Re: Authors’ reply to Turgeon and Tejani and to Manderville
In support of their claim that the addition of a long acting beta 2 agonist (LABA) to tiotropium (TIO) is supported by clinical trial evidence, Park et al (1) make reference to a 2011 meta-analysis (2) which showed improvement in FEV1 and symptoms (with LABA + TIO vs TIO alone) . While it is clear that there is no “gold standard” outcome for assessment of treatment response in COPD trials, many clinicians would suggest that change in FEV1 may be less clinically meaningful than other outcomes, such as mortality, exacerbation rate, health related quality of life (QOL), and hospitalizations. Indeed, FEV1 has been found to correlate poorly with dyspnea, health status, exercise capacity, and exacerbations (3-6).
The meta-analysis performed by Wang and colleagues did demonstrate a significant reduction in symptoms (as measured by the transitional dyspnea index) with combination formoterol and TIO, as compared to TIO alone (2). However, this result is based on the data from 4 clinical trials (7-10), 3 of which used nebulized formoterol, a preparation not available in my country, and, I might assume, not commonly used in other countries in the long term, outpatient setting. Furthermore, these 4 trials were of relatively short duration, ranging from 2 weeks to 6 weeks in length. Contrast this with two much longer trials that looked at the effect of the addition of a LABA to TIO vs TIO alone on clinically significant end points: the Vogelmeier et al trial (6 months) (11), which showed no benefit with respect to COPD-related bad days or exacerbation days, symptom scores, or disease-specific QOL, and the Canadian Optimal Therapy of COPD Trial (1 year) (12), which showed no reduction in exacerbation rate, hospitalizations, dyspnea, or a clinically important difference in QOL between the two groups. Based on this data, I will rephrase my previous assertion (13) and state that, in long term randomized controlled trials, the addition of long acting beta agonist therapy to tiotropium has not been shown to have a significant effect (vs tiotropium alone) on clinically important endpoints.
1. Park HY et al. Authors’ reply to Turgeon and Tejani and to Manderville. Park et al BMJ 2012;345:e8375
2. Wang J et al. Comparison of tiotropium plus formoterol to tiotropium alone in stable chronic obstructive pulmonary disease: a meta-analysis. Respirology 2011; 16: 350-358.
3. New Evidence in COPD. Dalhousie CME Academic Detailing Service. March 2009. http://cme.medicine.dal.ca/ad_resources.htm
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7. Hanania et al. Efficacy and safety of nebulized formoterol as add-on therapy in COPD patients receiving maintenance tiotropium bromide: Results from a 6-week, randomized, placebo-controlled, clinical trial. Drugs 2009; 69: 1205–16.
8. Tashkin DP et al. Concomitant treatment with nebulized formoterol and tiotropium in subjects with COPD: a placebo-controlled trial. Respir.Med. 2008; 102: 479–87.
9. Terzano C et al. Rational timing of combination therapy with tiotropium and formoterol in moderate and severe COPD. Respir.Med. 2008; 102: 1701–7.
10. Tashkin DP et al. Effects of arformoterol twice daily, tiotropium once daily, and their combination in patients with COPD. Respir.Med. 2009; 103: 516–24.
11. Vogelmeier C et al. Formoterol mono- and combination therapy with tiotropium in patients with COPD: A 6-month study. Respiratory Medicine 2008; 102, 1511e1520.
12. Aaron SD et al. Tiotropium in Combination with Placebo, Salmeterol, or Fluticasone–Salmeterol for Treatment of Chronic Obstructive Pulmonary Disease. Ann Intern Med. 2007;146: 545-555.
13. Manderville JR. Addition of long acting β agonist is not supported by clinical trial evidence. BMJ 2012;345:e8361.
Competing interests: No competing interests