Tiotropium Added to Inhaled Steroids, Long-Acting Beta-Agonists Linked to Lower COPD Mortality

Laurie Barclay, MD

August 12, 2009

August 12, 2009 — Tiotropium added to inhaled corticosteroids (ICS) and, long-acting beta-agonists (LABA) in patients with chronic obstructive pulmonary disease (COPD) was associated with reduced mortality rates, according to the results of a cohort study reported in the August 10/24 issue of the Archives of Internal Medicine. However, tiotropium added to other medication regimens had an adverse effect.

"To date, there is mixed evidence on the safety and effectiveness of tiotropium," write Todd A. Lee, PharmD, PhD, from the Center for Management of Complex Chronic Care, Edward Hines Jr VA Hospital in Hines, Illinois, and colleagues. "Our objective was to evaluate the comparative effectiveness of regimens containing tiotropium bromide vs other medication regimens for ...COPD in real-world clinical settings."

The study population consisted of 2 separate cohorts with a diagnosis of COPD in the Veterans Affairs (VA) healthcare system. Patients who were prescribed tiotropium were matched with use of propensity scores for comparison vs patients in a historic cohort before the introduction of tiotropium, with the base case including scores from 0.1 to 0.4.

During follow-up, the investigators determined all-cause mortality, COPD exacerbations, and COPD hospitalizations. These outcomes were evaluated with Cox proportional hazards regression, and exposure to COPD medication regimens was defined in a time-varying manner.

Compared with ICS plus LABA, the regimen of tiotropium plus ICS plus LABA was associated with a 40% reduced risk for death for 42,090 patients in the base case (hazard ratio [HR], 0.60; 95% confidence interval [CI], 0.45 - 0.79). Furthermore, tiotropium added to ICS plus LABA was associated with reduced rates of COPD exacerbations (HR, 0.84; 95% CI, 0.73 - 0.97) and COPD hospitalizations (HR, 0.78; 95% CI, 0.62 - 0.98). In contrast, when tiotropium was combined with 2 other medications, the risk for mortality, exacerbations, and hospitalizations was increased.

"When used with ICS and LABA, tiotropium use was associated with a decreased risk of mortality compared with treatment with ICS and LABA," the study authors write. "However, this result was not consistent in other medication regimens that included tiotropium. Patients and health care providers are often confronted by treatment alternatives with limited information by which to make decisions."

Limitations of this study include difficulty in adequately controlled-for severity differences, possible selection bias, possible confounding by indication, and limited generalizability because 98% of the population consisted of men. In addition, limitations were associated with use of historic controls, the analysis could not capture out-of-system use, and data were unavailable for other important covariates.

"One prominent gap in clinical information is the lack of direct comparisons between treatments, because much of the evidence in clinical practice guidelines comes directly from placebo-controlled trials rather than head-to-head comparisons," the study authors conclude. "Enrolling patients in trials that use rigid inclusion and exclusion criteria often leads to selected populations who may be different from those ultimately using the medication. Thus, to complement results from placebo-controlled trials, comparative effectiveness studies of treatment interventions are increasingly conducted to inform decision making for more general populations."

The Agency for Healthcare Research and Quality, US Department of Health and Human Services, supported this study as part of the Developing Evidence to Inform Decisions about Effectiveness (DEcIDE) program to the Chicago-area DEcIDE Research Center. Dr. Lee has disclosed various financial relationships with ALTANA, Aventis, AstraZeneca, Boehringer-Ingelheim, Chiesi, GlaxoSmithKline, Merck, Novartis, Pfizer, Schering-Plough, Sepracor, and the University of Kentucky.

Arch Intern Med. 2009;169:1403-1410. Abstract

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