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
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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,
1.02-2.06).
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
Handihaler.
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
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. 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.
2009.http://www.fda.gov/downloads/advisorycommittees/committeesmeetingmateria...
-allergydrugsadvisorycommittee/ucm190463.pdf Accessed July 30, 2011
3. Boehringer Ingelheim. Briefing Document. Tiotropium-Pulmonary
Allergy Drug Advisory Committee. November 2009
http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMateria...
-AllergyDrugsAdvisoryCommittee/UCM190466.pdf Accessed July 30, 2011
4. http://trials.boehringer-
ingelheim.com/res/trial/data/pdf/205.252_U043343_new_upload.pdf 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
http://trials.boehringer-
ingelheim.com/res/trial/data/pdf/Pooled_Analysis_U10-3255-01.pdf Accessed
July 30, 2011
7.http://www.circare.org/consents/consentform_bipiprotocol205-
452_20101011.pdf Accessed July 30, 2011
8. Electronic Medicines Compendium. Spiriva Respimat ?--summary of
product characteristics. 2011.
www.medicines.org.uk/EMC/medicine/20547/PIL/Spiriva%20Respimat%202.5%20m...
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 www.icmje.org/coi_disclosure.pdf (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.
Singh et al. recently reported the results of a meta-analysis of five
previously published randomized controlled trials communicating a
statistically significant increase in mortality risk associated with
tiotropium mist inhaler in patients with COPD (1). The authors conclude
that this meta-analysis "explains safety concerns by regulatory agencies".
Boehringer Ingelheim (BI) and Pfizer disagree with the authors'
interpretation of the data. The companies believe that the benefits and
risks associated with tiotropium Respimat have been appropriately
communicated through labelling to patients and physicians. All trials
considered for the meta-analysis have been made public either as a full
publication by the study investigators or as a website posting by
BI/Pfizer. Pooled-analyses based on the same dataset, yet evaluating
patient-level data, had been conducted by BI/Pfizer and were submitted to
regulatory authorities worldwide by 2009 with a request to modify
labelling, and were made public (2, 3, 4). The primary analysis was based
on the marketed dose in 4 major studies. The reported numerical, non-
statistically significant increase in all cause mortality was accepted as
an adequate representation of the data and included in the updated Product
Information in 2010, e.g. in the European Union stating: "In a
retrospective pooled analysis of the three 1-year and one 6-month placebo-
controlled trials with Spiriva Respimat including 6,096 patients a
numerical increase in all-cause mortality was seen in patients treated
with Spiriva Respimat (68; incidence rate (IR) 2.64 cases per 100 patient-
years) compared with placebo (51, IR 1.98) showing a rate ratio (95%
confidence interval) of 1.33 (0.93, 1.92) for the planned treatment
period; the excess in mortality was observed in patients with known rhythm
disorders." (5) Therefore, the meta-analysis recently reported by Singh
et al does not convey new information as the numerical mortality imbalance
has been included in the Product Information, which also includes updated
beneficial efficacy information for tiotropium Respimat, e.g. a
significant reduction of hospitalized exacerbations of COPD in the major 1
-year study (5, 6).
We noticed inconsistencies in Singh et al's selection and use of
available data as well as in the analytical approach and derived
conclusions, which merit consideration and can explain the differences
between the Singh analysis and the BI/Pfizer pooled-analysis.
First, Singh et al. have incorrectly assigned fatal cases to
treatment groups, one excess case in the tiotropium 5 mcg group (12-week
study BI code 205.251/2 (3, 7)), one excess case in the tiotropium 10 mcg
group and one missing case in the placebo group (1 year study BI code
205.255 (8)). After correcting the fatal event counts, non-significant
differences between the treatment groups result from a range of
sensitivity analyses except one (see Table 1).
Second, the primary analysis of Singh et al. included only 5 of 6
studies of more than 4 weeks duration reportedly due to missing detail on
trial characteristics. The excluded 6 months study was a randomised,
double blind, placebo controlled study including the approved dose (5 mcg)
of tiotropium Respimat and placebo as comparators (BI study code 1205.14
(3, 9)). The study was comparable in design and patient selection to the
tiotropium programme and included pre-planned follow-up of patients who
were discontinued early.
Third, the primary analysis of Singh et al. combined two doses, the
marketed 5 mcg dose and a 10 mcg dose. Singh et al. refer to the Cochrane
Handbook (10), which recommends "amalgamation of relevant treatment arms
into one group". However, one may question why a primary analysis would
include a non-marketed higher dose for the safety assessment of the
approved and marketed dose. Notably, the Product Information of
tiotropium Respimat advises that the recommended dose of 5 mcg/day should
not be exceeded (5). We recognize, though, that inclusion of the higher
than marketed dose may be appropriate to serve as a sensitivity analysis.
Fourth, the authors combined studies with different standards of
vital status follow-up of early discontinued patients, in which different
censoring rules were applied. In many COPD studies, active treatment
arms, e.g. tiotropium, showed a lower rate of premature discontinuation
than placebo, and patients who were discontinued early typically had more
serious COPD than completers. Such differential discontinuation bias can
induce a healthy survivor effect in control arms. Therefore, vital status
follow-up of all patients and the use of patient level rather than study
level data (e.g. rate-ratios adjusted for different exposure in treatment
arms) are of great importance for the validity of pooled data.
When following the analytical approach of Singh et al., but using the
corrected counts for fatal events, all analyses in Table 1, except one,
show a numerical difference in mortality with a confidence interval
including 1, so descriptive statistical significance was not observed.
The one exception, with a confidence interval not including 1, is the
approach published by Singh et al. as the primary analysis, which includes
the higher not marketed dose plus exclusion of the 6-month study plus
using a fixed effects approach.
Table 1: Sensitivity analyses within 6-study dataset, risk ratios
(RR) with 95% confidence intervals (CI) based on Mantel-Haenszel analysis.
* 1-year studies censored day 369 as reported by Bateman (8), 1-year study censored day 337 as
reported by Bateman (6), 3-months studies on treatment as reported by Voshaar (7), 6-month study
B.I. code 1205.14, on treatment (3, 9).
# Primary analysis following Singh et al. using corrected numbers of fatal events. Singh et al. had
published RR 1.50, CI 1.05, 2.15 (1)
BI/Pfizer had based their primary pooled analysis on patient level
data of the marketed dose of 5 mcg in the four studies, which include
vital status assessment of prematurely discontinued patients (risk
calculated as rate ratios, cases censored for time of planned exposure + 1
day, i.e. 337 days in 1-year studies and 169 days in the 6-months study).
The numerical difference of RR 1.33, CI 0.93, 1.92 is within the range of
results in Table 1, which means the approach by Singh et al. when using
correct data can be regarded a sensitivity analysis to the earlier
BI/Pfizer approach.
Lastly, Singh et al. hypothesize that the mortality imbalance may be
attributed to increased exposure to tiotropium administered through
Respimat Soft Mist Inhaler compared to tiotropium Handihaler (1).
However, a 16% greater exposure at steady state with widely overlapping
ranges of plasma levels describes no meaningful difference in exposure.
Furthermore, peak plasma levels, which rapidly decline, have no impact,
because tiotropium is a slowly equilibrating compound at muscarinic
receptors (11). Notably, another pharmacokinetic investigation showed
comparable systemic exposure with the two formulations (12).
The unexplained numerical increase in all-cause mortality compared to
placebo was concentrated in patients with cardiac arrhythmia at entry into
the study. However, the causes of death were diverse and a causal
relationship between the use of tiotropium Respimat and mortality has not
been established. Important differences between the two formulations,
tiotropium Respimat and Handihaler, could not be identified. Variability
of outcomes and trial related factors may also explain the finding.
A rigorous investigation between the tiotropium Respimat and
Handihaler formulations in a well controlled large outcome study,
including all-cause mortality, is warranted to investigate any
pharmacological differences between the formulations and for a reliable
determination of benefit and risk. Such a study must include an active
comparator with established safety to avoid ethical concerns with
prolonged placebo treatment and bias by trial related factors. TIOSPIR a
large-scale, prospective, randomized outcome study comparing tiotropium
Respimat 5 mcg, 2.5 mcg and Handihaler 18 mcg was designed to assess these
factors. The protocol was approved by health authorities in 50 countries
and the study is supervised by an independent Data Safety Monitoring Board
with access to fully unblinded data, which recommended continued study
conduct, as planned, in June 2011. To date the exposure in this trial of
more than 10,000 patient-years already exceeds the exposure reported in
both, the BI/Pfizer and Singh et al. pooled analyses for tiotropium
Respimat.
The selected active comparator, tiotropium Handihaler, has been
extensively characterised in several prospective, large, well controlled
(placebo and active) trials and pooled-analyses including 26 studies, one
of which was a 4-year study. This analysis of patient level data from
more than 17,000 patients showed a rate ratio for all-cause mortality of
0.85, CI 0.75-0.97 (tiotropium HandiHaler vs. placebo, rate ratio
calculated from rate differences as published (13)). Potential
cardiovascular and mortality risks of tiotropium Handihaler were recently
assessed by a US Food and Drug Administration Advisory Committee (14), who
confirmed that the safety of the product is adequately documented. This
conclusion is also reflected in a publication by FDA staff members
(Michele et al. (15)), so does not confirm an earlier meta-analysis by
Singh et al., that had identified an increased cardiovascular risk with
tiotropium Handihaler (16).
In conclusion, the present knowledge base of tiotropium Respimat Soft
Mist Inhaler has been in the public domain since 2009 and is derived from
rigorous scientific evaluation of all available patient level data. The
Product Information of tiotropium Respimat as updated in 2010 constitutes
an accurate reflection of benefit and risk. The recent meta-analyis by
Singh et al. does not add new clinical information. The suggestion of
confirmatory evidence and biological plausibility is not supported by the
data. Potential differences in efficacy and safety between the two
formulations of tiotropium are being explored in the large outcome study
TIOSPIR.
Bernd Disse, MD PhD, VP Therapeutic Area Respiratory*, Norbert
Metzdorf, PhD, Global Clinical Programme Leader Tiotropium*, Antonio
Martin MD PhD, Medical Affairs Product Lead, SPIRIVA, Allergy and
Respiratory Medical Affairs#, Franklin Cerasoli PhD, Global Therapeutic
Area Lead, Cardiovascular and Metabolic Disease Medical Affairs# Inge
Leimer, PhD, Statistician*, *Boehringer Ingelheim Pharma GmbH&Co KG,
Ingelheim, Germany, # Pfizer Inc, New York, NY, USA
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. 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. 2009.
www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drug...
-AllergyDrugsAdvisoryCommittee/UCM190463.pdf
(3) Boehringer Ingelheim, Briefing Document: Tiotropium (SPIRIVA):
Pulmonary Allergy Drug Advisory Meeting - November 2009
www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drug...
-AllergyDrugsAdvisoryCommittee/UCM190466.pdf
(4) Boehringer Ingelheim International. Tiotropium (Spiriva)
Respimat: evaluation of fatal events--February 2010. 2010. http://
trials.boehringer-ingelheim.com/res/trial/data/pdf/Pooled_Analysis_U10-
3255-01.pdf
(5) Summary of Product Characteristics (SPC): Spiriva Respimat 2.5
micrograms solution for inhalation (United Kingdom):
www.medicines.org.uk/EMC/medicine/20547/PIL/
(6) Bateman ED, Tashkin D, Siafakas N, Dahl R, Towse L, Massey D,
Pavia D, Zhong NS. A one-year trial of tiotropium Respimat plus usual
therapy in COPD patients. Respir Med 2010;104: 1460-1472
(7) Voshaar T, Lapidus R, Maleki-Yazdi R, Timmer W, Rubin E, Lowe L,
Bateman E. A randomized study of tiotropium Respimat Soft Mist inhaler vs.
ipratropium pMDI in COPD. Respir Med 2008;102(1):32-41
(8) Bateman E, Singh D, Smith D, Disse B, Towse L, Massey D,
Blatchford J, Pavia D, Hodder R. Efficacy and safety of tiotropium
Respimat SMI in COPD in two 1-year randomized studies. Int J Chronic
Obstruct Pulm Dis 2010;5:197-208
(9) ClincalTrials.gov: An Efficacy and Safety Study to Compare Three
Doses of BEA 2180 BR to Tiotropium and Placebo in the Respimat Inhaler
www.clinicaltrials.gov/ct2/show/NCT00528996
(10) Higgins, JPT, Green S (eds.) and Sally Green Cochrane Handbook
for Systematic Reviews of Interventions, Version 5.1.0 www.cochrane-
handbook.org/
(11) Disse B, Speck GA, Rominger KL, Witek TJ, Hammer R. Tiotropium
(Spiriva): Mechanistical considerations and clinical profile in
obstructive lung disease. Life Sci 1999; 64(6/7): 457-464
(12) Ichinose M, Fujimoto T, Fukuchi Y. Tiotropium 5 ?g via Respimat
and 18 ?g via HandiHaler; efficacy and safety in Japanese COPD patients.
Respir Med 2010;104(2):228-236
(13) Kesten S, Celli B, Decramer M, Leimer I, Tashkin D. Tiotropium
HandiHaler in the treatment of COPD: a safety review. Int J Chronic
Obstruct Pulm Dis 2009;4:397-409
(14) Summary Minutes of the Pulmonary-Allergy Drugs Advisory
Committee (PADAC), November 19, 2009:
www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drug...
-AllergyDrugsAdvisoryCommittee/UCM196995.pdf
(15) Michele TM, Pinheiro S, Iyasu S. The safety of tiotropium - the
FDA's conclusions. N Engl J Med 2010;363(12):1097-1099
(16) Singh S, Loke YK, Furberg CD. Inhaled anticholinergics and risk
of major adverse cardiovascular events in patients with chronic
obstructive pulmonary disease: a systematic review and metaanalysis. JAMA
2008;300:1439-50. (Erratum in JAMA 2009;301:1227-30.)
Competing interests: Bernd Disse, Norbert Metzdorf and Inge Leimer are full-time employees of B.I., Antonio Martin and Frank Cerasoli are full time employees of Pfizer
Singh and colleague have been suggested that tiotropium mist inhaler
increased the mortality risk up to 52% in patients with chronic
obstructive pulmonary disease (COPD).[1] This type of meta-analysis is
elegant and impressive. However, non-physician analyzers often take
serious mistake. Unfortunately, they do not understand the disease itself
or the patient's condition with disease. Obviously, COPD is not just a
disease, but as a serious disabled status with systemic inflammation.[2]
Although the diagnostic criteria are totally based on the pulmonary
function, the patient's condition is not depended on the pulmonary
function itself. The COPD patients are usually older subjects,
accompanying with the cardiovascular abnormality, locomotive abnormality,
and immune abnormality. The Towards a Revolution in COPD Health (TORCH)
study has revealed that the causes of death in patients with mild COPD are
predominantly cancer and cardiovascular disease.[3] However, the patients
with severe COPD are likely to be dead from non-malignant respiratory
diseases including penumonaia.[4,5] Thus, the mortality of COPD subjects
cannot be analyzed just on the desk. The morality is considerably
affective by the concomitant abnormalities rather than COPD itself.
The most importantly, the overall mortality risk in the current study is
around 1-2 percent of the COPD patients. The aged subjects with COPD
encounter many adverse health threats including cardiovascular and
infectious events. The one or two percent of death may be inevitable in
older patients with COPD irrespective to therapeutic regimens. We
considered overall mortality risk in the older subjects with any disease.
The improved health-related quality of life (QOL) is not always associated
with the good prognosis. However, the good health condition with the very
slightly increased mortality risk may be acceptable in energetic elderly
COPD patients.
Finally, the author have already agitated that tipotropium increased the
risk of stroke in patients with COPD. [6] The similar flaw may be
repeated. The report also based on the very small incidence of a large
number of the patients. The small number of incidence could be analyzed
either rightly or wrongly. The percent changes of the small definite
numbers should be very carefully assessed by general physician in clinical
setting, but not by non-physician scientific statisticians in office
settings.
Reference List
[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; 342:d3215.
[2] Fabbri LM, Rabe KF. From COPD to chronic systemic inflammatory
syndrome?
Lancet. 2007;370(9589):797-9.
[3] Calverley PM, Anderson JA, Celli B, Ferguson GT, Jenkins C, Jones
PW, Yates JC, Vestbo J; TORCH investigators. Salmeterol and fluticasone
propionate and survival in chronic obstructive pulmonary disease.N Engl J
Med. 2007 Feb 22;356(8):775-89.
[4] Sin DD, Tashkin D, Zhang X, Radner F, Sj?bring U, Thor?n A,
Calverley PM, Rennard SI. Budesonide and the risk of pneumonia: a meta-
analysis of individual patient data. Lancet. 2009 Aug 29;374(9691):712-9.
[5] Berry CE, Wise RA. Mortality in COPD: causes, risk factors, and
prevention. COPD. 2010 ;7(5):375-82.
[6] Singh S, Loke YK, Furberg CD. Inhaled anticholinergics and risk
of major adverse cardiovascular events in patients with chronic
obstructive pulmonary disease: a systematic review and meta-analysis.
JAMA. 2008;300(12):1439-50.
Competing interests: No competing interests
The meta-analysis reported by Singh et al (1) indicated an increased
risk of all cause mortality for tiotropium delivered with the Respimat
Soft Mist Inhaler when compared to a placebo group. They observe that no
such mortality increase has been demonstrated for tiotropium delivered
with a Handihaler device. The only biologically plausible mechanism
offered by the authors to explain possible differential toxicity for these
two modes of tiotropium delivery is an increase in cardiovascular deaths
resulting from the higher peak plasma concentrations of tiotropium
achieved when delivered by the mist inhaler as compared to the Handihaler.
They acknowledge the limitations of their study in establishing cause
specific reasons for mortality differences.
One other potential difference in toxicity between the two modes of
delivery relates to the excipients. The only excipient present in the
capsules for use in the Handihaler is lactose. One of the four excipients
present in the solution for use in the Respimat Soft Mist Inhaler is the
biocide, benzalkonium chloride, which has been reported to cause
bronchospasm in asthmatics when present in nebuliser solutions.(2)
Furthermore several cases (3-6) of occupational asthma resulting from
sensitisation to this chemical have been reported following a latent
period of exposure in the workplace with confirmation by specific
inhalation challenge testing. Whilst the airways of patients with chronic
obstructive pulmonary disease (COPD) may not demonstrate the same irritant
reactivity exhibited by some asthmatics using nebulisers containing
benzalkonium chloride they may be prone to immunological sensitisation and
subsequent bronchospasm on inhaling small quantities of the chemical.
No data seems to be available on whether the excess mortality
associated with the tiotropium mist inhaler can be explained by acute
bronchoconstriction in patients with underlying COPD but it may be worthy
of consideration as a possible alternative biologically plausible
mechanism.
Martin J Seed - consultant occupational physician, Centre for
Occupational and Environmental Health, University of Manchester,
Manchester M13 9PL, UK martin.seed@manchester.ac.uk
Raymond Agius - professor of occupational and environmental
medicine, University of Manchester, Manchester, UK
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;342:d3215.
2 Beasley CRW, Rafferty P, Holgate ST. Bronchoconstrictor properties
of preservatives in ipratropium bromide (Atrovent) nebuliser solution.
BMJ 1987;294:1197-8.
3 Innocenti A. Occupational asthma due to benzalkonium chloride.
Med Lavoro 1978;69:713-5.
4 Bernstein JA, Stauder T, Bernstein DI, Bernstein IL. A combined
respiratory and cutaneous hypersensitivity syndrome induced by work
exposure to quaternary amines. J Allergy Clin Immunol 1994;94:257-9.
5 Burge PS, Richardson MN. Occupational asthma due to indirect
exposure to lauryl dimethyl benzyl ammonium chloride used in a floor
cleaner. Thorax 1994;49:842-3.
6 Purohit A, Kopferschmitt-Kubler M-C, Moreau C, Popin E, Blaumeiser
M, Pauli G. Quaternary ammonium compounds and occupational asthma. Int
Arch Occup Environ Health 2000;73:423-7.
Competing interests: No competing interests
Dear Sir,
COPD is always a disease of the pulmonary artery system. (1)
Only low-dose Coumarin (INR 2,0) is a beneficial drug in
seriously ill patients.
Recurrent pulmonary artery thrombo-embolism should be prevented.
And there will be no studies, because Coumarin is too cheap.
And nobody will pay for such studies.
Best wishes
Yours, Friedrich Flachsbart
1. W. M. Thurlbeck, A. M. Churg: Pathology of the Lung
Sec. Edition.
Thieme Medical Publishers Inc., New York, 1995
Competing interests: No competing interests
Bronchodilating agents, like tiotropium, are the cornerstone of
symptomatic COPD management.[1] Contrary to the recent reported safety of
tiotropium administered as dry powder,[2] Singh et al. observed such a
dose-dependent hazardous (cardiovascular) effect by soft mist inhalers.[3]
Both studies are well-designed meta-analyses on rather severe COPD
patients. As tiotropium has an increased systemic uptake by soft mist
inhalation, the disparity in safety profiles was attributed to the
difference in delivery devices, although device differences would be
difficult to untangle from other trial differences and none of the
included studies were primarily designed for analysing (cardiovascular)
mortality.[3;4]
However, baseline cardiovascular disease was not tested for its
effect on outcome, and both studies used different measures for smoking
history which was not analysed for its modifying effect in the Respimat
study.[3] Moreover, substantial smoking (>55 packyears) may have a
modifying effect on the cardiovascular benefit obtained from tiotropium
dry powder.[2] In addition, a subgroup analysis revealed that the
mortality reduction by tiotropium dry powder did not apply for patients
that continued to smoke.[5]
We wonder if part of the reported discrepancies could indeed be the
result of an interaction between bronchodilators and smoking, in which
bronchodilators influence the pulmonary deposition and hence the toxicity
of cigarette smoke.[6] In other words, do we need to worry specifically
about COPD patients that continue smoking during their bronchodilating
treatment?
Reference List
[1] Global Strategy for the Diagnosis, Management and Prevention of
COPD, Global Initiative for Chronic Obstructive Lung Disease (GOLD),
updated 2010. www.goldcopd.org. accessed 2011.
[2] Rodrigo GJ, Castro-Rodriguez JA, Nannini LJ, Moral VP, Schiavi
EA. Tiotropium and risk for fatal and nonfatal cardiovascular events in
patients with chronic obstructive pulmonary disease: Systematic review
with meta-analysis. Respir Med 2009.
[3] 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; 342.
[4] Cates CJ. Safety of tiotropium. BMJ 2011; 342.
[5] Tashkin DP, Celli B, Kesten S, Lystig T, Mehra S, Decramer M.
Long-term efficacy of tiotropium in relation to smoking status in the
UPLIFT trial. Eur Respir J 2010; 35(2):287-294.
[6] van Dijk WD, Heijdra Y, Scheepers PT, Lenders JW, van Weel C,
Schermer TR. Interaction in COPD experiment (ICE): A hazardous combination
of cigarette smoking and bronchodilation in chronic obstructive pulmonary
disease. Med Hypotheses 2010; 74(2):277-280.
Competing interests: No competing interests
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