Comparison of physician-, biomarker-, and symptom-based strategies for adjustment of inhaled corticosteroid therapy in adults with asthma: the BASALT randomized controlled trial

Abstract

Context: No consensus exists for adjusting inhaled corticosteroid therapy in patients with asthma. Approaches include adjustment at outpatient visits guided by physician assessment of asthma control (symptoms, rescue therapy, pulmonary function), based on exhaled nitric oxide, or on a day-to-day basis guided by symptoms.

Objective: To determine if adjustment of inhaled corticosteroid therapy based on exhaled nitric oxide or day-to-day symptoms is superior to guideline-informed, physician assessment-based adjustment in preventing treatment failure in adults with mild to moderate asthma.

Design, setting, and participants: A randomized, parallel, 3-group, placebo-controlled, multiply-blinded trial of 342 adults with mild to moderate asthma controlled by low-dose inhaled corticosteroid therapy (n = 114 assigned to physician assessment-based adjustment [101 completed], n = 115 to biomarker-based [exhaled nitric oxide] adjustment [92 completed], and n = 113 to symptom-based adjustment [97 completed]), the Best Adjustment Strategy for Asthma in the Long Term (BASALT) trial was conducted by the Asthma Clinical Research Network at 10 academic medical centers in the United States for 9 months between June 2007 and July 2010.

Interventions: For physician assessment-based adjustment and biomarker-based (exhaled nitric oxide) adjustment, the dose of inhaled corticosteroids was adjusted every 6 weeks; for symptom-based adjustment, inhaled corticosteroids were taken with each albuterol rescue use.

Main outcome measure: The primary outcome was time to treatment failure.

Results: There were no significant differences in time to treatment failure. The 9-month Kaplan-Meier failure rates were 22% (97.5% CI, 14%-33%; 24 events) for physician assessment-based adjustment, 20% (97.5% CI, 13%-30%; 21 events) for biomarker-based adjustment, and 15% (97.5% CI, 9%-25%; 16 events) for symptom-based adjustment. The hazard ratio for physician assessment-based adjustment vs biomarker-based adjustment was 1.2 (97.5% CI, 0.6-2.3). The hazard ratio for physician assessment-based adjustment vs symptom-based adjustment was 1.6 (97.5% CI, 0.8-3.3).

Conclusion: Among adults with mild to moderate persistent asthma controlled with low-dose inhaled corticosteroid therapy, the use of either biomarker-based or symptom-based adjustment of inhaled corticosteroids was not superior to physician assessment-based adjustment of inhaled corticosteroids in time to treatment failure.

Trial registration: clinicaltrials.gov Identifier: NCT00495157.

Figure 1

Participant Allocation in BASALT and TALC Trials Patients were allocated to the Best Adjustment Strategy for Asthma in the Long Term (BASALT) trial based on achievement of forced expiratory volume in the first second of expiration of greater than 70% during the run-in period and concomitant control of symptoms (score of 0 or 1 on each of 3 questions on the Asthma Evaluation Questionnaire; eSupplement at http://www.jama.com). Patients whose lung function was less than 70% of predicted or had quantitatively greater symptom burden were allocated to the Tiotropium Bromide as an Alternative to Increased Inhaled Glucocorticoid in Patients Inadequately Controlled on a Lower Dose of Inhaled Corticosteroid (TALC) trial, which was a concurrently recruited Asthma Clinical Research Network trial. ^aDetails for those screened but ineligible were not collected. ^bDropouts were included as censored observations.

Figure 2

Time to First Treatment Failure No significant differences among the 3 treatment groups were seen. A confirmatory truncated analysis was performed with truncation at day 258 (week 37), beyond which less than 10% of the study population was still in follow-up. These results confirm the primary analysis with a pairwise P value for PABA vs BBA of .64; PABA vs SBA, P=.15; and BBA vs SBA, P=.33. The hazard ratios and 97.5% confidence intervals were identical to 1 decimal place. Short vertical bars on the curves indicate censored data.

Figure 3

Dose Level Distribution of Prescribed Inhaled Corticosteroids No significant differences in dose distribution were observed between the biomarker-based adjustment (BBA) and the physician assessment–based adjustment (PABA) strategies. Because there was no regularly scheduled dose in the symptom-based adjustment group, equivalent dose distributions cannot be reliably calculated for participants randomized to this group. The corresponding dose and frequency for the dose levels appear in Table 2.

Figure 4

Mixed-Model Treatment Means of Pulmonary Function and Exhaled Nitric Oxide The data markers indicate geometric means and the error bars indicate 97.5% confidence intervals. FEV₁ indicates forced expiratory volume in the first second of expiration. No significant differences in prebronchodilator FEV₁, postbronchodilator FEV₁, or albuterol-induced reversibility were observed. The BBA group had very little change in exhaled nitric oxide over the course of the trial because dosing of inhaled corticosteroids was adjusted to control exhaled nitric oxide. The SBA group showed a small and statistically significant increase in exhaled nitric oxide over the course of the trial vs the BBA group (P=.007). Level of exhaled nitric oxide in the SBA group did not differ significantly from the PABA group (P=.15).

Figure 5

Treatment Failure by Season Spring included March, April, and May; summer, June, July, and August; autumn: September, October, and November; and winter: December, January, and February. The dotted lines indicate the lower and upper number of all treatment failure events in all groups across the 4 seasons (range, 3-7); the dashed line indicates the middle value of 5 treatment failure events (actual mean of the 10 within-range observations: 5.6). The physician assessment–based adjustment (PABA) group showed a significantly higher number of treatment failure events during autumn vs either the symptom-based adjustment (SBA) group or the biomarker-based adjustment (BBA) group. ^aP=.02 for PABA vs BBA and SBA in autumn). We infer from these data that the expected number of treatment failure events for all 3 treatment modalities is typically 5 per 100 persons or about 5%, doubling to 10% to 11% in the autumn and winter within the PABA group.