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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: (Published 14 June 2011) Cite this as: BMJ 2011;342:d3215

Re:Mortality associated with tiotropium mist inhaler? A critical appraisal of the authors' selection and use of previously communicated tiotropium Respimat data

We disagree with Disse and coworkers at BIPI regarding the
cardiovascular and mortality risks of tiotropium mist inhaler.1

Firstly, we used an intention-to-treat analysis that counted deaths
in study 254/255 during the active treatment plus the additional 10 deaths
that occurred during the prespecified trial duration of 12 months cut-off,
as reported in the FDA review. 2, 3 In study 205.251/252 we assigned one
death to tiotropium 5 mcg during the pre-specified post-treatment period
of the trial in accordance with the intention to treat principle of
analysis of randomized controlled trials.4

Secondly, the sponsor's alternative approach to reclassify deaths
during the trial only serves to attenuate unfavorable findings. Despite
this reclassification, the sponsor's analysis in the response letter also
demonstrates a statistically significant increased risk of death,
associated with tiotropium mist inhaler as compared to placebo (RR 1.45,

Thirdly, the marketing status of the 10 mcg tiotropium Respimat
inhaler is not relevant to the validity of demonstrating the plausibility
of a dose-response relationship. The more than two-fold, statistically
significant, increased risk of death seen with the 10 mcg version of
tiotropium Respimat is potentially applicable to certain subgroups. Some
older patients with COPD and chronic renal failure (with creatinine
clearance below 50) may have delayed excretion of tiotropium resulting in
higher mean systemic exposures and cardiovascular toxicity from the
tiotropium 5 mcg inhaler. 5

Fourthly, it is unlikely that differential discontinuations would
explain the result. The sponsor's analytical plan to remove participants
violates the principle of intention to treat analysis of randomized
controlled trials and would result in biased estimates. The sponsor's
pooled analysis reported on the website is cited as showing an increased
risk of mortality with tiotropium Respimat which does not reach
statistical significance with an incidence Rate Ratio of 1.33 (0.92 -
1.92) for mortality. 6 This strong trend is noteworthy considering that
the sponsor's trials were underpowered for the evaluation of safety.

We agree that patient level data are relevant. However unlike our
meta-analysis, the company's pooled analysis demonstrating an excess of
deaths is unavailable to the medical community. There are neither details
on the validity of studies, or the statistical methods used in pooling,
nor an assessment of heterogeneity. Selective outcome reporting bias was
noted for 1205.14 where relatively 'favourable' safety findings on
mortality have been prematurely released while details on patient
characteristics, study methods, and validity of outcome measures remain
unavailable. It is a violation of analytical principles to include a trial
in the primary analysis without being able to assess the details about
trial characteristics. Despite this, the inclusion of "favorable" data
from this study in our primary analysis did not change the significantly
increased risk of death associated with tiotropium mist inhaler.

The ongoing randomized controlled trial TIOSPIR study which compares
two different formulations of tiotropium (Handihaler vs Respimat) will not
provide any useful information on cardiovascular risks. The consent form
for TIOSPIR states "that the higher number of deaths in the trials has not
been considered related to tiotropium." 7 On the contrary, the observed
excess deaths associated with tiotropium Respimat in the two pivotal
trials was confirmed in a third trial, which makes chance an unlikely
explanation for these findings. Tiotropium Respimat has not received
regulatory approval in the United States.

The argument that the causes of death were "diverse" is axiomatic
when the outcome is the composite endpoint of "all cause" mortality.
However, Respimat deaths are mostly cardiac deaths. The excess of deaths
in the subgroup of patients with known rhythm disorders and cardiac
disorders at baseline is largely due to cardiac deaths. There is a
statistically significant eight-fold increased risk of cardiovascular
death with tiotropium Respimat (RR=8.61 95%CI 1.10, 67.23) compared to
placebo in this subgroup of patients.2,6 This increase is much greater
than the three-fold overall risk of death in this subgroup ( RR 3.42, 95%
CI, 1.29-9.07), 2 or the all-cause mortality risk (RR 1.33, 95 % CI, 0.92
- 1.92) included in the current label.

The clinical bottom-line is that there is a reproducible and
consistent increase in mortality with tiotropium Respimat that is
virtually identical in each sensitivity analysis including the one
conducted by the sponsor for which no non-causal explanation has been
offered. Tiotropium can potentially cause serious cardiac events in
patients with arrhythmias and cardiac disorders. Both Respimat and
Handihaler formulations are associated with increased risk of
tachyarrhythmia's. 2,3,7,8,9,10,11 Both formulations are also
consistently associated with serious angina in the large trials including
the Understanding Potential Long-term Impacts on Function with Tiotropium
(UPLIFT) trial and the largest randomized controlled trial of tiotropium
handihaler compared to salmeterol- the Prevention Of Exacerbations with
Tiotropium in COPD (POET-COPD)trial . 9-11 Although clinically significant
in and of themselves, in certain situations supraventricular
tachyarrhythmias and serious angina events also could manifest as
myocardial infarctions, as was observed in the POET-COPD trial or CV
deaths, as was observed in the Respimat studies in a dose-related manner.
1 Thus physicians and patients need to be informed of these serious
cardiac risks associated with tiotropium Respimat and tiotropium

Sonal Singh MD, MPH, Johns Hopkins University, USA

Yoon K Loke MD, MRCP University of East Anglia, UK

Paul Enright MD, University of Tucson, Arizona, USA

Curt D Furberg MD, PhD Wake Forest University, USA

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. Br Med J 2011; 342: d3215

2. Division of Pulmonary-Allergy Drugs Advisory Committee and Office
of Surveillance and Epidemiology, US Food and Drug Administration.FDA
briefing document.
-allergydrugsadvisorycommittee/ucm190463.pdf Accessed July 30, 2011

3. Boehringer Ingelheim. Briefing Document. Tiotropium-Pulmonary
Allergy Drug Advisory Committee. November 2009
-AllergyDrugsAdvisoryCommittee/UCM190466.pdf Accessed July 30, 2011

4. Accessed
July 30, 2011

5. T?rck D, Weber W, Sigmund R, Budde K, Neumayer HH, Fritsche L,
Rominger KL, Feifel U, Slowinski T. Pharmacokinetics of intravenous,
single-dose tiotropium in subjects with different degrees of renal
impairment. J Clin Pharmacol. 2004 Feb;44(2):163-72.

6. Boehringer Ingelheim International. Tiotropium (SPIRIVA?)
RESPIMAT?: Evaluation of Fatal Events - February 2010 Accessed
July 30, 2011
452_20101011.pdf Accessed July 30, 2011

8. Electronic Medicines Compendium. Spiriva Respimat ?--summary of
product characteristics. 2011.
Accessed July 30, 2011

9. Tashkin DP, Celli B, Senn S, et al for the UPLIFT Study
Investigators. A 4-year trial of tiotropium in chronic obstructive
pulmonary disease. N Engl J Med 2008; 359:1543-54.

10. Bateman E, Singh D, Smith D, et al. Efficacy and safety of
tiotropium Respimat? SMI in COPD in two 1-year randomized studies. Int J
Chron Obstruct Pulmon Dis 2010; 5:197-208.

11. Vogelmeier C, Hederer B, Glaab T, Schmidt H, Rutten-van M?lken
MP, Beeh KM, Rabe KF, Fabbri LM; POET-COPD Investigators. Tiotropium
versus salmeterol for the prevention of exacerbations of COPD. N Engl J
Med 2011; 364(12):1093-1103.

Competing interests: All authors have completed the Unified Competing Interest form at (available on request from the corresponding author) and declare: no support from any companies for the submitted work; PE has received about $30, 000 from Pfizer to review the quality of spirometry tests done for an international study of varenicline for smoking cessation in patients with chronic obstructive pulmonary disease; no author has non-financial interests that may be relevant to the submitted work; no other relationships or activities that could appear to have influenced the submitted work.

02 August 2011
Sonal Singh
Yoon K Loke, Paul Enright, Curt D Furberg
Johns Hopkins University