“Asthma’s been bugging me again, Doc,” intones the 72-year-old woman in front of you, “Saw this ad in a magazine and I think it might help.” As Mrs. Jackson fishes the crumpled advert from her purse, you look at your clinic notes. Multiple co-morbidities, medication intolerances, and confessions of previous treatment non-adherence seem to stare right back. In a spiraling vortex of therapeutic existentialism, you begin to wonder: Do the asthma clinical trial data apply to this complicated elderly smoker? When study nurses aren’t there to promote medication adherence and proper inhaler technique, will clinical trial efficacy translate into real-world effectiveness? What if the patient’s got some powerful preconceived notions about what kind of treatment will work?
Enter the pragmatic trial: Designed to bridge the chasm between clinical trials and clinical practice, pragmatic trials recruit broadly from typical practice settings, omit study procedures (such as blinding) that are not a part of usual care, and measure outcomes that are important to patients and decision-makers. As a thoughful analysis of pragmatic trials points out, the aim of a pragmatic trial is to produce study conclusions that are applicable to real-world care.
Two such open-label, multi-center, randomized pragmatic trials by Dr. David Price and colleagues are reported in this week’s NEJM. In Trial #1 (the “First Controller” trial), 326 patients with mild persistent asthma but no current controller medication were randomized to inhaled corticosteroids (ICS) or to an oral leukotriene receptor antagonist (LTRA). Trial #2 (the “Add-on Therapy” trial) recruited 361 patients with asthma inadequately controlled by inhaled corticosteroids, randomizing them to an inhaled long-acting beta-agonist (LABA) or an oral LTRA. For both trials, LTRAs were the underdog, at least from the perspective of previous randomized controlled trials and current asthma therapy guidelines.
Did LTRAs meet the standard set by its rivals in the real world? Almost – but not quite. On the Mini Asthma Quality of Life Questionnaire, LTRAs were equivalent to an ICS as “first controller” therapy and equivalent to LABAs as “add-on” therapy at two months. However, statistical equivalency didn’t hold at two years. The authors advise a cautious interpretation of the two-month results. They outline several features of pragmatic trials that are likely to bias their results toward equivalence, such as differential non-adherence, treatment crossover, and the enrollment of a heterogeneous patient population.
Even so, these trials still challenge conventional asthma treatment strategies. They underline the influence that medication adherence can have on real-world effectiveness, as discussed in an accompanying editorial. To some extent, they suggest that an “LTRA First” treatment strategy might be reasonable when adherence to inhaled medications is anticipated to be poor.
“The real world is a messy place,” says pulmonologist and NEJM editor-in-chief Dr. Jeffrey Drazen, “These pragmatic trials do an admirable job of approaching this messiness in a systematic, prospective fashion – one that we hope will be interesting and useful to clinicians, policy-makers, and the broader scientific community.”