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Mortality associated with tiotropium mist inhaler in patients with chronic obstructive pulmonary disease: systematic review and meta-analysis of randomised controlled trials

BMJ 2011; 342 doi: https://doi.org/10.1136/bmj.d3215 (Published 14 June 2011) Cite this as: BMJ 2011;342:d3215

Respimat mist inhaler safety

We read with interest the recent meta-analysis by Singh and
colleagues (1), reporting on increased mortality among users of tiotropium
Respimat mist inhaler, when compared to placebo.

The meta-analysis includes data from five double-blind randomized
controlled trials (RCTs). However, interesting, withdrawal rates were
different between studies. Likewise, all included studies, except one, did
not specify cardiovascular or any other exclusion criteria. This induces
quite massive potential for heterogeneity between the studies. To test for
possible heterogeneity bias, the authors performed statistics and
sensitivity analysis (fixed versus random effects). However, although
random effect analysis is more sensitive in case of heterogeneity, authors
selectively presented sensitivity analysis in the paper. Sensitivity
analysis was shown only for a part of their study, namely, pooled analysis
on studies with tiotropium 10 and 5 microgr versus placebo, showing
similar statistically significant results, and, thereby, stating no risk
of heterogeneity. However, usual recommended dose in clinical practice for
patients with chronic obstructive lung disease is 5 microgr. We performed
an identical fixed versus random effects analysis for studies with
tiotropium 5 microgr versus placebo using RevMan 5 (Cochrane). The fixed
analysis showed point estimates of risk ratio (RR) 1.46, (P= 0.04; 95%
Confidence Interval (CI); 1.01-2.10). The random analysis demonstrated
similar point estimates of RR 1.44, albeit non-significant (P= 0.05; 95%
CI; 1.00-2.08), indicating potential heterogeneity bias in the study.
Singh et al used an additional study in their sensitivity analysis, which
revealed reduced RR for the 5 microgr dose to 1.36 (P=0.09; CI 0.96-1.96).
(2) However, we were unable to locate data to assess study quality, so
inclusion of this study might not be justified.

Celli et al. performed a pooled safety analysis consisting of 30
clinical trials, which found tiotropium to be associated with a reduction
in mortality (3) and the contemporary UPLIFT study with approximately
6000 patients showed lower mortality in patients using tiotropium powder
compared to placebo (4).

Singh and colleagues advocate that biological plausibility for harm
of Respimat mist inhaler could be higher bioavailability of this
formulation compared to the powder, and consider these two formulations as
distinct products. They refer to a study showing 35% higher peak
concentration of tiotropium in steady state after inhalation of 5 microgr
tiotropium solution compared to 18 micro tiotopium powder (11.5 pg/ml and
8.5 pg/ml, respectively) (5). Area under the curve (AUC) in steady state
was 22% higher for solution (26.4 pg h/ml and 21.7 pg h/ml for solution
and powder respectively). The difference was even greater, when
considering 10 microgr Respimat mist.
In contrast, data from Summary of Product Characteristics (Danish Medical
Agency) show that peak concentration of tiotropium in plasma in steady
state was 10.5-11.7 pg/ml with 5 microgr Respimat mist and 17 to 19 pg/ml
after inhalation of 18 microgr tiotropium powder. Steady state trough-
plasma concentration was 1.5-1.7 pg/ml with 5 microgr tiotropium solution
compared to 3-4 pg/ml with 18 microgr tiotropium powder.

The meta-analysis by Singh et al. has several methodological problems
including heterogeneity bias, selectively presented analysis in the paper,
as well as, selective use of pharmacokinetic data to support their
biological plausibility for increased mortality with Respimat mist. To
our opinion, the paper does not document use of tiotropium, in any
administration form, as having increased mortality.

References:

1.Singh S, Loke YK, Enright PL, Furberg CD. Mortality associated with
tiotropium
mist inhaler in patients with chronic obstructive pulmonary disease:
systematic
review and meta-analysis of randomised controlled trials. BMJ. 2011 Jun
14;342:d3215

2.ClinicalTrials.gov. An efficacy and safety study to compare three
doses of BEA 2180 BR to tiotropium and placebo in the Respimat? inhaler.
NCT00528996. 2010. http://clinicaltrials.gov/ct2/show/NCT00528996.

3.Celli B, Decramer M, Leimer I, Vogel U, Kesten S, Tashkin DP.
Cardiovascular
safety of tiotropium in patients with COPD. Chest. 2010 Jan;137(1):20-30.
Epub
2009 Jul 10.

4.Tashkin DP, Celli B, Senn S, Burkhart D, Kesten S, Menjoge S,
Decramer M; UPLIFT Study Investigators. A 4-year trial of tiotropium in
chronic obstructive pulmonary disease. N Engl J Med. 2008 Oct
9;359(15):1543-54.

5.van Noord JA, Cornelissen PJ, Aumann JL, Platz J, Mueller A,
Fogarty C. The efficacy of tiotropium administered via Respimat Soft Mist
Inhaler or HandiHaler in COPD patients. Respir Med. 2009 Jan;103(1):22-9.

Competing interests: No competing interests

29 September 2011
Ljubica V. Andersen
MD, PhD
Lene Hoeimark and Lars Peter Nielsen
Department of Clinical Pharmacology, Aarhus University Hospital, Denmark