The NEW ENGLA ND JOURNAL of MEDICINE

Perspective september 16, 2010

The Safety of Tiotropium — The FDA’s Conclusions

Theresa M. Michele, M.D., Simone Pinheiro, Sc.D., and Solomon Iyasu, M.D., M.P.H.

C hronic obstructive pulmonary disease (COPD)

is a leading cause of death worldwide, and the
rate of COPD-related death is increasing.1 No cur-
rent drug therapy alters the progressive decline in
lung function that characterizes
this disease. In 2004, the Food
and Drug Administration (FDA)
approved the use of tiotropium
delivered by the HandiHaler de-
vice, the first long-acting anti­
cholinergic bronchodilator for
treatment of COPD. Trials sup-
porting tiotropium’s approval
demonstrated sustained broncho­
dilation over a 24-hour period.
More recent studies have shown
that treatment with the tiotropium
HandiHaler reduces COPD exacer-
bations. Concerns have been
raised, however, about tiotropi-
um’s safety. In particular, dispa-
rate sources have identified stroke,
cardiovascular events, and death
— which have been studied as in-
dividual or composite end points
— as possible adverse outcomes.
The potential for a drug-relat-
ed increase in the risk of stroke
was first reported to the FDA in
November 2007 by Boehringer
Ingelheim, tiotropium’s manufac-
turer. Pooled data from 29 pla-
cebo-controlled tiotropium trials,
stratified by study, demonstrated
an increase in the rate of stroke
(see table). This analysis, like
most pooled analyses of adverse
events, explored a large number
of adverse events and was not
corrected for analysis of multi-
ple safety end points. Rather, it
was performed to detect any po-
tential safety signals warranting
further investigation. However,
because of the severity of the
type of event and the FDA’s com-
mitment to informing the public
early about investigations of po-
tentially serious safety concerns,
we issued a communication in
March 2008 while continuing to
investigate this finding.2
In September 2008, Singh et
al. published a meta-analysis of
17 randomized clinical trials eval-
uating the cardiovascular risk
associated with inhaled anticho-
linergic agents.3 After correcting
for double counting of trials, the
authors reported a relative risk
of cardiovascular events of 1.60
(95% confidence interval [CI],
1.22 to 2.10) for inhaled anti­
cholinergics (a combination of
tiotropium HandiHaler and ipra-
tropium) as compared with a
combination of placebo and ac-
tive controls. They concluded that
the use of inhaled anticholiner­
gics was associated with a sig-
nificantly increased risk of major
adverse cardiovascular events, in-
cluding death from cardiovascu-
lar causes, myocardial infarction,
and stroke.
Boehringer Ingelheim also re-
ported a potential increase in the
rate of death from any cause in
association with an alternative

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PERS PE C T IV E The Safety of Tiotropium — The FDA’s Conclusions

In a vote that was nearly unani-

Safety Data from Pooled Analysis of Tiotropium Trials and UPLIFT.*
mous, the PADAC decided that
29 Pooled Trials UPLIFT the data from UPLIFT adequate-
Attribute (N = 13,544) (N = 5992) ly addressed the potential stroke
Study duration 1–12 mo 48 mo signal (11 yes votes, 1 no vote)
Patient-years (placebo group) 3065 8499 and cardiovascular signal (11 yes
Patient-years (tiotropium group) 4571 9222 votes, 1 abstention). Participants
Relative risk (95% CI) noted certain methodologic lim-
itations in the Singh meta-analy-
Stroke 1.37 (0.73–15.6) 0.95 (0.70–1.29)
sis that may explain the dispari-
Myocardial infarction 0.71 (0.51–0.99)
ties between the studies. These
Death from cardiovascular causes† 0.97 (0.54–1.75) 0.73 (0.56–0.95) included potentially biased study
Death from any cause 0.85 (0.74–0.98) selection, which was limited to
trials reporting cardiovascular
* Data from UPLIFT (Understanding Potential Long-Term Impacts on Function with Tiotropium)
are for the treatment period plus 30 days of follow-up, not including vital status for patients
events; lack of assessment of pa-
who withdrew from the trial. Data may be found at www.fda.gov/AdvisoryCommittees/ tient follow-up time, with no ac-
CommitteesMeetingMaterials/Drugs/Pulmonary-AllergyDrugsAdvisoryCommittee/ucm190461 counting for differential discon-
.htm. CI denotes confidence interval.
† Deaths include those categorized as resulting from an adverse event in the cardiac system
tinuation rates, which were
organ class or the vascular system organ class, myocardial infarction, stroke, sudden death, significantly higher among pa-
cardiac death, or sudden cardiac death. tients given placebo (patients who
continue to take placebo may be
generally healthier than those
formulation of tiotropium deliv- diovascular causes, or death from who stop taking it, and poten-
ered by the Respimat device any cause in its comparison of tial differences in baseline car-
(which has not been approved for tiotropium HandiHaler with pla- diovascular risk factors were not
marketing in the United States). cebo (see table).4 UPLIFT was a accounted for in the analy­sis);
Each of three 1-year, placebo- large, 4-year, randomized, con- lack of information on occurrence
controlled clinical trials of tio­ trolled trial whose results became of adverse events in patients who
tropium Respimat showed a nu- available in late 2008. In this withdrew from many of the in-
merical imbalance in mortality, study, data on deaths, including cluded trials; lack of patient-level
favoring placebo, without a con- the vital status of patients who data; and the fact that trials on
sistent cause of death. In the withdrew from the study, were short-acting and long-acting anti­
combined trials, the risk ratio collected prospective­ly, and the cholinergics were combined in the
for death during treatment with cause of death was adjudicated main analysis.
5 μg of tiotropium Respimat once by an independent committee. In contrast, the UPLIFT trial
daily as compared with placebo With 17,721 patient-years of ex- had a large sample size, a long
was 1.7 (95% CI, 1.1 to 2.8). Vital posure, the UPLIFT study quad- follow-up period, and prespeci-
status information was collected rupled the safety database for pa- fied safety end points, including
for patients who discontinued tients with COPD participating in all adverse events, serious adverse
the trial prematurely to assess the placebo-controlled trials of tiotro- events, and death from any cause.
effects of differential discontinu- pium HandiHaler and doubled Information on vital status was
ation and a potential healthy- the size of the overall safety data- collected for 97% of treated pa-
survivor effect. With the inclusion base for tiotropium. tients until the end of treatment
of this vital status information, Because of the disparate re- day 1440, and for 75% of treated
the risk ratio decreased to 1.4 sults between the UPLIFT trial patients until off-treatment follow-
(95% CI, 0.9 to 2.0). and the meta-analysis conducted up day 1470. Findings regarding
In contrast with these trials, by Singh et al., the FDA convened stroke, cardiovascular events, and
the Understanding Potential Long- a meeting of the Pulmonary–­ death were consistent across a
Term Impacts on Function with Allergy Drugs Advisory Commit- variety of analyses.
Tiotropium (UPLIFT) trial did not tee (PADAC) on November 19, Although the reported poten-
show an increased risk of myo- 2009, to discuss the data on car- tial risk of death seen in trials
cardial infarction, death from car- diovascular risk and mortality. of tiotropium Respimat remains

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The New England Journal of Medicine

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Copyright © 2010 Massachusetts Medical Society. All rights reserved.
PE R S PE C T IV E
unresolved, committee members
noted that delivery devices are
important components of locally
acting drugs such as inhaled
bronchodilators. Differences be-
tween the products in terms of
lung deposition and other fac-
tors may result in differential risk.
They also noted that the causes
of death were diverse and that
Boehringer Ingelheim was per-
forming a large safety study to
further evaluate the finding.
Because of the strength of
the UPLIFT data, the absence of
a strong signal related to stroke
or cardiovascular events with
tiotropium, and the potential
methodologic limitations of the
Singh meta-analysis, the FDA con-
cluded that current data do not
support the conclusion that there
is an increased risk of stroke,
heart attack, or death associated
with tiotropium HandiHaler.2 We
placed significant emphasis on
UPLIFT because it was the larg-
est and longest randomized trial
of tiotropium to date, mortality-
related end points were prespec-
ified, information on vital status
Preparing for a Consumer-Driven Genomic Age
James P. Evans, M.D., Ph.D., David C. Dale, M.D., and Cathy Fomous, Ph.D.
A dvances in genomic technol-
ogies permit the simultane-
ous analysis of millions of vari-
ants across the genome and may
soon allow for meaningful esti-
mation of one’s risks of develop-
ing cancer, diabetes, and other
common diseases. These advanc-
es are converging with the move-
ment toward consumer-driven
health care and patient empower-
ment. Whereas in the past, medi-
cal testing was firmly under the
control of medical practitioners,
n engl j med 363;12  nejm.org  september 16, 2010
The New England Journal of Medicine
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Copyright © 2010 Massachusetts Medical Society. All rights reserved.
The Safety of Tiotropium — The FDA’s Conclusions
was systematically collected and
adjudicated, and mortality re-
sults were robust across differ-
ent analyses.
We have entered an era of in-
creasingly frequent publication
of meta-analyses, some of which
identify potential safety signals.
Such publication commonly leads
to urgent calls to take immedi-
ate regulatory action, without ac-
knowledgment of potential pit-
falls in the interpretation of data
from meta-analyses and pooled
analyses, such as those encoun-
tered in the tiotropium evalua-
tion. We must use measured re-
straint during our evaluations to
ensure that safe drugs remain
on the market and that their use
is not restricted in a way that
unnecessarily denies beneficial
interventions to patients who
need them. The continuing eval-
uation of potential safety signals
at the FDA requires assessment
of all available data from many
sources, with the goal of reach-
ing sound conclusions in a man-
ner that is transparent to physi-
cians and patients.
genomic information is now in-
creasingly available outside tradi-
tional medical settings. Patients
are no longer subordinate, passive
recipients of physician-initiated
genetic testing; rather, patients
can instigate their own testing and
often know more than their cli-
nicians about particular genetic
topics. Indeed, health care pro-
viders are increasingly bypassed
altogether, as patients embrace
direct-to-consumer (DTC) genetic
tests and turn to social networks
Disclosure forms provided by the au-
thors are available with the full text of this
article at NEJM.org.
From the Division of Pulmonary, Allergy,
and Rheumatology Products, Office of New
Drugs (T.M.M.), and the Division of Epidemi-
ology, Office of Surveillance and Epidemi-
ology (S.P., S.I.), Center for Drug Evaluation
and Research, Food and Drug Administra-
tion, Silver Spring, MD.
This article (10.1056/NEJMp1008502) was
published on September 8, 2010, at NEJM.org.
1. The world health report 2008 — primary
health care (now more than ever). Geneva:
World Health Organization. (Accessed Au-
gust 27, 2010, at http://www.who.int/whr/
2008/en/index.html.)
2. Early communication about an ongoing
safety review of tiotropium (marketed as
Spiriva HandiHaler). Rockville, MD: Food
and Drug Administration. (Accessed August
27, 2010, at http://www.fda.gov/Drugs/
DrugSafety/PostmarketDrugSafety
InformationforPatientsandProviders/
DrugSafetyInformationforHeathcare
Professionals/ucm070651.htm.)
3. 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:
1439-50. [Erratum, JAMA 2009;301:1227-30.]
4. Tashkin DP, Celli B, Senn S, et al. A 4-year
trial of tiotropium in chronic obstructive
pulmonary disease. N Engl J Med 2008;359:
1543-54.
Copyright © 2010 Massachusetts Medical Society.
for help in interpreting their re-
sults. In the future, a primary role
of health care professionals may
be to interpret patients’ DTC ge-
netic test results and advise them
about appropriate follow-up.
How can we maximize the
benefits of these new develop-
ments and minimize the harms?
How can we encourage patients’
involvement and autonomy yet
establish appropriate safeguards
while avoiding inappropriate pa-
ternalism? How do we promote
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