Tiotropium for Mild to Moderate COPD

Worldwide, about 1 in 10 adults have chronic obstructive pulmonary disease (COPD). Although 70% of cases are mild to moderate in severity, we know little about treatment efficacy for mild disease. Most major, randomized COPD inhaler trials enrolled patients with moderate to severe disease.[1,2,3,4] With COPD, the lung function decline is progressive, and once lung is lost, it does not return. It seems reasonable to wonder whether intervention earlier in the disease course might improve outcomes. Given their sheer number, effective treatment for patients with mild disease would have a major impact on overall disease burden.

The concept is not without controversy. Although some have come close, no currently marketed inhaler therapies definitively slow lung function decline or affect mortality.[5] Also, patients with mild COPD are relatively asymptomatic. While legions of studies show that patients with mild COPD have respiratory impairment with activity,[6,7,8] it’s not clear that inhalers alone will increase activity levels. So, what’s the point?

A recent, randomized, placebo-controlled trial[9] published in the New England Journal of Medicine adds fuel to this fire. The authors enrolled 841 patients with mild-to-moderate COPD and compared treatment with tiotropium versus placebo. The primary outcome was change from baseline in prebronchodilator forced expiratory volume in 1 second (FEV1). There were a host of important secondary outcomes measuring change in symptoms (using COPD Assessment Test [CAT], modified Medical Research Council [mMRC] dyspnea scale, and Clinical COPD Questionnaire scores) and time to exacerbation. They followed patients for 24 months. They just missed significance for their primary outcome, while a host of secondary outcomes, including change from baseline in postbronchodilator FEV1, did show significance.

There is a lot to like here. Although more than half of the subjects met criteria for moderate disease, greater than 70% had a CAT <10, and the average mMRC was <1.0. The placebo group averaged only one exacerbation every 2 years. So even though they were not all mild by spirometric criteria, they were not particularly sick. This is the population we would want to study, and the results are encouraging. There is room for debating the difference in decline seen with post- but not prebronchodilator FEV1, but I would not bother. The effects on exacerbations and symptoms are impressive enough.

The 2017 Global Initiative for Chronic Obstructive Lung Disease guidelines already recommend a bronchodilator (short- or long-acting) for “Group A” disease.[5] Should that bronchodilator be daily tiotropium as opposed to a short-acting agent taken as needed? There are significant cost differences, and the debate will continue. That said, I’m leaning toward using a daily long-acting agent. The secondary outcomes are enough to convince me.

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