There are currently a few types of medications used to treat COPD. Bronchodilators do what they sound like they would, open up the airways. There are two types: anit-cholinergics and beta agonists that work by different mechanisms. Each type has a short acting version lasting a few hours and taken several times a day and a long acting version lasting 12 hours and taken twice a day. In the US, the short acting bronchodilator (SABA) used is albuterol and common long acting bronchodilators (LABA) are salmeterol (Serevent) and formoterol (Foradil). The short acting anticholinergic used is ipratriopum and te long acting anti-cholinergic is tiotropium (TIO) sold as Spiriva. Another common bronchodilator is a combination of ipratropium and albuterol sold as Combivent (there is not yet a combination of the long acting bronchodilators). In addition, inhaled corticosteroids (ICS) have been used to treat COPD, usually in combination with a LABA, such as Advair and more recently Symbicort.
With all of these medications, which one should be used and when? According to the Global Initiative for Chronic Obstructive Lung Disease (GOLD) guidelines (jointly sponsored by the NIH and the World Health Organization), in addition to smoking cessation and other preventative measures such as flu shots, patients are initially to use SABA or ipratropium, and when lung function becomes decreased to add LABA and/or TIO, and reserve adding an ICS for when lung function is worse that 50% of what it should be, especially if there are frequent exacerbations.
So what do the new studies show?
As mentioned previously, the first study published in the Annals of Internal Medicine studied a VA population and found that patients taking ipratropium had significantly higher death rate of about 11%. This was the headline in the media, but the study also found a 20% lower risk of death for patients on ICS and an 8% lower risk of death for patients on LABA.
The second study was a meta-analysis published in JAMA that analysed date from 14,783 patients with COPD and found that patients taking either ipratropium or TIO (or both) had a 58% increase in cardiovascular death, heart attack or stroke when compared to patients taking other meds (Advair, albuterol or placebo). As I mentioned in this post meta-analysis need to be interpreted with caution, using the Avandia meta-analysis as an example, since the more scientifically rigorous long-term, large randomized controlled trials have not showed similar results.
This leads to the recent UPLIFT trial, which was a long-term, large randomized controlled trial (4 years, almost 6000 patients) looking at TIO and its ability do decrease that rate of lung function decline which normally accompanies COPD. The trial showed no difference in this outcome between patients taking TIO and placebo. However, there were fewer exacerbations and improved quality of life. Additionally, there was about 10% relatively fewer deaths, though this result did not reach statistical significance. Thus, though anti-cholinergic medicines may cause some harm, it appears that this is likely mainly for the short acting ipratropium and not for the long acting tiotropium.
Also important to understanding the implications of the results of these three studies, one has to consider the TORCH trial This was also another long term (3 year) large (over 6000 patients) in patients with COPD taking either ICS, LABA or both (Advair) that found a significant reduction in exacerbations and almost (like UPLIFT) decreased death. In addition, a recent analysis of this study showed what UPLIFT (and any other medication for COPD for that matter) could not: preventing the decline in lung function seen with COPD. One downside of TORCH was an increase in pneumonia in patients taking ICS (alone or in combination).
What to do now?
According to the GOLD guidelines, "the effects of oral and inhaled glucocorticosteroids in COPD are much less dramatic than in asthma" and "regular treatment with inhaled glucocorticosteroids does not modify the longterm decline of FEV1 in patients with COPD." The first statement does not seem very evidence based, especially in light of recent data and the later statement is now incorrect.
It is time to update COPD guidelines in light of the new data. Short acting bronchodilators should likely be used with caution given the risk of death, and inhaled corticosteroids (used in combination with a long acting beta agonist) should likely be given a more prominent role given robust exacerbation reduction, disease modifying properties and potential mortality benefit. The UPLIFT study is reassuring for patients using Spiriva.