COMMENTARY

The Best in Pulmonary Medicine

Nicholas J. Gross, MD, PhD

Disclosures

January 19, 2011

In This Article

Cardiovascular Safety of Tiotropium in Patients With COPD

Celli B, Decramer M, Leimer I, Vogel U, Kesten S, Tashkin DP
Chest. 2010;137:20-30

Study Summary

Concerns have been raised about the safety of anticholinergic bronchodilators.[35,36,37] Because these concerns have been published in widely read medical journals and republished in the lay press, and also because anticholinergic agents are very widely used in the maintenance treatment of COPD, the issue needed to be re-examined. Celli and colleagues reviewed the entire clinical trial database of tiotropium bromide and included only those trials lasting longer than 4 weeks and using a randomized, double-blind, placebo-controlled protocol. Nearly 20,000 patients with COPD were involved, half in the tiotropium group, and half in the placebo group. Cumulative exposures to these agents were 13,146 and 11,095 patient-years, respectively.

The relative risk of all-cause mortality in patients taking tiotropium vs placebo was 0.88 (95% CI, 0.77-0.999). The relative risk for any cardiovascular event was 0.83; and for cardiovascular mortality it was 0.77; all the above relative risks were significantly lower in patients who received tiotropium. None of the other risks that were reported showed a significantly higher risk for the tiotropium group. The investigators concluded that "tiotropium was associated with a reduction in the risk for all-cause mortality, cardiovascular mortality, and cardiovascular events."

Viewpoint

The advent of electronic medical databases has made it possible to review enormous amounts of raw information, such as the association of specific treatments with adverse outcomes. With respect to anticholinergic bronchodilators, the retrospective review of large pharmacy databases has seemed to indicate that adverse cardiovascular events including mortality were statistically more common in patients who had received ipratropium and/or tiotropium.[35,36,37] These and a few other similar reports have been of considerable concern to both the profession and our patients. The present report and some others[38,39] contradict the earlier reports and even suggest that the use of tiotropium, now the most widely used anticholinergic bronchodilator, is, if anything, associated with better outcomes than placebo. How can one reconcile these disparate reports?

Two major shortcomings of outcomes derived from pharmacy databases are that there is not an appropriate control group, and it is difficult if not impossible to control for confounding factors such as disease severity. How, for example, does one correct for the likelihood that patients with more severe disease will have received more therapy? Their worse outcomes might be a consequence of greater disease severity, rather than the additional therapy. Nor can other highly relevant risk factors such as smoking status be obtained from a pharmacy database. At best, outcomes based on pharmacy records might suggest trends that could be tested by appropriately designed prospective trials. Meta-analyses are one step above pharmacy databases in terms of quality of evidence because they at least have a defined control group. However, they too may have drawbacks. For example, trials that have different primary outcomes or durations cannot be appropriately conflated. Numerous factors such as the study populations and drop-out rates will inevitably differ, throwing into question the validity of the outcome.

The strongest evidence is that obtained by the prospective, randomized, controlled trials, appropriately powered for a well-defined primary outcome. Fortunately, in the present controversy, a large such trial known as UPLIFT [Understanding Potential Long-Term Impacts on Function with Tiotropium][40] was published. It included 6000 patients with COPD who received either tiotropium or placebo for 4 years. Although safety was not the primary outcome, the data amply support the conclusion that cardiovascular outcomes, including mortality, are if anything, significantly lower when tiotropium is used, even though the patients were free to use any other therapy excluding other anticholinergic agents. The only reservation is that most of the authors of publications favorable to the safety of anticholinergics have close connections to or are employees of the pharmaceutical company that manufactures those agents.

If there is a lesson to be learned from this issue, apart from the Celli and associates' conclusion that tiotropium has not been shown to have cardiovascular risks, it is that the quality of clinical trial evidence is extremely important. One accepts the claims of outcomes based on incomplete, observational, or retrospective data at considerable risk.

Abstract

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