Tiotropium as add-on "triple therapy" for COPD associated with better outcomes - PulmCCM
Dec 172012
Adding Spiriva to LABA and Inhaled Steroid Might Improve COPD

No strong outcomes-based evidence exists as to the benefits in treating chronic obstructive pulmonary disease (COPD) with tiotropium, long-acting beta-agonist and inhaled corticosteroid together -- so called "triple therapy." LABA and tiotropium together do provide additive bronchodilation over either agent alone, evidence suggests. However, only one underpowered randomized trial has reported on adding tiotropium to ICS/LABA (it suggested a small benefit to triple therapy). The most recent U.S. guidelines don't advocate or advise on triple therapy, although 2009 GOLD guidelines encourage triple therapy when symptoms persist on ICS/LABA.

Using National Health Service databases in the UK, Philip Short et al looked retrospectively at 1,857 Scottish COPD patients prescribed ICS + LABA + tiotropium, and compared them to 996 prescribed ICS + LABA, between 2001 - 2010. Mean follow-up was 4 1/2 years.

Those prescribed triple therapy had (all stat. significant):

  • An adjusted hazard ratio for all-cause mortality of 0.65, compared to those taking LABA + ICS only;
  • Adjusted HR for hospitalization of 0.85;
  • Adjusted HR for oral steroid burst of 0.71.

The HRs were regressed for covariates obtainable in the databases: cardiovascular & respiratory disease, diabetes, smoking, age, sex, and socioeconomic level.

A VA study by Lee et al in Archives of Internal Medicine in 2009 made the same conclusion -- tiotropium was associated with better outcomes when added to long-acting beta agonist and inhaled corticosteroid as "triple therapy."

Appropriately, the authors encourage a randomized trial to test this intriguing finding.

What about the safety of tiotropium and its rumored association with cardiovascular events? There's been a stir about this for the past few years, starting in 2007 with Spiriva's manufacturer Boehringer-Ingelheim's donating to the FDA its safety data collected during tiotropium's approval process, which showed a potential signal for increased stroke risk. A 2008 JAMA meta-analysis concluded tiotropium was associated with increased risk for stroke and myocardial infarction. However, the FDA placed much more weight on the UPLIFT trial data, which (unlike the previous two analyses) actually observed for and recorded cardiovascular events rigorously and prospectively, and showed no increased risk. In a NEJM editorial in September 2010, the FDA gave tiotropium a clean bill of cardiovascular health (for now).

Short PM et al. The impact of Tiotropium on Mortality and Exacerbations when added to Inhaled Corticosteroids and Long-Acting Beta-Agonist therapy in COPD. CHEST 2012;141:81-86.

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Tiotropium as add-on “triple therapy” for COPD associated with better outcomes