COPD and Safety of Tiotropium: Disproving a Negative?

Andrew F. Shorr, MD, MPH


January 06, 2014

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This is Andy Shorr, from George Washington University in Washington, DC, with the Pulmonary and Critical Care literature update.

I want to highlight an article[1] that was in the October 17 issue of the New England Journal of Medicine. This is the TIOSPIR study, a large randomized controlled trial looking at tiotropium, our prototype of long-acting antimuscarinic agents, administered via 2 mechanisms: the HandiHaler® (Boehringer Ingelheim; Ridgefield, Connecticut) and the Respimat® (Boehringer Ingelheim).

Tiotropium is a crucial tool in our armamentarium to address chronic obstructive pulmonary disease (COPD). The original large, randomized, controlled trial that underscored the value of this molecule, the UPLIFT study,[2] made it relatively clear that this drug was important at reducing the rate of COPD exacerbations in our patients with COPD. Subsequent to that trial, a number of meta-analyses have reached conflicting results regarding the safety of tiotropium delivered either via the HandiHaler, which is what we currently use, or via the newer mechanism, the Respimat. The focus has been on cardiovascular toxicity.

The cardiovascular safety of tiotropium was of concern before UPLIFT, but UPLIFT, which was a placebo-controlled trial, showed no signal of cardiovascular toxicity. After that trial and considering the studies with the Respimat, several meta-analyses have suggested there might be cardiovascular toxicity associated with the Respimat device that is not seen with the HandiHaler device. Why might that be? Well, compared with the HandiHaler, the Respimat uses a different technology that potentially allows the delivery of more drug to the lung and perhaps, therefore, more systemic absorption. That might point to a mechanism that would biologically explain or support the hypothesis that there is a safety concern with the Respimat device.

In order to address this concern specifically and forthrightly, these investigators conducted a nearly 17,500-person study, randomly assigning patients with COPD to 1 of 3 arms: a low-dose Respimat arm for tiotropium, a higher-dose Respimat arm for tiotropium, and then the standard tiotropium dose for the HandiHaler. On average, these patients were followed for nearly 2.3 years; some longer, some shorter. This was an event-driven trial, not a time-driven trial.

The primary endpoint for this study was all-cause mortality, but the investigators looked at a number of important secondary endpoints, such as cardiovascular-related toxicities and time to first exacerbation of COPD -- all of which are crucial issues that we would need to understand if we are going to understand how the Respimat device could be used or could replace the traditional HandiHaler.

In this study, the patients tended to have what you would expect for COPD. The mean FEV1 was at about the 50% range; nearly two thirds of patients were on other agents besides the tiotropium, including inhaled corticosteroids and long-acting beta-agonists (LABAs); and about one third continued to smoke. Thus, it was essentially an appropriate population in terms of generalizability.

When they looked at mortality, the mortality rate was approximately 7.5% in each of the 3 arms -- the traditional HandiHaler arm and then the 2 Respimat arms. When they pooled the 2 Respimat arms to compare the Respimat combined vs the HandiHaler, they found no difference in mortality. Again, with a very long follow-up period, there was no difference in mortality between these 2 devices.

In addition, there was no difference in cardiovascular toxicity profiles between these devices, and both drugs tended to be very well tolerated. Of importance, investigators in this trial made an effort to specifically include patients with underlying cardiovascular disease, either ischemic disease or stroke. About 10%-15% of the patients had a history of such cardiovascular diseases; they were not excluded from the trial. That population again was not the largest part of the population, but in the subgroup analyses of these patients, there was no signal of a difference in terms of morbidity or mortality. Again, by taking on that challenge, it really helps conclusively answer some questions.

Safety issues are always a challenge, because you are being asked to disprove a negative. Essentially, no initial clinical trial ever answers enough safety questions. Our history of drug development in this country is littered with examples of drugs that were approved on small to medium sample sizes, and when introduced to a larger and more diverse marketplace, new toxicities became evident.

The beauty of TIOSPIR is that it is a very large, 17,000-person study with a very long follow-up period. As the accompanying editorial says, “This essentially conclusively answers this question about safety.” It also demonstrates an important principle when you look at the literature. The meta-analyses cannot be considered conclusive; they can be considered hypothesis-generating. Sometimes for some disease states, that is the best we're going to get because of the sample size; but when we have definitive, large, randomized, controlled trials, that is the way to go.

Basically, the experience with UPLIFT and TIOSPIR demonstrates that we can execute these large, randomized, controlled trials in pulmonary populations, particularly those with COPD, and do it very expeditiously. So we should now hold ourselves to the standard of expecting these kinds of studies to help guide our therapy.

The article, again, is in the October 17 issue of the New England Journal of Medicine. I think it’s an important article for us to look at as pulmonologists who treat COPD.

This is Andy Shorr from Washington, DC. Thank you.


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