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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-
March 2008 while continuing to
investigate this finding.2
In September 2008, Singh et
al. published a meta-analysis of
rent drug therapy alters the progressive decline in 17 randomized clinical trials eval-
uating the cardiovascular risk
lung function that characterizes ed increase in the risk of stroke associated with inhaled anticho-
this disease. In 2004, the Food was first reported to the FDA in linergic agents.3 After correcting
and Drug Administration (FDA) November 2007 by Boehringer for double counting of trials, the
approved the use of tiotropium Ingelheim, tiotropium’s manufac- authors reported a relative risk
delivered by the HandiHaler de- turer. Pooled data from 29 pla- of cardiovascular events of 1.60
vice, the first long-acting anti­ cebo-controlled tiotropium trials, (95% confidence interval [CI],
cholinergic bronchodilator for stratified by study, demonstrated 1.22 to 2.10) for inhaled anti­
treatment of COPD. Trials sup- an increase in the rate of stroke cholinergics (a combination of
porting tiotropium’s approval (see table). This analysis, like tiotropium HandiHaler and ipra-
demonstrated sustained broncho­ most pooled analyses of adverse tropium) as compared with a
dilation over a 24-hour period. events, explored a large number combination of placebo and ac-
More recent studies have shown of adverse events and was not tive controls. They concluded that
that treatment with the tiotropium corrected for analysis of multi- the use of inhaled anticholiner­
HandiHaler reduces COPD exacer- ple safety end points. Rather, it gics was associated with a sig-
bations. Concerns have been was performed to detect any po- nificantly increased risk of major
raised, however, about tiotropi- tential safety signals warranting adverse cardiovascular events, in-
um’s safety. In particular, dispa- further investigation. However, cluding death from cardiovascu-
rate sources have identified stroke, because of the severity of the lar causes, myocardial infarction,
cardiovascular events, and death type of event and the FDA’s com- and stroke.
— which have been studied as in- mitment to informing the public Boehringer Ingelheim also re-
dividual or composite end points early about investigations of po- ported a potential increase in the
— as possible adverse outcomes. tentially serious safety concerns, rate of death from any cause in
The potential for a drug-relat- we issued a communication 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

1098 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.
PE R S PE C T IV E The Safety of Tiotropium — The FDA’s Conclusions

unresolved, committee members was systematically collected and Disclosure forms provided by the au-
thors are available with the full text of this
noted that delivery devices are adjudicated, and mortality re- article at NEJM.org.
important components of locally sults were robust across differ-
acting drugs such as inhaled ent analyses. From the Division of Pulmonary, Allergy,
bronchodilators. Differences be- We have entered an era of in- and Rheumatology Products, Office of New
Drugs (T.M.M.), and the Division of Epidemi-
tween the products in terms of creasingly frequent publication
ology, Office of Surveillance and Epidemi-
lung deposition and other fac- of meta-analyses, some of which ology (S.P., S.I.), Center for Drug Evaluation
tors may result in differential risk. identify potential safety signals. and Research, Food and Drug Administra-
tion, Silver Spring, MD.
They also noted that the causes Such publication commonly leads
of death were diverse and that to urgent calls to take immedi-
This article (10.1056/NEJMp1008502) was
Boehringer Ingelheim was per- ate regulatory action, without ac- published on September 8, 2010, at NEJM.org.
forming a large safety study to knowledgment of potential pit-
further evaluate the finding. falls in the interpretation of data 1. The world health report 2008 — primary
Because of the strength of from meta-analyses and pooled health care (now more than ever). Geneva:
World Health Organization. (Accessed Au-
the UPLIFT data, the absence of analyses, such as those encoun- gust 27, 2010, at http://www.who.int/whr/
a strong signal related to stroke tered in the tiotropium evalua- 2008/en/index.html.)
or cardiovascular events with tion. We must use measured re- 2. Early communication about an ongoing
safety review of tiotropium (marketed as
tiotropium, and the potential straint during our evaluations to Spiriva HandiHaler). Rockville, MD: Food
methodologic limitations of the ensure that safe drugs remain and Drug Administration. (Accessed August
Singh meta-analysis, the FDA con- on the market and that their use 27, 2010, at http://www.fda.gov/Drugs/
cluded that current data do not is not restricted in a way that InformationforPatientsandProviders/
support the conclusion that there unnecessarily denies beneficial DrugSafetyInformationforHeathcare
is an increased risk of stroke, interventions to patients who Professionals/ucm070651.htm.)
3. Singh S, Loke YK, Furberg CD. Inhaled
heart attack, or death associated need them. The continuing eval- anticholinergics and risk of major adverse
with tiotropium HandiHaler.2 We uation of potential safety signals cardiovascular events in patients with chronic
placed significant emphasis on at the FDA requires assessment obstructive pulmonary disease: a systematic
review and meta-analysis. JAMA 2008;300:
UPLIFT because it was the larg- of all available data from many 1439-50. [Erratum, JAMA 2009;301:1227-30.]
est and longest randomized trial sources, with the goal of reach- 4. Tashkin DP, Celli B, Senn S, et al. A 4-year
of tiotropium to date, mortality- ing sound conclusions in a man- trial of tiotropium in chronic obstructive
pulmonary disease. N Engl J Med 2008;359:
related end points were prespec- ner that is transparent to physi- 1543-54.
ified, information on vital status cians and patients. Copyright © 2010 Massachusetts Medical Society.

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-
genomic information is now in-
creasingly available outside tradi-
tional medical settings. Patients
for help in interpreting their re-
sults. In the future, a primary role
of health care professionals may
ants across the genome and may are no longer subordinate, passive be to interpret patients’ DTC ge-
soon allow for meaningful esti- recipients of physician-initiated netic test results and advise them
mation of one’s risks of develop- genetic testing; rather, patients about appropriate follow-up.
ing cancer, diabetes, and other can instigate their own testing and How can we maximize the
common diseases. These advanc- often know more than their cli- benefits of these new develop-
es are converging with the move- nicians about particular genetic ments and minimize the harms?
ment toward consumer-driven topics. Indeed, health care pro- How can we encourage patients’
health care and patient empower- viders are increasingly bypassed involvement and autonomy yet
ment. Whereas in the past, medi- altogether, as patients embrace establish appropriate safeguards
cal testing was firmly under the direct-to-consumer (DTC) genetic while avoiding inappropriate pa-
control of medical practitioners, tests and turn to social networks ternalism? How do we promote

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Copyright © 2010 Massachusetts Medical Society. All rights reserved.