Annals of Internal Medicine: Asthma Topic Collection

Tiotropium improved lung function and delayed exacerbations in poorly controlled asthma

Greenstone M. — Tue, 18 Dec 2012 00:00:00 GMT

Question

In adults with poorly controlled asthma who are receiving inhaled corticosteroids (ICSs) and long-acting β-agonists (LABAs), does tiotropium improve control?

Methods

Design

2 randomized placebo-controlled trials (PrimoTinA-asthma 1 [Trial 1] and PrimoTinA-asthma 2 [Trial 2]). ClinicalTrials.gov NCT00772538 and NCT00776984.

Allocation

{Concealed}.*†

Blinding

Blinded† (patients, clinicians, {data collectors, outcome assessors,}* and sponsor).

Follow-up period

48 weeks.

Setting

Clinical centers in 15 countries.

Patients

Adults 18 to 75 years of age (Trial 1: n = 459, mean age 53 y, 63% women; Trial 2: n = 453, mean age 53 y, 58% women) who had a ≥ 5 year history of asthma; persistent airflow limitation despite daily ICSs and LABAs; ≥ 1 exacerbation treated with systemic glucocorticoids in the past year; asthma diagnosed at < 40 years of age; score ≥ 1.5 on Asthma Control Questionnaire 7 (ACQ7); and were life-long nonsmokers or had a smoking history of < 10 years with no smoking in the past year. Exclusion criteria included chronic obstructive pulmonary disease (COPD), serious comorbid illness, and current use of anticholinergic bronchodilators.

Intervention

2 puffs of 2.5 µg tiotropium (Trial 1: n = 237; Trial 2: n = 219) or placebo (Trial 1: n = 222; Trial 2: n = 234) with a soft-mist inhaler (Respimat) each morning. Patients maintained their pretrial maintenance asthma therapy of ICSs and LABAs. Salbutamol was provided as a rescue medication.

Outcomes

Peak FEV₁ response (within 3 h of receipt of maintenance and study drugs) and trough FEV₁ at 24 weeks, and time to first severe asthma exacerbation (requiring initiation or at least doubling of systemic glucocorticoids for ≥ 3 d) at 48 weeks. Secondary outcomes included the ACQ7 and Asthma Quality of Life Questionnaire (AQLQ) at 24 weeks, and adverse events.

Patient follow-up

90% (Trial 1) and 89% (Trial 2).

Main results

The main results are in the Table. Clinically important differences in the ACQ-7 and AQLQ were not achieved. Across both trials, 8% of the tiotropium group and 9% of the placebo group had serious adverse events.

Conclusion

In adults with asthma that was poorly controlled on inhaled corticosteroids and long-acting β-agonists, tiotropium improved lung function and time to first severe exacerbation.Tiotropium vs placebo for poorly controlled asthma‡OutcomesMean difference between tiotropium and placebo in change from baseline (95% CI)Trial 1Trial 2Peak FEV₁ at 24 wk (mL)86 (20 to 152)154 (91 to 217)Trough FEV₁ at 24 wk (mL)88 (27 to 149)111 (53 to 169)Severe exacerbationsHazard ratio (CI)TiotropiumPlaceboTime to first event (d)2822260.79 (0.62 to 1.00)‡CI defined in Glossary.

Review: In asthma controlled with ICSs plus LABAs, stopping LABAs increases asthma impairment

Singh J. — Tue, 18 Dec 2012 00:00:00 GMT

Question

In patients with asthma controlled with inhaled corticosteroids (ICSs) plus a long-acting β₂-agonist (LABA), what are the effects of discontinuing LABAs?

Review scope

Included studies compared LABA discontinuation and unchanged ICS dose with continued use and unchanged dose of both LABAs and ICSs in patients ≥ 4 years of age who had asthma and were receiving combined LABA (salmeterol or formoterol fumarate dihydrate) and ICS therapy twice daily for ≥ 3 months, and had well-controlled asthma for ≥ 3 months before LABA discontinuation. Outcomes included emergency department visit or unscheduled consultation for asthma, use of systemic corticosteroids, withdrawal from treatment due to lack of efficacy or loss of asthma control, serious adverse events, quality of life (Asthma Quality of Life Questionnaire), asthma control (Asthma Control Questionnaire), symptom-free days, rescue bronchodilator use, death, and hospitalization.

Review methods

MEDLINE, EMBASE/Excerpta Medica, Cochrane Library, ClinicalTrials.gov, Database of Abstracts of Reviews of Effects, and National Health Service Economic Evaluation Database (all to Aug 2010); manufacturer trials registries; reviews; and reference lists were searched for randomized controlled trials (RCTs). Manufacturers of salmeterol and formoterol were contacted. 5 RCTs (n = 1352, mean age 38 to 47 y, 49% to 65% women) met selection criteria. All studies included older adolescents (≥ 15 y) or adults, and ICSs and LABAs were delivered in a single inhaler. All studies had low risk for bias based on randomization, allocation concealment, blinding, and intention-to-treat analysis. Risk for bias was high for loss to follow-up (12% to 38% discontinued treatment and were excluded from some analyses). All studies were funded by study drug manufacturers.

Main results

The main results are in the Table. No deaths or hospitalizations occurred in either group.

Conclusion

In patients with asthma controlled with inhaled corticosteroids plus a long-acting β₂-agonist (LABA), discontinuation of LABAs worsens asthma control and quality of life.LABA discontinuation (D/C) vs continuation (C) in patients with asthma controlled with combined ICS and LABA therapy*OutcomesNumber of trials (n)Weighted event ratesAt 12 to 16 wkLABA-D/CLABA-CRRI (95% CI)NNH (CI)Emergency or unscheduled visits†3 (949)2.4%1.0%124% (−21 to 535)NSUse of systemic corticosteroids4 (1257)3.2%1.9%68% (−16 to 238)NSLoss of control‡4 (1257)14%4.2%227% (116 to 396)11 (6 to 21)RRR (CI)NNT (CI)Serious adverse events5 (1342)1.1%1.3%21% (−109 to 71)NSMean difference (CI)§AQLQ||2 (359)0.32 lower (0.14 to 0.51)ACQ¶3 (645)0.24 higher (0.13 to 0.35)Symptom-free days4 (1230)9.2% fewer (1.6 to 17)Rescue bronchodilator use4 (1226)0.71 puffs/d more (0.29 to 1.14)*ACQ = Asthma Control Questionnaire; AQLQ = Asthma Quality of Life Questionnaire; ICS = inhaled corticosteroid; LABA = long-acting β₂-agonist; NS = not significant; other abbreviations defined in Glossary. Weighted event rates, RRI, RRR, NNH, NNT, and CI calculated from control event rates and risk ratios in article using a random-effects model.†Emergency department visit or unscheduled consultation for asthma.‡Withdrawal from treatment due to lack of efficacy or loss of asthma control.§Differences in scores favor LABA continuation group.||Score range 1 to 7, higher scores = better quality of life.¶Score range 0 to 6, lower scores = better asthma control.

Physician-, biomarker-, and symptom-based adjustment of inhaled corticosteroids for asthma had similar effects

Stanbrook MB. — Tue, 15 Jan 2013 00:00:00 GMT

Question

Is biomarker- or symptom-based adjustment of inhaled corticosteroid (ICS) dose better than physician assessment–based adjustment for preventing treatment failure in adults with mild to moderate asthma?

Methods

Design

Randomized, placebo-controlled, 3-group trial (Best Adjustment Strategy for Asthma in the Long Term [BASALT] trial). ClinicalTrials.gov NCT00495157.

Allocation

Unclear allocation concealment.*

Blinding

Blinded* (patients).

Follow-up period

36 weeks.

Setting

10 academic medical centers in the USA.

Patients

342 adults (mean age 35 y, 69% women) who had physician-diagnosed, mild to moderate, persistent asthma that was well- or partially controlled with low-dose ICSs; reversible airflow limitation or airway hyperresponsiveness; and ≥ 75% treatment adherence between enrollment and randomization.

Interventions

Beclomethasone HFA inhaler, twice daily, with dose adjusted every 6 weeks based on exhaled nitric oxide levels, plus 2 placebo inhalers (1 used twice daily and 1 as needed) (biomarker group, n = 115); beclomethasone inhaler used only when rescue albuterol was used, plus 2 placebo inhalers used twice daily (symptom group, n = 113); or beclomethasone inhaler, twice daily, with dose adjusted every 6 weeks based on guideline-informed physician assessment, plus 2 placebo inhalers (1 used twice daily and 1 as needed) (physician group, n = 114). All groups used an albuterol inhaler as needed for asthma symptoms.

Outcomes

Primary outcome was first treatment failure (clinically important worsening of asthma). Other outcomes included exacerbations. The study was powered to detect a 60% reduction in treatment failure rate from 30% in the physician assessment–based adjustment group (87% power, 2-sided α = 0.025 for each of 2 main comparisons: biomarker or symptom group vs physician group).

Patient follow-up

85% (intention-to-treat analysis).

Main results

Biomarker and symptom groups did not differ from the physician group for treatment failure (Table) or asthma exacerbations (biomarker vs physician groups, 0.21 vs 0.23 events per person-y, P = 0.89; symptom vs physician groups, 0.12 vs 0.23 events per person-y, P = 0.11).

Conclusion

In adults with mild to moderate asthma, biomarker- or symptom-based adjustment of inhaled corticosteroid dose did not reduce treatment failure compared with physician assessment–based adjustment.Adjustment of ICS dose based on a biomarker (BBA) or symptoms (SBA) vs physician assessment (PABA) in adults with mild to moderate asthma†OutcomeBBASBAPABAAt 36 wkRRR (97.5% CI)NNT (CI)Treatment failure18%—21%13% (−57 to 52)Not significant—14%21%33% (−28 to 65)Not significant†ICS = inhaled corticosteroid; other abbreviations defined in Glossary. Event rates, RRR, and CI calculated from number of events and randomized patients reported in article.