Should We Turn To Tiotropium?

Author(s)
Oralia V. Bazaldua, Pharm.D., FCCP, BCPS

Reviewed By
Katie Kiser, Pharm.D., BCPS
William Linn, Pharm.D.

Citation
Peters SP, Kunselman SJ, Icitovic N, et al. Tiotropium bromide step-up therapy for adults with uncontrolled Asthma. N Engl J Med. 2010; 363: 1715-1726.

Step one, short-acting beta agonists (SABA) as needed.  Step two: low dose inhaled corticosteroids (ICS). Step three, increase to medium dose ICS or add a long-acting beta agonist (LABA).  These are the preferred steps that are recommended by current asthma guidelines.¹  But is there a better option for step three?  A recent double-blind, three-way, crossover trial set out to answer this question.² Would the addition of tiotropium, a long-acting anticholingergic approved for the treatment of COPD, be useful for the management of chronic asthma?  More specifically, how does adding tiotropium to low dose ICS compare to either doubling the dose of ICS or to adding salmeterol to low dose ICS? The current options (increase ICS or add LABA) have their shortcomings and safe alternatives are needed for clinicians to manage chronic asthma in adults.  Medium dose ICS seems to be an appropriate step but many patients remain symptomatic.³  The use of LABA agents may increase the risk for severe exacerbation of asthma symptoms, leading to hospitalizations as well as death in some patients.⁴  Is tiotropium a safer and more effective alternative?

The Tiotropium Bromide as an Alternative to Increased Inhaled Glucocorticoid in Patients Inadequately Controlled on a Lower Dose of Inhaled Corticosteroid (TALC) study explored two hypotheses: (1) the addition of tiotropium to low dose ICS would be superior to doubling the dose of ICS, and (2) the addition of tiotropium to low dose ICS would not be inferior to the addition of a LABA.  A total of 210 adult patients with inadequately controlled asthma were randomized to this double-blind, three-way, cross-over trial.  Patients were at least 18 years, had a history of confirmed asthma, an FEV₁ > 40% predicted and a non-smoking status (<10 pack-years).  The primary outcome was the morning peak expiratory flow (PEF), but a number of secondary outcomes were also evaluated.  Patients were randomized to one of three initial treatments for 14 weeks: (1) low dose ICS plus tiotropium, (2) double-ICS, (3) low dose ICS plus salmeterol.  After 14 weeks, patients had a 2-week wash out period and then crossed-over to one of the other treatments for another 14 weeks.  Patients were then crossed-over for a third treatment period.  During the washout periods, patients were only treated with low dose ICS (beclomethasone 80 mcg twice daily) and data collected during the washout served as baseline data for the next treatment period.

Outcome Measures and Mean Difference in Change from Baseline

Measure	Baseline	Tiotropium vs. Double ICS	Tiotropium vs. Salmeterol
		Drug favored (if any)	Drug favored
		Change from baseline	(if any)
		MD = Mean difference
Primary Outcome
Morning PEF (L/min)	377 + 117	Tiotropium
		24.4 vs. -1.4 (MD=25.8)
Secondary Outcomes
Evening PEF (L/min)	383.6 + 119	Tiotropium
		29.6 vs -5.7 (MD=35.3)
Albuterol rescue use (puffs/day)	1.71 + 2.09	-0.11 vs. -0.07
		(MD= -0.05)
Mean daily symptoms [scale of 0-3 (3=severe)]	0.46 + 0.44	Tiotropium
		-0.09 vs. 0.03
		(MD= -0.11)
Proportion of Asthma control days	0.212 + 0.331 (77 +120 days/year)	Tiotropium
		0.131 vs. 0.051 (MD=0.079)
		48 vs.19 days/year more
Pre-bronchodilator FEV1(liters)	2.31 + 0.77	Tiotropium	Tiotropium
		0.12 vs. 0.02 (MD=0.10)
Asthma Symptom Utility Index Score             [scale of 0 – 1 (1=best)]	0.78 + 0.15	0.03 vs. 0.00 (MD=0.03)
Asthma Control Questionnaire score [scale of 0–6 (6=worse)]	1.64 + 0.73	Tiotropium
		-0.22 vs. -0.03
		(MD= -0.18)
		MID = 0.5
Asthma Quality of Life [scale of 0-7 (7=best)]	5.43 + 1.05	0.15 vs. 0.05 (MD=0.10)
FEV1 after 4 puffs of albuterol (liters)	2.64 + 0.82	Tiotropium	Tiotropium
		0.02 vs. -0.02 (MD=0.04)

MID=minimal important difference

One hundred and seventy four patients completed the study.  With regard to the primary outcome, those treated with tiotropium plus low dose ICS had a PEF that was 25.8 L/min higher than patients receiving a double dose of ICS.  Although statistically significant, one has to consider whether this is a clinically important difference.  For secondary outcomes, a statistical benefit was observed in favor of tiotropium with regard to evening PEF, daily symptoms, proportion of asthma control days, pre-bronchodilator FEV₁, score on Asthma Control Questionnaire and the FEV₁ after 4 puffs of albuterol.  When compared to salmeterol, the overall effects of tiotropium appear to be equivalent and it was deemed “non-inferior.”  The only two measures that favored tiotropium when compared to salmeterol were the pre-bronchodilator FEV₁ and the FEV₁ after 4 puffs of albuterol.  Considering the concern of a small but statistically significant increase in asthma-related deaths and life-threatening experiences with the use of salmeterol,⁵ the non-inferiority of tiotropium is certainly attractive.

At first glance, the results of this study might lead us to change our practice and start using tiotropium routinely as part of add on treatment for patients with asthma that is not well controlled on standard therapies.  However, a closer look reveals that these results are not a justification for practice change.  Even the authors of the study admit that “our findings cannot be considered clinically directive.”²  They appropriately point out that this study did not examine the rate of asthma exacerbations or long-term safety issues.

According to current asthma guidelines, measures to assess severity and control include: (1) symptoms, (2) use of SABAs for quick relief, (3) limitations to normal activities, (4) pulmonary function, and (5) exacerbations.¹  Let’s examine each one of these outcomes with respect to the TALC study.  Tiotropium did have a statistical advantage over doubling the beclomethasone dose with respect to daily symptoms but not when using the Asthma Symptom Utility Index Score.  While the Asthma Control Questionnaire Score favored tiotropium, a clinically important difference (MID) of 0.5 was not achieved.  With regard to the use of SABAs for rescue, tiotropium was not better than doubling the ICS dose.  If we use the Asthma Quality of Life scale to evaluate the effects of tiotropium on limitations to normal activities, there was no benefit when compared to doubling the beclomethasone dose.  Using the PEF as a measure of pulmonary function, tiotropium did have a statistical advantage.  It improved the morning PEF by 24.4 L/min which was 25.8 L/min higher than using double ICS.  If we use the author’s definition of clinically important lung-function response (increase in morning PEF of ³7.5%), the 24.4 L/min observed increase is only a 6.5% change from a baseline (377.2 L/min).  To be fair, an increase in PEF of 24.4 L/min is comparable to other trials which have shown a therapeutic benefit and exceeds the threshold for the minimally perceptible benefit.^6,7  Whether the improvement seen in PEF with tiotropium is clinically relevant is yet to be determined and will need further exploration. Moreover, the study period was not long enough nor was the study powered to examine asthma exacerbations.  I think the most compelling data in this study are the proportion of asthma control days.  The trial was powered to detect a proportional difference of 0.07 or 25 days per year.  At baseline, the average number of asthma control days was 77 for most patients.  This number of days per year was increased by 48 days with tiotropium compared to 19 days with double ICS.

So should we start using tiotropium routinely in the chronic management of asthma? Not so fast, in my opinion. While this study is certainly promising, long-term studies evaluating asthma exacerbations and safety are needed.  While the FDA determined that tiotropium is not associated with an increased risk of cardiovascular events or death, a critical question still needs to be explored:  Is the long-term use of tiotropium in asthma patients safer than LABA therapy?⁸ Moreover, cost issues must also be considered.  Tiotropium is still more expensive than LABAs such as salmeterol and formoterol⁹ and certainly more expensive than generic inhaled corticosteroids.  Some clinicians have already started substituting tiotropium for LABAs.⁸  Have you?   Under what circumstances would you?