Asthma: No Clear Winners in Combination Treatment in Blacks

Diana Phillips

November 18, 2015

Long-acting anticholinergic agents may be a reasonable substitute for long-acting beta-agonists (LABAs) in combination with inhaled corticosteroids (ICS) for asthma in black adults, according to the findings of a clinical efficacy trial comparing both combination regimens in this population.

Current treatment guidelines for patients with poor asthma control receiving low-dose ICS recommend increasing the dose of ICS or adding a LABA, although the safety of LABA therapy has been called into question. There have been reports of possible increases in serious events, including hospitalizations and death, Michael E. Wechsler, MD, from National Jewish Health in Denver, Colorado, and colleagues write in an article published in the October 27 issue of JAMA.

These risks, "if they exist," the authors write, "may disproportionately affect black populations." In addition, black individuals with allelic variation at the Arg16Gly locus of the β2-adrenergic receptor (ADRB2) gene may not benefit from LABAs to the same degree as individuals of other races. For these reasons, the investigators designed a multisite, open-label randomized clinical trial to assess the relative safety and efficacy of the long-acting anticholinergic tiotropium in combination with ICS compared with combination treatment with LABAs and ICS, and to determine whether the genetic polymorphism was associated with differential treatment outcomes.

The researchers conducted the trial at 20 practice sites from March 2011 through July 2013. They randomly assigned 1070 black adults with moderate to severe asthma to treatment with ICS plus either once-daily tiotropium (n = 532) or twice-daily LABAs (n = 538). Participants underwent genotyping, completed monthly questionnaires, and attended study visits at baseline and 1, 6, 12, and 18 months.

The primary outcome was time to asthma exacerbation. Secondary outcomes included scores on the Asthma Quality of Life Questionnaire, Asthma Control Questionnaire, Asthma Symptom Utility Index, and Asthma Symptom Free Days questionnaire, spirometry (FEV1), rescue medication use, asthma deteriorations, and adverse events.

The results showed no significant difference in time to first exacerbation between groups. The mean number of exacerbations in the LABA + ICS group was 0.42 exacerbations per person-year compared with 0.37 exacerbations per person year for tiotropium + ICS (rate ratio [RR], 0.90; 95% confidence interval [CI], 0.73 - 1.11; P = .31). The probability of being exacerbation-free at 1 year was 74.0% for LABA + ICS vs 75.7% for tiotropium + ICS (hazard ratio [HR], 0.91; 95% CI, 0.70 - 1.18; P = .47).

In addition, no significant differences between groups were observed in proportions of patients who had at least 1 exacerbation or in the number of exacerbations per patient, even after adjusting for geographic region, age, sex, and baseline percentage of FEV1 predicted.

No between-group differences were observed in the secondary outcomes of Asthma Control Questionnaire score, Asthma Quality of Life Questionnaire score, Asthma Symptom Free Days annualized score, and Asthma Symptom Utility Index score, all of which improved in both groups. There was also no between-group difference in change in lung function, as measured by FEV1 over the course of the entire study or average rescue medication use, the authors write.

When the researchers stratified participants by genotype, no between-group differences were observed in time to first asthma exacerbation, the mean number of exacerbations, or lung function at 6, 12, or 18 months, indicating "the Arg16Gly polymorphism of the ADRB2 was not associated with differential responses to therapy," they write.

Given specific concerns regarding the safety of LABA therapy among black patients, the investigators analyzed the frequency of asthma-related hospitalizations and deaths. "The adjusted rates of hospitalizations due to asthma were higher with tiotropium + ICS compared with LABA + ICS," they write. "However, because hospitalizations were not a prespecified outcome for this trial, no conclusions can be reached regarding rates of hospitalizations among patients receiving LABA + ICS vs those receiving tiotropium + ICS."

Although the investigators did not observe a difference in exacerbations between either combination therapy, "we found that, despite combination therapy, this population experienced a high rate of exacerbations," which points to the need for additional targeted interventions and further study to reduce the rate of asthma exacerbations in this population, they conclude.

The findings may have practice-changing implications, Dr Wechsler said in an interview. "Prior to this, LABA would have been considered the 'go to' step-up drug for patients poorly controlled on ICS alone, but prior data suggested that there may be some concern with LABA in this population," he explained. "Our study shows that tiotropium, which was only approved for asthma a few months ago, can be a suitable alternative to those across many outcomes. This could certainly alter practice, as physicians might now consider [tiotropium] as step-up."

The trial outcomes "are not too surprising," according to pulmonologist Nicholas Gross, MD, professor emeritus, Loyola University Chicago Stritch School of Medicine, Maywood, Illinois, and staff physician at St. Francis Hospital, Hartford, Connecticut.

"Tiotropium, an anticholinergic agent, was not approved or much used as a maintenance treatment for asthma for many years. However, everyone knew that it was a bronchodilator, even in asthma, and most pulmonologists used it, certainly for difficult asthma cases," he explained in an interview. "This study confirms its utility in asthma as the primary outcome and most secondary outcomes."

Of particular interest is the observation that blacks continue to have a significant number of asthma exacerbations, independent of treatment option, noted Dr Gross, who was not involved in the trial. "The asthma acute exacerbation rate is known to be high in African Americans. Speculations for why this is include inner-city habitation conditions and poor compliance with medications in general," he said. Given the findings of this trial as well as previous reports, he said, these patients need to be included in acute exacerbation trials.

Dr Wechsler agrees. "We desperately need new therapies for this patient population and better educational efforts for these patients to help them avoid potentially serious outcomes."

This study was supported by a grant from the Agency for Healthcare Research and Quality. The study authors disclosed the following potential conflicts of interest: Dr Wechsler reports receiving grant funding from the National Heart, Lung, and Blood Institute, honoraria from Merck, and consultant fees from GlaxoSmithKline, Novartis, Teva, Sunovion, NKT Therapeutics, Asthmatx/Boston Scientific, Genzyme, MAP Pharma, Genentech, Boehringer Ingelheim, Merck, Cytos, Regeneron, Vectura, Ambit Bioscience, Sanofi, AstraZeneca, Genentech, Meda, Mylan, and MedImmune. Several coauthors report various financial relationships with AstraZeneca, Boehringer Ingelheim, Novartis, Pulmone, Lovelace Respiratory Research Institute, Merck, GlaxoSmithKline, the Respiratory Measurement Advisory Panel for the National Committee for Quality Assurance, the Joint Adjudication Committee for ICON Medical Imaging, Sanofi, Mallinckrodt, Genova Diagnostics, Nova Nordisk, Pfizer, Abbott, Sanofi, Eli Lilly, Amgen, Aeris Therapeutics, the Novartis Institutes for BioMedical Research, UpToDate, Cowen and Company, Infinity Pharmaceuticals, Phillips Respironics, Regeneron Pharmaceuticals, Teva Specialty Pharmaceuticals, Johnson & Johnson, i3 Research (Biota), Genentech, Boehringer Ingelheim, Sunovion, Campbell Trial Lawyers, Fox Rothschild, Ficksman and Conley, Ryan Ryan Deluca, and Crammer, Bishop, and O'Brien, and Research in Real Life. Dr. Gross disclosed financial relationships with DEY, Mylan Laboratories Inc.; Boehringer Ingelheim Pharmaceuticals Inc, GlaxoSmithKline, AstraZeneca Pharmaceuticals LP, Elevation Pharmaceuticals Inc, ALTANA Pharma US, Almirall Prodesfarma SA, Forest Laboratories Inc, and Almirall Prodesfarma, SA.

JAMA. 2015;314:1720-1730. Abstract


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