Spiriva (Tiotropium) for Uncontrolled Asthma
Most people with asthma can achieve good control with inhaled corticosteroids (ICS) and a long-acting beta-agonist (LABA). Some people living with asthma, though, experience persistent symptoms despite maximum doses of these inhaled medications. Fairly or not, LABAs have also been sullied with an FDA black-box warning for worsening bronchospasm in a small minority of people.
Three short-term studies have shown the potential benefits of tiotropium (Spiriva) as an step-up therapy for asthma uncontrolled by inhaled corticosteroids, including one NIH-funded study in the New England Journal in 2010 that suggested tiotropium was at least as good as the LABA salmeterol as an add-on therapy to ICS in improving spirometry and asthma symptoms.
Boehringer Ingelheim and Pfizer can now boast of 2 more randomized trials showing modest benefits of tiotropium in asthma uncontrolled by ICS and LABAs -- these lasting for almost a year of follow-up. Their sponsored investigators' findings are in the September 27, 2012 New England Journal of Medicine.
What They Did
907 adults with symptomatic asthma (>1.5 on the Asthma Control Test) and persistent airflow limitation (FEV1 < 80%) after albuterol while taking daily inhaled corticosteroids and long-acting beta agonists, who had smoked less than 10 pack years or never, and who had had a systemic steroid-treated asthma exacerbation in the past year, were enrolled into 2 identical randomized trials. They inhaled tiotropium 5 μg daily or placebo for 48 weeks, in addition to their ICS + LABA and any other asthma medicines (doses stable throughout the trials).
Change in FEV1 (peak and trough) measured at 24 weeks were the primary endpoints, and exacerbations, symptoms, and peak flows were also measured after 48 weeks.
What They Found
Tiotropium, when added to inhaled corticosteroids and long-acting beta agonists, slightly improved lung function, with improvements in peak and trough FEV1s over placebo by about 5-9% predicted (~88 mL improvements in one trial, ~125 mL in the other, measured at 24 weeks).
Most patients did not have severe asthma exacerbations, in either group. Tiotropium appeared to reduce severe exacerbations:
- Only 27% of tiotropium users vs. 33% of placebo users had a severe exacerbation during the trial.
- This was an absolute reduction of 27 severe exacerbations, and of 0.07 severe exacerbations per patient year, or a number needed to treat of 15 for one year to prevent one severe exacerbation.
- Among the first 25% that did have a severe exacerbation, those in the tiotropium group had a delay to the time of their first asthma exacerbation: 282 days vs 226 days.
Interestingly, there were no clinically meaningful differences between groups on multiple measures of daily asthma symptom control or asthma related quality of life (ACQ, AQLQ, symptom diaries), and no difference in daily rescue albuterol use.
Authors say serious "drug-related cardiac events" occurred in 2 patients (0.4%) taking tiotropium and 1 (0.2%) taking placebo; no deaths occurred. In the appendix, it looks like these might have been "coronary occlusion" and arrhythmia. Patients with known cardiovascular disease were excluded from the trials.
Two patients taking tiotropium had life-threatening asthma exacerbations (vs. none who were taking placebo), although "asthma" as an adverse event was reported much more often in the placebo group.
What It Means
Boehringer Ingelheim, makers of Spiriva, would surely be bronchospastic with excitement to get an FDA indication for asthma. It's hard to predict whether these trials will tip the balance in their favor, although they surely can't hurt. Although the average benefit in the trial was small, it would arguably be unfair to expect miraculous improvements in asthma among patients already on inhaled steroids and long-acting beta agonists. This trial could also provide the basis for a larger trial testing Spiriva head-to-head against LABAs as an add-on therapy to inhaled steroids, which if successful could change prescribing patterns dramatically.
Based on these results, Spiriva would certainly help some of the many thousands of people with refractory asthma ... but be prescribed empirically as a trial of therapy to countless more without it. For perspective, a number needed to treat of 15 with tiotropium for one year to prevent an exacerbation translates to about $30,000 per severe asthma exacerbation prevented; this sticker-shock-inducing figure doesn't include any potential daily benefits of Spiriva for asthma symptoms, or prevention of milder exacerbations.
Since patients with cardiac disease were excluded from the trial, and events were rare, it's hard to conclude anything more than what FDA said in 2010 about tiotropium's safety. Boehringer-Ingelheim is reportedly conducting a study of over 17,000 patients taking Spiriva to confirm its safety, with results expected in 2014.
Kerstjens HAM et al. Tiotropium in Asthma Poorly Controlled with Standard Combination Therapy. N Engl J Med 2012; 367: 1198-1207.