Pragmatic Trials Point to Equivalence of LTRAs for Asthma

Two "pragmatic" studies of leukotriene receptor antagonists in real-world asthma patients fell just short of demonstrating the drugs’ equivalence with inhaled glucocorticoids as first-line therapy and with beta-agonists as add-on therapy for exacerbations, according to a report in the May 5 issue of the New England Journal of Medicine.

Leukotriene receptor antagonists (LTRAs) met the criteria for equivalence to the other medications at 2-month follow-up, a time point that "represents a standard efficacy period" in most clinical trials. But LTRAs fell just shy of meeting the criteria for equivalence at 2-year follow-up, and that was the primary outcome measure for both studies, said Dr. David Price of the University of Aberdeen (Scotland) and his associates.

Despite this negative finding, "our [results] suggest that there is little difference in real-world effectiveness between an LTRA and an inhaled glucocorticoid as first-line controller therapy and between an LTRA and a long-acting beta-agonist as an add-on to an inhaled glucocorticoid," they said.

"Caution is needed in interpreting the results of these pragmatic trials," they noted.

In a perspective piece accompanying Dr. Price’s report, James H. Ware, Ph.D., and Dr. Mary Beth Hamel agreed, citing the "many challenges" involved in conducting pragmatic trials and interpreting their findings (N. Engl. J. Med. 2011;364:1685-7).

But "despite the trials’ limitations, the data provide encouraging evidence of equivalence or near-equivalence of the treatment strategies over the course of 2 years. Though imperfect, they provide helpful guidance for clinical care," said Dr. Ware, professor of biostatistics at Harvard School of Public Health, Boston, and a statistical consultant to the New England Journal of Medicine, and Dr. Hamel, also of Harvard and a deputy editor of the journal.

The two studies, conducted in parallel at 53 primary care practices throughout the United Kingdom, were funded primarily by the U.K. Health Technology Assessment Programme "for the explicit purpose of informing guidelines for asthma management in the British National Health Service," Dr. Ware and Dr. Hamel noted.

Both studies were unblinded and sought to enroll a broad spectrum of asthma patients aged 12-80 years, so as to reflect the complexity and diversity of routine clinical practice. However, because the studies ended up with very few subjects younger than 25 years of age, "our findings apply only to adults," Dr. Price and his colleagues said.

In the first study, 306 patients were randomly assigned to open-label treatment with either an LTRA (montelukast or zafirlukast) or an inhaled glucocorticoid (beclomethasone, budesonide, or fluticasone) as first-line therapy. Mean scores on the Mini Asthma Quality of Life Questionnaire (MiniAQLQ) were equivalent between the two groups at 2 months, as were secondary end points of the frequency of exacerbations and mean scores on the Asthma Control Questionnaire, the Royal College of Physicians three-item questionnaire (RCP3), and the Mini Rhinoconjunctivitis Quality of Life Questionnaire.

All these secondary end points also were equivalent at 2-year follow-up. But mean scores on the MiniAQLQ did not meet the prespecified criteria for equivalence at 2 years.

In the second study, 352 patients whose asthma was not well controlled with inhaled glucocorticoids were randomly assigned to open-label add-on treatment with either an LTRA or a long-acting beta-agonist. Again, mean scores on the MiniAQLQ demonstrated equivalence of the two medications at 2 months, as did all the secondary end points at both 2 months and 2 years.

But again, the primary end point of mean scores on the MiniAQLQ at 2 years fell just outside the prespecified criteria for equivalence.

These results "suggest that an LTRA is equivalent to both comparison drugs with regard to the effect on asthma-related quality of life at 2 months in a diverse patient population with asthma," the investigators said (N. Engl. J. Med. 2011;364:1695-707).

However, they also "suggest that caution should be applied in extrapolating results from randomized clinical trials to the broad population of patients with asthma who are treated in community settings."

In both of these trials, leukotriene receptor antagonists were "essentially equivalent" in efficacy – findings that challenge current guidelines that favor inhaled glucocorticoids, according to Dr. Sven-Erik Dahlen and Dr. Barbro Dahlen of the Karolinska Institutet, Stockholm, and Dr. Jeffrey M. Drazen, editor in chief of the New England Journal of Medicine.

"The data reported by Price et al. send an important message to both the family doctor and the hospital specialist," they said in an editorial (N. Engl. J. Med. 2011;364:1769-70) accompanying Dr. Price’s report.

"Oral leukotriene modifiers provide an alternative treatment that may help patients pursue their activities of daily life as effectively as inhaled glucocorticoids do."