: 0.46 days/person-year
SBA: 0.11 days/person-year
The odds ratio (OR) for missing days was higher for BBA compared to either PABA (OR 2.0; 97.5% CI 1.1-3.8; P=0.01) or SBA (OR 4.3; 97.5% CI 1.9-9.6; P<0.001).
Asthma exacerbation rate
PABA: 0.23 events/person-year
BBA: 0.21 events/person-year (HR 1.1; 97.5% CI .4-2.8; P=0.89)
SBA: 0.12 events/person-year (HR 1.9; 97.5% CI 0.7-4.9; P=0.11)
Proportion of treatment failures that progressed to exacerbations
PABA: 0.58 (standard deviation [SD] 0.46)
SBA: 0.48 (SD 0.47; P=0.65)
BBA: 0.79 (SD 0.41; P=0.08)
There were no between-group differences in the following
Lung function measurements
Exhaled nitric oxide
Sputum eosinophil count

Additional Outcomes

Predictors of time to treatment failures
Race/ethnicity
Comparisons are vs. non-hispanic whites.
Hispanic: OR 3.6 (95% CI 1.8-7.0; P<0.02)
Black: OR 2.1 (95% CI 1.2-4.0; P<0.02)
Albuterol reversibility (P=0.004)

Criticisms

  • Exhaled NO is no longer a choice biomarker (but sputum eosinophils are)[8]
  • Mild disease severity of the patients limits the generalizability to patients with uncontrolled disease[8][9]
  • The ICS dose may have been too low[9]
  • Dose adjustments may have precipitated the primary outcome in some patients, a comparator arm with a stable ICS would have helped delineate this[9]
  • Patients with a poor asthma symptoms awareness are unlikely to derive benefit from SBA; including these patients may have negated some of the benefit seen in the SBA group.
  • Any benefits derived from patient empowerment is likely to have been lost given the burden of the multiple placebo inhalers in this trial.
  • These outcomes may not generalize to patients with poor understanding of asthma treatment plans.
  • Patients who were poorly adherent to PABA may have mimicked the intervention for a participant in the SBA group.
  • The poorer control of Hispanic patients in the SBA group may be due to a small sample size, access to care, linguistic barriers, or genomic variables.

Further Reading