You’re an asthmatic. You’re on low-dose inhaled corticosteroids (ICS) and you’ve addressed all the lifestyle modifications that your doctor has recommended, but you’re still symptomatic almost every day. It’s clearly time to step-up treatment – but step-up to what? You could increase your ICS dose, or add an inhaled long-acting beta agonist (LABA), or even try something “off label” such as adding an inhaled long-acting anti-cholinergic. But what would be best?
This is exactly the question that Peters et al attempt to address in this week’s NEJM. They report on the NIH-sponsored TALC trial, a double blind, placebo controlled, three-way crossover study examining 210 asthmatics with inadequate symptom control on low-dose ICS. Patients underwent sequential 14-week treatment periods comparing three different strategies: A doubling of their ICS dose, low-dose ICS plus salmeterol (a LABA), or low-dose ICS plus tiotropium (an inhaled long-acting anti-cholinergic). Measures of lung function on each therapeutic strategy were then compared.
The results? The addition of tiotropium produced a morning peak expiratory flow superior to that obtained with a doubling of the ICS dose, and was non-inferior to that obtained with the addition of salmeterol. In the treatment of obstructive lung disease, this is big news: Inhaled anti-cholinergics are currently approved for the treatment of chronic obstructive pulmonary disease, but not for asthma. Evidence to suggest that they are as effective as LABAs is potentially paradigm-shifting, especially since the safety of LABAs in asthmatics remains controversial.
So do the results of TALC indicate that tiotropium should now take a dominant place in the step-up therapy of asthma? It’s almost certainly too early for that kind of breathless excitement. In an accompanying editorial, Dr. Lewis Smith of Chicago’s Northwestern University points out that the study isn’t of sufficient duration or power to detect differences in clinical endpoints. For patients (and payers), this remains a critically important comparative outcome. And although tiotropium appears to be safe among patients with chronic obstructive pulmonary disease, asthmatics are a very different group of patients, and the possibility of a unique safety profile in this group remains a very real concern.
“While this trial shouldn’t necessarily change clinical practice quite yet, it certainly paves the way for further evaluation of inhaled long-acting anti-cholinergics in asthma step-up therapy,“ says pulmonologist and NEJM editor-in-chief Dr. Jeffrey Drazen. “This trial is exciting because it provides some evidence to support what many pulmonologiests have long suspected. It gives us a potential new option that we did not have before.”
A fascinating twist to the TALC story is discussed in a second editorial. Glaxo-SmithKline refused to provide free salmeterol and matching placebo to trial investigators, and the NIH subsequently spent almost a million dollars on these trial materials alone. Do pharmaceutical companies have a moral obligation to sponsor clinical trials that put their products “at risk” of an unfavorable result? The editorialists argue that they do, and that GSK failed in this obligation.
So what’s best for your hypothetically asthmatic self? TALC doesn’t provide a definitive answer, but it suggests that the addition of tiotropium is a promising option. What’s more, it demonstrates that investigator persistence and NIH commitment can move science forward despite the reluctance of sponsors with products potentially “at risk.” At the very least, this last point should cause us all to breathe a little easier.