Cochrane Database of Systematic Reviews (Reviews) || Tiotropium versus ipratropium bromide for...

Tiotropium versus ipratropium bromide for chronic

obstructive pulmonary disease (Review)

Cheyne L, Irvin-Sellers MJ, White J

This is a reprint of a Cochrane review, prepared and maintained by The Cochrane Collaboration and published in The Cochrane Library

2013, Issue 9

http://www.thecochranelibrary.com

Tiotropium versus ipratropium bromide for chronic obstructive pulmonary disease (Review)

Copyright © 2013 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

http://www.thecochranelibrary.com

T A B L E O F C O N T E N T S

1HEADER . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

1ABSTRACT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

2PLAIN LANGUAGE SUMMARY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

4SUMMARY OF FINDINGS FOR THE MAIN COMPARISON . . . . . . . . . . . . . . . . . . .

6BACKGROUND . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

7OBJECTIVES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

7METHODS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

9RESULTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Figure 1. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10

Figure 2. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12

14DISCUSSION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

15AUTHORS’ CONCLUSIONS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

15ACKNOWLEDGEMENTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

16REFERENCES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

17CHARACTERISTICS OF STUDIES . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

24DATA AND ANALYSES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Analysis 1.1. Comparison 1 Tiotropium versus ipratropium, Outcome 1 Change in baseline trough FEV1 at 3 months. 25

Analysis 1.2. Comparison 1 Tiotropium versus ipratropium, Outcome 2 Change in baseline trough FEV1 at 12 months. 26

Analysis 1.3. Comparison 1 Tiotropium versus ipratropium, Outcome 3 Patients with at least one serious adverse event. 26

Analysis 1.4. Comparison 1 Tiotropium versus ipratropium, Outcome 4 Patients with at least one disease specific adverse

event (=COPD exac). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 27

Analysis 1.5. Comparison 1 Tiotropium versus ipratropium, Outcome 5 Patients with at least one hospital admission (all

cause). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 28

Analysis 1.6. Comparison 1 Tiotropium versus ipratropium, Outcome 6 Patients with at least one exacerbation requiring

hospitalisation. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 29

Analysis 1.7. Comparison 1 Tiotropium versus ipratropium, Outcome 7 All cause mortality. . . . . . . . . . 30

Analysis 1.8. Comparison 1 Tiotropium versus ipratropium, Outcome 8 SGRQ. . . . . . . . . . . . . . 31

Analysis 1.9. Comparison 1 Tiotropium versus ipratropium, Outcome 9 Withdrawals. . . . . . . . . . . . 31

Analysis 1.10. Comparison 1 Tiotropium versus ipratropium, Outcome 10 Patients with one or more exacerbations. 32

Analysis 1.11. Comparison 1 Tiotropium versus ipratropium, Outcome 11 Mean number of exacerbations per patient per

year. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 33

Analysis 1.12. Comparison 1 Tiotropium versus ipratropium, Outcome 12 BDI. . . . . . . . . . . . . . 34

Analysis 1.13. Comparison 1 Tiotropium versus ipratropium, Outcome 13 TDI. . . . . . . . . . . . . . 34

Analysis 1.14. Comparison 1 Tiotropium versus ipratropium, Outcome 14 Change from baseline in total SGRQ score. 35

35APPENDICES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

37CONTRIBUTIONS OF AUTHORS . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

37DECLARATIONS OF INTEREST . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

37NOTES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

iTiotropium versus ipratropium bromide for chronic obstructive pulmonary disease (Review)


[Intervention Review]

Tiotropium versus ipratropium bromide for chronicobstructive pulmonary disease

Leanne Cheyne1, Melanie J Irvin-Sellers2, John White3

1Respiratory Medicine, Bradford Teaching Hospitals NHS Foundation Trust, Bradford, UK. 2Respiratory Medicine, St Peter’s Hospital,

Chertsey, UK. 3Respiratory Medicine, York District Hospital, York, UK

Contact address: Leanne Cheyne, Respiratory Medicine, Bradford Teaching Hospitals NHS Foundation Trust, Duckworth Lane,

Bradford, UK. [email protected].

Editorial group: Cochrane Airways Group.

Publication status and date: New, published in Issue 9, 2013.

Review content assessed as up-to-date: 25 November 2012.

Citation: Cheyne L, Irvin-Sellers MJ, White J. Tiotropium versus ipratropium bromide for chronic obstructive pulmonary disease.

Cochrane Database of Systematic Reviews 2013, Issue 9. Art. No.: CD009552. DOI: 10.1002/14651858.CD009552.pub2.


A B S T R A C T

Background

Tiotropium and ipratropium bromide are both recognised treatments in the management of people with stable chronic obstructive

pulmonary disease (COPD). There are new studies which have compared tiotropium with ipratropium bromide, making an update

necessary.

Objectives

To compare the relative effects of tiotropium to ipratropium bromide on markers of quality of life, exacerbations, symptoms, lung

function and serious adverse events in patients with COPD using available randomised controlled trial (RCT) data.

Search methods

We identified RCTs from the Cochrane Airways Group Specialised Register of trials (CAGR) and ClinicalTrials.gov up to November

2012.

Selection criteria

We included parallel group RCTs of 12 weeks duration or longer comparing treatment with tiotropium with ipratropium bromide for

patients with stable COPD.

Data collection and analysis

Two review authors independently assessed studies for inclusion and then extracted data on study quality and outcome results. We

contacted trial sponsors for additional information. We analysed the data using Cochrane Review Manager (RevMan 5.2).

Main results

This review included two studies of good methodological quality that enrolled 1073 participants with COPD. The studies used a

similar design and inclusion criteria and were of at least 12 weeks duration; the participants had a mean forced expiratory volume in

one second (FEV1) of 40% predicted value at baseline. One study used tiotropium via the HandiHaler (18 µg) for 12 months and the

other via the Respimat device (5 µg and 10 µg) for 12 weeks. In general, the treatment groups were well matched at baseline but not

all outcomes were reported for both studies. Overall the risk of bias across the included RCTs was low.

1Tiotropium versus ipratropium bromide for chronic obstructive pulmonary disease (Review)


mailto:[email protected]

For primary outcomes this review found that at the three months trough (the lowest level measured before treatment) FEV1 significantly

increased with tiotropium compared to ipratropium bromide (mean difference (MD) 109 mL; 95% confidence interval (CI) 81 to

137, moderate quality evidence, I2 = 62%). There were fewer people experiencing one or more non-fatal serious adverse events on

tiotropium compared to ipratropium (odds ratio (OR) 0.5; 95% CI 0.34 to 0.73, high quality evidence). This represents an absolute

reduction in risk from 176 to 97 per 1000 people over three to 12 months. Concerning disease specific adverse events, the tiotropium

group were also less likely to experience a COPD-related serious adverse event when compared to ipratropium bromide (OR 0.59;

95% CI 0.41 to 0.85, moderate quality evidence).

For secondary outcomes, both studies reported fewer hospital admissions in the tiotropium group (OR 0.34; 95% CI 0.15 to 0.70,

moderate quality evidence); as well as fewer patients experiencing one or more exacerbations leading to hospitalisation in the people

on tiotropium in both studies (OR 0.56; 95% CI 0.31 to 0.99, moderate quality evidence). There was no significant difference in

mortality between the treatments (OR 1.39; 95% CI 0.44 to 4.39, moderate quality evidence). One study measured quality of life

using the St George’s Respiratory Questionnaire (SGRQ); the mean SGRQ score at 52 weeks was lower in the tiotropium group than

the ipratropium group (lower on the scale is favourable) (MD -3.30; 95% CI -5.63 to -0.97, moderate quality evidence). There were

fewer participants suffering one of more exacerbations in the tiotropium arm (OR 0.71; 95% CI 0.52 to 0.95, high quality evidence)

and there was also a reported difference in the mean number of exacerbations per person per year which reached statistical significance

(MD -0.23; 95% CI -0.39 to -0.07, P = 0.006, moderate quality evidence). From the 1073 participants there were significantly fewer

withdrawals from the tiotropium group (OR 0.58; 95% CI 0.41 to 0.83, high quality evidence).

Authors’ conclusions

This review shows that tiotropium treatment, when compared with ipratropium bromide, was associated with improved lung function,

fewer hospital admissions (including those for exacerbations of COPD), fewer exacerbations of COPD and improved quality of life.

There were both fewer serious adverse events and disease specific events in the tiotropium group, but no significant difference in deaths

with ipratropium bromide when compared to tiotropium. Thus, tiotropium appears to be a reasonable choice (instead of ipratropium

bromide) for patients with stable COPD, as proposed in guidelines. We would advise some caution with tiotropium via the Respimat

inhaler and suggest waiting for further information from an ongoing head-to-head trial comparing mortality in relation to tiotropium

delivery devices and doses.

P L A I N L A N G U A G E S U M M A R Y

Tiotropium versus ipratropium bromide in the management of COPD

Background

Chronic obstructive pulmonary disease (COPD) is a lung disease that includes the conditions chronic bronchitis and emphysema.

COPD is mainly caused by smoking or inhaling dust, which leads to blockage or narrowing of the airways. The symptoms include

breathlessness and a chronic cough. Tiotropium is an inhaled medication, taken once a day, to help widen the airways (bronchodilator)

and is used in the management of COPD. Ipratropium bromide is also a bronchodilator but has a shorter duration of action and has

to be taken several times a day.

What did we find?

We found two studies including 1073 participants that compared the long-term effectiveness and side effects of tiotropium compared

to ipratropium bromide. One trial was 12 weeks long and one was a year long. The people included in the studies had moderate to

severe COPD (average forced expiratory volume in one second (FEV1) was 40% the predicted value).

Compared to ipratropium bromide, tiotropium treatment led to improved lung function, fewer COPD exacerbations, fewer hospital

admissions (including those for exacerbations of COPD) and improved quality of life. Tiotropium appears to be safer with fewer adverse

events, but there was no significant difference in deaths with ipratropium bromide when compared to tiotropium.

Quality of the evidence

Overall the evidence was of moderate to high quality. Tiotrpium is available in two different inhalers, Respimat and Handihaler. There

are some safety concerns regarding the safety of the Respimat device but we await the publication of a trial before we can conclusively

say that this is the case; and this will be reported in another Cochrane Review.

Conclusions



http://onlinelibrary.wiley.com/doi/10.1002/14651858.CD009285.pub2/abstract









Based on this review, tiotropium has more benefits than ipratropium bromide for people with stable moderate to severe COPD.

The review was current as of November 2012.



S U M M A R Y O F F I N D I N G S F O R T H E M A I N C O M P A R I S O N [Explanation]

Tiotropium versus ipratropium for chronic obstructive pulmonary disease

Patient or population: chronic obstructive pulmonary disease (COPD). Participants in included studies had an average baseline FEV1 of around 40% predicted and are regarded as having

moderate to severe COPD

Settings: community

Intervention: tiotropium versus ipratropium

Outcomes Illustrative comparative risks* (95% CI) Relative effect

(95% CI)

No of Participants

(studies)


(GRADE)

Comments

Assumed risk Corresponding risk

Ipratropium Tiotropium

Change in baseline

trough FEV1

Follow-up: 12 weeks

The mean drop in trough

FEV1 was 20 to 30 mL in

the ipratropium group

The mean change from

baseline in trough FEV1 in

the tiotropium group was

109 mL better

(80 to 137 better)

1073

(2)

Moderate1 MCID = 150 mL

All-cause serious ad-

verse events

Follow-up: 12 weeks to

12 months

176 per 1000 97 per 1000

(68 to 135)

OR 0.50 (0.34 to 0.73) 1073

(2)

High

Hospital admissions

(all-cause)

Follow-up: 12 weeks

84 per 1000 30 per 1000

(14 to 65)

OR 0.34

(0.15 to 0.76)

538

(1)

Moderate2 There were also fewer

hospitalisation due to

exacerbations in the

tiotropium group OR 0.56

(95% CI 0.31 to 0.99)

Mortality (all-cause)


12 months

11 per 1000 15 per 1000

(5 to 47)

OR 1.39

(0.44 to 4.39)

1073

(2)

Moderate3

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Quality of life (measured

with the SGRQ).

The SGRQ scale runs

from 0 to 100 and lower

on the scale indicates a

better quality of life

Follow-up: 12 months

The mean SGRQ score

was 44 (SD 13) on iprat-

ropium

The mean SGRQ in the

tiotropium group was

3.3 better

(0.97 to 5.63 better)

535

(1)

Moderate2 MCID = 4 points

Patients with one or

more exacerbations


12 months

297 per 1000 231 per 1000

(180 to 286)

OR 0.71

(0.52 to 0.95)

1073

(2)

High

Withdrawals


12 months

193 per 1000 122 per 1000

(89 to 166)

OR 0.58

(0.41 to 0.83)

1073

(2)

High

*The basis for the assumed risk is the mean control group risk across studies. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison

group and the relative effect of the intervention (and its 95% CI).

CI: Confidence interval; FEV1: forced expiratory volume in one second; OR: Odds ratio; MCID: minimal clinically important difference

GRADE Working Group grades of evidence

High quality: Further research is very unlikely to change our confidence in the estimate of effect.

Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.

Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.

Very low quality: We are very uncertain about the estimate.

1. Heterogeneity present between the trial results (I2 = 62%)

2. Results from a single paper only, so heterogeneity could not be assessed

3. The number of participants and/or events were low, leading to wide CIs and imprecision in the result

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B A C K G R O U N D

Description of the condition

Chronic obstructive pulmonary disease (COPD) is characterised

by airflow obstruction in the lungs. The airflow obstruction is usu-

ally progressive, not fully reversible, and does not change markedly

over several months. Symptoms include progressive breathlessness

on exertion and frequent lower respiratory tract infections. The

disease is predominantly caused by smoking (NICE 2010). An

estimated three million people are affected by COPD in the UK.

About 900,000 have been diagnosed with COPD and an esti-

mated two million people have COPD which remains undiag-

nosed (Healthcare Commission 2006). COPD is usually a pro-

gressive disease and lung function can be expected to worsen over

time, even with the best available care (GOLD 2010). Manage-

ment of the disease includes reduction of risk factors, pharmaco-

logical treatments, education, pulmonary rehabilitation and exer-

cise programmes (Karner 2011b).

Description of the intervention

Medications for COPD are used to decrease symptoms or com-

plications, or both. Bronchodilator medications are central to the

management of COPD (GOLD 2010). Beta2-agonists act directly

on bronchial smooth muscle to cause bronchodilation whereas an-

ticholinergics act by inhibiting resting bronchomotor tone. As well

as improving breathlessness through their direct bronchodilator

effects, both classes of drugs also appear to work by reducing hy-

perinflation (NICE 2010). Long-acting bronchodilators are used

to prevent and reduce symptoms in COPD. Inhaled anticholiner-

gic agents, such as tiotropium, have been shown to improve symp-

toms, reduce exacerbations and improve quality of life in patients

with COPD (Ogale 2010); they can be used alone or in combina-

tion with inhaled corticosteroids and long-acting beta2-agonists

(LABA). Both of these inhaled therapies can be used alone or in

combination (Karner 2011; Karner 2011a; Karner 2011b; Karner

2012).

Tiotropium

Tiotropium is a long-acting (lasting for 24 hours) anticholiner-

gic bronchodilator used in the management of COPD. Contin-

uous treatment with tiotropium significantly reduces the number

of exacerbations and the risk of hospitalisation due to exacerba-

tions compared with placebo (Barr 2005; Karner 2012). Treat-

ment trials in COPD show a greater benefit in symptom control

and lung function obtained from tiotropium compared with ei-

ther short-acting anticholinergics (ipratropium) or LABA (Sears

2008). Tiotropium is intended as a maintenance treatment for

COPD and is not indicated for the initial treatment of acute ex-

acerbations. In the UK, a tiotropium inhaler (either HandiHaler

(18 µg) or Respimat (5 µg)) may be introduced for once daily use

for patients with frequent exacerbations, exertional breathlessness,

or both, and with a diagnosis of COPD regardless of their lung

function (NICE 2010).

Ipratropium bromide

The short-acting (lasting six to eight hours) anticholinergic agent

ipratropium bromide is used in both the long-term and acute man-

agement of patients with COPD. In trials, it has been suggested

to have equal or superior efficacy compared with LABA (Salpeter

2006). According to the British National Formulary (BNF) the

optimal dosing is 20 to 40 µg three to four times a day.

How the intervention might work

Tiotropium

Tiotropium is a long-acting anticholinergic agent which blocks the

action of the neurotransmitter acetylcholine. It has similar affinity

for the M1 to M5 subtypes of muscarinic (M) receptors. Acti-

vation of M3 receptors on airway smooth muscle leads to bron-

choconstriction through stimulation of phospholipase C, which

generates the formation of diacylglycol and inositol triphosphate.

These in turn stimulate a number of intracellular signalling cas-

cades leading to changes in intracellular calcium homeostasis and

bronchoconstriction (Lubinski 2004).

Tiotropium exhibits pharmacological effects through the inhibi-

tion of these M3 receptors. Prevention of methacholine-induced

bronchoconstriction is dose dependent and lasts longer than 24

hours. The bronchodilation following inhalation of tiotropium is

predominantly site specific.

Ipratropium bromide

Ipratropium bromide is a short-acting anticholinergic, with effects

lasting six to eight hours. It is a non-selective muscarinic antagonist

and therefore blocks M2 receptors as well as M1 and M3 receptors

in airway smooth muscle and prevents the increases in intracellular

concentrations of cyclic guanosine monophosphate (cyclic GMP).

M2 receptors at cholinergic nerve endings inhibit the release of

acetylcholine and therefore act as inhibitory feedback receptors.

Inhibition of these receptors with ipratropium bromide results in

increased acetylcholine release in the airways, which may overcome

the blockade of other muscarinic receptors in the muscle (Barnes

2000).

Why it is important to do this review

Both tiotropium and ipratropium bromide are separately recom-

mended for the treatment of COPD (GOLD 2010; NICE 2010).



They both work by blocking M3 receptors. The long-acting an-

ticholinergic tiotropium has pharmacokinetic selectivity for M3

and M1 receptors, whereas the short-acting drug also blocks M2

receptors, thought to be less important in COPD. Tiotropium

has a much longer duration of action compared with ipratropium

bromide (GOLD 2010). It has been suggested that the use of

tiotropium may be more cost-effective (NICE 2010). The review

is necessary to examine the potential benefit of tiotropium com-

pared with ipratropium bromide.

This review forms part of a suite of reviews comparing tiotropium

with placebo, ipratropium, and long-acting beta2-agonists for

the treatment of COPD (including Karner 2011; Karner 2011a;

Karner 2011b; Welsh 2010).

O B J E C T I V E S

To compare the relative effects of tiotropium to ipratropium bro-

mide on markers of quality of life, exacerbations, symptoms, lung

function and serious adverse events in patients with COPD using

available randomised controlled trial data.

M E T H O D S

Criteria for considering studies for this review

Types of studies

We included randomised controlled trials (RCTs) of at least 12

weeks duration and with a parallel group design, both open label

studies and blinded studies.

Types of participants

We included adult patients with a diagnosis of COPD as defined by

an external set of diagnostic criteria (for example from the Global

Initiative for Chronic Obstructive Lung Disease (GOLD), Amer-

ican Thoracic Society (ATS), British Thoracic Society (BTS) and

the Thoracic Society of Australia and New Zealand (TSANZ)).

Both reversible COPD (greater than 15% improvement in the

forced expiratory volume in one second (FEV1) after a single dose

of short or long-acting bronchodilator) and non-reversible COPD

were included.

Types of interventions

We included patients randomised to receive tiotropium or iprat-

ropium bromide. Participants were allowed inhaled steroids and

other co-medications provided they were not part of the ran-

domised treatment.

Types of outcome measures

Primary outcomes

1. Trough forced expiratory volume in one second (FEV1) at

three months

2. All-cause non-fatal serious adverse events (SAEs)

3. Disease specific serious adverse events, if independently

adjudicated

We chose all-cause SAEs in addition to disease specific SAEs be-

cause disease specific adverse events are at higher risk of ascertain-

ment bias.

Secondary outcomes

1. Hospital admissions, all-cause and due to exacerbations

2. Mortality, all-cause

3. Quality of life (measured with a validated scale e.g. St

George’s Respiratory Questionnaire, Chronic Respiratory

Disease Questionnaire)

4. Disease specific mortality, if independently adjudicated

5. Exacerbations, requiring short burst oral corticosteroids or

antibiotics, or both

6. Symptoms (measures of breathlessness - Baseline Dyspnea

Index (BDI) and Transition Dyspnea Index (TDI))

7. Withdrawals

Search methods for identification of studies

Electronic searches

Trials were identified using the Cochrane Airways Group Spe-

cialised Register of trials, which is derived from systematic searches

of bibliographic databases including the Cochrane Central Reg-

ister of Controlled Trials (CENTRAL), MEDLINE, EMBASE,

CINAHL, AMED and PsycINFO, and handsearching of respira-

tory journals and meeting abstracts (please see Appendix 1). All

records in the Specialised Register coded as ’COPD’ were searched

using the following terms:

(tiotropium or Spiriva or “Ba 679 BR”) AND (ipratropium or

Atrovent or n-isopropylatropine).

A search of ClinicalTrials.gov was also conducted using the same

terms. All databases were searched from their inception to the

present and there was no restriction on language of publication.

Searching other resources

Reference lists of all primary studies and review articles were

checked for additional references. Authors of identified trials were

contacted and asked to identify other published and unpublished

studies. Manufacturers and experts in the field were also contacted.



Data collection and analysis

Selection of studies

Two review authors (LC, MI) independently assessed all the po-

tential studies identified as a result of the search strategy for inclu-

sion in the review. Disagreement was resolved by discussion and a

third person (JW) was arbiter.

Data extraction and management

Two review authors (LC, MI) independently extracted informa-

tion from each study for the following characteristics.

1. Design (design, total study duration and run-in, number of

study centres and location, withdrawals, date of study).

2. Participants (number (N), mean age, age range, gender,

COPD severity, diagnostic criteria, baseline lung function, co-

morbidities, concomitant medication, smoking history, inclusion

criteria, exclusion criteria).

3. Interventions (run-in, intervention treatment and inhaler

type, control treatment and inhaler type).

4. Outcomes (primary and secondary outcomes specified and

collected, time points reported).

Assessment of risk of bias in included studies

Two review authors independently assessed the risk of bias for each

study using the criteria outlined in the Cochrane Handbook for Sys-

tematic Reviews of Interventions (Higgins 2008). Any disagreement

was resolved by discussion or by involving a third assessor. We

assessed the risk of bias according to the following domains:

1. allocation sequence generation;

2. concealment of allocation;

3. blinding of participants and investigators;

4. incomplete outcome data;

5. selective outcome reporting.

Other sources of bias were noted. Each potential source of bias

was graded as high, low, or unclear risk of bias.

Measures of treatment effect

Dichotomous data

We analysed dichotomous data variables (such as mortality and

withdrawals) using odds ratios. If count data were not available

as the number of participants experiencing an event, we analysed

the data as continuous, time-to-event or rate ratios, depending on

how the data were reported. This includes the outcomes: hospital

admissions, exacerbations, serious adverse events and side effects.

Continuous data

We analysed continuous outcome data (such as FEV1 and quality

of life) as fixed-effect model mean differences when the same scale

was used, and as standardised mean differences when different

scales were employed in different studies. Mean difference based

on change from baseline was preferred over mean difference based

on absolute values.

If data were not available for the same time point in all studies, the

closest time points were used. Alternatively, end of study was used

as the time of analysis for all studies. We used an intention-to-

treat (ITT) analysis of outcomes from all randomised participants

for primary analyses, where possible.

Unit of analysis issues

We analysed dichotomous data using participants as the unit of

analysis (rather than events) to avoid counting the same participant

more than once. Where trials included two active treatment arms,

we split the participants in the comparison arm to avoid double

counting.

Dealing with missing data

We contacted investigators or study sponsors in order to verify key

study characteristics and obtain missing numerical outcome data,

where possible.

Assessment of heterogeneity

We used the I2 statistic to measure heterogeneity among the tri-

als in each analysis. If we identified substantial heterogeneity we

planned to explored it by pre-specified subgroup analysis.

Assessment of reporting biases

Where we suspected reporting bias (see ’Selective reporting bias’

above), we attempted to contact the study authors asking them to

provide the missing outcome data. Where this was not possible,

and the missing data were thought to introduce serious bias, we

planned to explore the impact of including such studies in the

overall assessment of results by a sensitivity analysis.

Data synthesis

We combined dichotomous data using Mantel-Haenzsel odds ra-

tios with 95% confidence intervals, with a fixed-effect model.

Where events were rare, we employed the Peto odds ratio (since

this does not require a continuity correction for zero cells).

Where treatment effects were reported as a mean difference with

95% confidence interval or exact P value, we calculated the stan-

dard error, entered it with the mean difference and combined the

results using a fixed-effect model Generic Inverse Variance (GIV)

in RevMan 5.



Rate ratios and hazard ratios were combined using a fixed-effect

model GIV.

Numbers needed to treat were calculated from the pooled odds

ratio and its confidence interval, and applied to appropriate levels

of baseline risk.

We have presented the findings of our primary outcomes in a

summary of findings table.

Subgroup analysis and investigation of heterogeneity

We planned to carry out the following subgroup analyses.

1. Tiotropium formulation or delivery device formulation.

2. Severity at baseline.

3. Concomitant medication.

4. Smoking status.

5. Co-morbidity (i.e. vascular diseases, cardiac diseases,

metabolic disease etc.).

6. Open and double-blind trial design.

Sensitivity analysis

We planned to assess the sensitivity of our primary outcomes to

degree of bias by comparing overall results with those exclusively

from trials assessed as being at low risk of bias. We also planned to

compare the results from the fixed-effect model with results from

the random-effects model.

R E S U L T S

Description of studies

Results of the search

The search identified a total of 76 references and was conducted

up to November 2012 (Figure 1). We identified seven references

for further appraisal. Two studies were included in the systematic

review.



Figure 1. study flow diagram.



Included studies

Two separate studies that met the inclusion criteria were included

(1073 participants), studying the effects of tiotropium compared

with ipratropium bromide (Vincken 2002; Voshaar 2008).

Interventions

One study used the tiotropium HandiHaler 18 µg device for 12

months (Vincken 2002) and the other used both tiotropium 5

µg and 10 µg with the Respimat (soft mist) device for 12 weeks

(Voshaar 2008). Both studies used an ipratropium bromide me-

tered dose inhaler (MDI). Voshaar 2008 was technically two sepa-

rate, identical RCTs, but the results were reported together. When

results from these trials were meta-analysed, we halved the num-

ber of participants in the control group to avoid double counting.

Voshaar 2008 also included a placebo arm, which was not eligible

for this review.

Participant characteristics

Inclusion criteria were similar for both of the studies with partic-

ipants required to be 40 years or over and with a smoking history

of equal to or greater than 10 pack years. A clinical diagnosis of

COPD according to ATS guidance was used in Vincken 2002

and spirometric criteria were specified in Voshaar 2008 (FEV1 of

≤ 65% predicted and a FEV1/FVC ratio of ≤ 70%). The mean

smoking history was 34 pack years in Vincken 2002 and 51 pack

years in Voshaar 2008. COPD severity was described as moder-

ate-severe in both studies. The study participants had a mean age

of 65 years and were predominately male. Theophylline, inhaled

steroids and oral steroids (prednisolone) up to and including a

dose of 10 mg (if the dose was stable for at least six weeks) were

allowed in both studies. Inhaled beta2-agonists and other anti-

cholinergic drugs (not used in the study) were disallowed. We felt

that the baseline data were well balanced between the treatment

and control groups.

Not all outcomes were reported in the study reports and we ob-

tained some information from the manufacturer.

Both studies were sponsored by Boehringer Ingelheim (BI) (the

manufacturer of tiotropium). For further details see Characteristics

of included studies.

Excluded studies

We excluded five studies after obtaining the full study reports.

Studies were excluded due to be being less than 12 weeks in

duration, including an ipratropium and albuterol combination,

and not being conducted as an RCT. For further information see

Characteristics of excluded studies.

Risk of bias in included studies

Full details of our ’Risk of bias’ judgments can be found in

Characteristics of included studies and in the summary graph in

Figure 2.



Figure 2. Risk of bias summary: review authors’ judgements about each risk of bias item for each included

study.

Allocation

Random sequence generation and allocation concealment were

sufficiently described for Voshaar 2008. Allocation concealment

was not described in Vincken 2002, but because the trial was run

by a manufacturer it is safe to assume that the allocation sequence

was protected (although we did not request this information from

BI).

Blinding

Double-blinding of participants and study personnel was de-

scribed in both studies.

Incomplete outcome data

The withdrawal rates were relatively low for both studies.

Selective reporting

All specified outcomes were reported. Data on adverse events were

gained from BI for both studies.

Other potential sources of bias

None identified



Effects of interventions

See: Summary of findings for the main comparison Tiotropium

versus ipratropium for chronic obstructive pulmonary disease

See Summary of findings for the main comparison.

We had planned several subgroup analyses. Although we sub-

grouped by tiotropium inhaler type and dose, due to possible dif-

ferences in the dose received, we did not perform any further sub-

group analysis as there were insufficient data to allow this.

Primary outcome: forced expiratory volume in one second

(FEV1) at three months

Combining the two studies on 1073 participants, trough FEV1

values at three months significantly increased with tiotropium

compared to ipratropium bromide (mean difference (MD) 109

mL; 95% confidence interval (CI) 81 to 137, moderate quality

evidence; Analysis 1.1). However, there was a high level of het-

erogeneity (I2 = 62%). In addition one study of 535 participants

reported change in baseline trough FEV1 at 12 months (Vincken

2002). At 12 months, the trough FEV1 was 120 mL above base-

line for patients on tiotropium and the trough FEV1 declined by

30 mL in participants on ipratropium (MD 150 mL; 95%CI 111

to 190; Analysis 1.2).

Primary outcome: all-cause non-fatal serious adverse events

Both included studies reported serious adverse events (1073 partic-

ipants). There were fewer people experiencing one or more non-fa-

tal serious adverse events on tiotropium compared to ipratropium

(odds ratio (OR) 0.50; 95% CI 0.34 to 0.73; Analysis 1.3). Spe-

cific details on cardiovascular events were not presented and at 12

weeks the Voshaar 2008 trial may be too short to assess long-term

cardiovascular risk.

Primary outcome: disease specific serious adverse events

One study on 535 participants reported on serious adverse events

related to COPD (Vincken 2002). There were fewer disease spe-

cific adverse events (described as COPD exacerbations) in the

tiotropium group (OR 0.59; 95% CI 0.41 to 0.85, moderate qual-

ity evidence; Analysis 1.4).

Secondary outcome: hospital admissions, all-cause and due

to exacerbations

There were fewer people experiencing one or more hospital admis-

sions in the intervention group in Voshaar 2008 (OR 0.34; 95%

CI 0.15 to 0.70, moderate quality evidence; Analysis 1.5). We

were not able to obtain data for hospital admissions from Vincken

2002.

There were also fewer patients experiencing one or more exacer-

bations leading to hospitalisation in people on tiotropium (OR

0.56; 95% CI 0.31 to 0.99; Analysis 1.6); we were able to obtain

data from both studies on this outcome.

Secondary outcomes: mortality, all-cause

All-cause mortality was recorded in both studies (1073 partici-

pants). Overall, there was no statistically significant difference in

the number of deaths between tiotropium and ipratropium (OR

1.39; 95% CI 0.44 to 4.39, moderate quality evidence; Analysis

1.7).

Secondary outcomes: quality of life (QoL)

One study on 535 participants measured QoL using the SGRQ

(Vincken 2002). The mean QoL score on the SGRQ at 52 weeks

was lower in the tiotropium group than in the ipratropium group

(lower on the scale is favourable) (MD -3.30; 95%CI -5.63 to -

0.97, moderate quality evidence; Analysis 1.8). Four units differ-

ence is regarded as clinically significant.

Secondary outcomes: disease specific mortality

Neither study reported disease specific mortality.

Secondary outcomes: exacerbations requiring short burst

oral corticosteroids or antibiotics, or both

Both studies reported the number of people experiencing one or

more COPD exacerbations but it was not clear how the exacer-

bations were defined. There were fewer participants suffering one

or more exacerbations in the tiotropium arm (OR 0.71; 95% CI

0.52 to 0.95, high quality evidence; Analysis 1.10).

Vincken 2002 also reported the difference in the mean number of

exacerbations per person per year and this reached statistical sig-

nificance (MD -0.23; 95% CI -0.39 to -0.07; P = 0.006; Analysis

1.11).

Secondary outcomes: symptoms

One trial on 535 participants reported the baseline dyspnoea index

(BDI) and transition dyspnoea index (TDI) (Vincken 2002). BDI

was not significantly different for the treatments (MD -0.28; 95%

CI -0.74 to 0.18; Analysis 1.12) but TDI did show a statistically

significant difference in favour of tiotropium (MD 0.90; 95% CI

0.39 to 1.41; Analysis 1.13).

Secondary outcomes: withdrawals

Both studies reported withdrawals from their trials. From the 1073

participants there were significantly fewer withdrawals from the

tiotropium group (OR 0.58; 95% CI 0.41 to 0.83, high quality

evidence; Analysis 1.9).



D I S C U S S I O N

Summary of main results

This systematic review set out to investigate the medium to long-

term (three months or longer) effects of tiotropium when com-

pared to ipratropium bromide. We identified two eligible ran-

domised, parallel group, placebo-controlled trials with a total of

1073 participants and a mean duration of seven months. Both

studies were sponsored by Boehringer Ingelheim (the manufac-

turer of tiotropium) and both studies had participants with a mean

FEV1 of 40% predicted at baseline. The studies were of high me-

thodical quality with relatively low withdrawal rates, which were

balanced between treatment arms. We found that, compared to

ipratropium bromide, treatment with tiotropium led to a signif-

icant increase in trough FEV1 at three months. On one hand

this is not surprising given that tiotropium is a long-acting bron-

chodilator and ipratropium is not, however trough FEV1 is the

best measure for long-acting bronchodilators because other out-

come benefits may be conferred due to improvements in FEV1

over the course of 24 hours. Significantly more adverse events

and disease specific events were seen in the ipratropium group

(although events remain low for both groups). Of the secondary

outcomes, tiotropium showed fewer hospital admissions due to

exacerbations of COPD and exacerbation of COPD not requir-

ing hospitalisation. There was no significant difference in all-cause

mortality between tiotropium and ipratropium, although disease

specific mortality was not recorded. Quality of life was better in

the tiotropium group but this did not reach the threshold for clin-

ical significance, which is four units on the SGRQ. Whilst there

was an effect seen in symptom indices using TDI, this was not

seen using BDI. There were fewer withdrawals in the intervention

arm.

Overall completeness and applicability ofevidence

Tiotropium has been on the market for several years. It was ap-

proved in Europe in 2002 and the United States in 2004. To

date, numerous trials on tiotropium have been completed. De-

spite this there have only been two good quality studies compar-

ing tiotropium and ipratropium. Both trials are described in this

review and are of high methodological standard, giving good evi-

dence regarding the relative risks and benefits of tiotropium treat-

ment. Ideally further research should be done.

The increase in trough FEV1 at 12 weeks for tiotropium compared

to ipratropium would suggest that tiotropium may have advan-

tages over ipratropium bromide, and that it would be suitable for

those patients diagnosed with COPD who have exertional breath-

lessness, frequent infections and worsening lung function.

This review does not show any significant difference in mortal-

ity with the use of tiotropium in comparison with ipratropium

(although cardiovascular risk was not looked at specifically, and

Voshaar 2008 only presented 12 weeks of data). In addition a re-

cent systematic review, including 19,545 randomised patients in

studies of four weeks or longer, showed that tiotropium was asso-

ciated with a reduction in the risk of serious cardiovascular events

(Celli 2010). When we compared the two trials (Vincken 2002;

Voshaar 2008) withdrawal rates where lower in Voshaar 2008

(which used the soft mist inhaler) when compared to Vincken

2002 (dry powder inhaler) and the mortality rates showed no sig-

nificant difference between the tiotropium dry powder and soft

mist inhaler. Based on the limited data available from the two stud-

ies included in this review we cannot recommend one inhaler over

the other. Further analyses of an ongoing head-to-head study of

dry powder inhaler versus soft mist inhaler are awaited to estimate

the difference in mortality risk, although these data will ultimately

be reported in the Cochrane review comparing tiotropium with

placebo (Karner 2012). A further limitation is that the participants

in both trials had a mean FEV1 of 40% predicted, and many were

already taking inhaled corticosteroids. This means that the find-

ings are applicable to patients with moderate to severe COPD.

The review supports that fewer hospital admissions and COPD ex-

acerbations occur with tiotropium when compared to ipratropium

in the patient population recruited to the two included studies.

Since serious adverse events are largely defined by admission to

hospital, it is not possible to separate out the beneficial effects of

tiotropium in reducing exacerbations from the assessment of all-

cause serious adverse events. The disease specific serious adverse

event data provided by the manufacturers were descried as related

to COPD exacerbations.


The studies included in this review were of high methodological

quality. Both were sponsored by Boehringer Ingelheim and were

conducted with similar protocols and definitions.

Potential biases in the review process

We performed comprehensive searches to identify relevant stud-

ies. We contacted Boehringer Ingelheim to supply missing data.

They supplied the majority of the missing data requested, where

available.

Agreements and disagreements with otherstudies or reviews

Our results are comparable with other reviews looking at

tiotropium versus ipratropium bromide for COPD.



A systematic review by Yohannes 2011 looked at the effective-

ness of tiotropium versus placebo, ipratropium or LABA. The re-

view had similar selection criteria to our review and identified the

same two studies. The review reported comparable results with im-

proved quality of life (OR 2.03; 95% CI 1.34 to 3.07; P = 0.001),

improved symptoms using TDI (OR 2.10; 95% CI 1.28 to 3.44;

P = 0.003), a non-significant reduction in hospitalisations related

to exacerbations (OR 0.59; 95% CI 0.32 to 1.09; P = 0.09) and

overall exacerbations of COPD (OR 0.64; 95% CI 0.44 to 0.92; P

= 0.02). They also showed no statistically significant difference in

the number of patients experiencing a serious adverse event (OR

1.06; 95% CI 0.97 to 1.17).

Celli 2010 is a safety review of Boehringer Ingelheim-sponsored

tiotropium trials (19,545 patients). The review only included stud-

ies comparing tiotropium to placebo and therefore did not include

any studies from this review. The pooled result showed a signifi-

cant decrease in both fatal (RR 0.88; 95% CI 0.77 to 1.00) and

serious adverse events (RR 0.94; 95% CI 0.89 to 1.00), including

fatal events with tiotropium. Meta-analysis of the cardiovascular

data from these trials showed tiotropium to be associated with a

reduction in major cardiovascular events (RR 0.83; 95% CI 0.71

to 0.98) and fatal cardiovascular events (RR 0.77; 95% CI 0.60 to

0.98) when compared to placebo. The cardiovascular composite

endpoint included fatal events in the system organ classes cardiac

and vascular disorders combined with myocardial infarction (fa-

tal and non-fatal), stroke (fatal and non-fatal), and the preferred

terms sudden death, sudden cardiac death, and cardiac death.

Kesten 2009 is another safety review of Boehringer Ingelheim-

sponsored tiotropium trials but only covered trials using the dry

powder inhaler compared to placebo. It included 24 trials with

a minimum of four weeks duration. None were included in our

review. Presenting the data as a risk difference per 100 patient-

years at risk showed a significantly lowered risk of mortality with

tiotropium compared to placebo (RD -0.63; 95% CI -1.14 to -

0.12) (Kesten 2009). Kesten 2009 found a statistically significant

decrease in serious adverse events (RD -1.41; 95% CI -2.81 to -

0.00) using tiotropium dry powder inhaler.

Two recent meta-analyses and systematic reviews by Singh et al

(Singh 2008; Singh 2013) have looked at the cardiovascular risk

with anticholinergic drugs. Singh 2013 found that people with

known rhythm and cardiac disorders at baseline had a higher risk

of cardiac death (RR 8.6; 95% CI 1.1 to 67.2).

A further meta-analysis (Dong 2013) with the fixed-effect model

indicated that the tiotropium soft mist inhaler was associated with

a universally increased risk of overall death compared with placebo

(OR 1.51; 95% CI 1.06 to 2.19), the tiotropium HandiHaler (OR

1.65; 95% CI 1.13 to 2.43), LABA (OR 1.63; 95% CI 1.10 to

2.44) and LABA-inhaled corticosteroid (ICS) (OR 1.90; 95% CI

1.28 to 2.86). The risk was more evident for cardiovascular death,

in patients with severe COPD, and at a higher daily dose.

Another systematic review has looked at direct comparisons be-

tween the soft mist inhaler and other inhaler devices (Ram 2011).

It found three studies looking at the difference between tiotropium

via the soft mist inhaler and tiotropium via the dry powder in-

haler. These were short-term (three to four weeks) cross-over or

parallel group trials. They showed no statistically significant dif-

ference between soft mist and dry powder inhalers in the risk of

exacerbation (715 patients, RR 0.94; 95% CI 0.58 to 1.54). The

results of a head-to-head study comparing the dry powder and the

soft mist inhaler for tiotropium are awaited to elucidate whether

or not there is any difference in mortality associated with the use

of the two inhalers (Cates 2011).

A U T H O R S ’ C O N C L U S I O N S

Implications for practice

Compared with ipratropium bromide, tiotropium treatment was

associated with an improvement in lung function. It did not appear

to increase numbers of serious adverse events. Improvement in

COPD patients’ quality of life was seen along with a reduction

in the risk of exacerbations, including exacerbations leading to

hospitalisation.

This review confirms the recommendations for the use of

tiotropium in place of ipratropium bromide in the management

of patients with stable COPD, but acknowledges that evidence

is scare and further research is advised. Advice regarding choice

of device should be reserved until the comparative study of the

different forms of tiotropium is completed.

Implications for research

Because of the high and often uneven withdrawal rates in COPD

trials, new trials should follow up the vital status of all participants,

even if they have withdrawn from the study. Head-to-head trials

comparing the dry powder Handihaler to the soft mist Respimat

inhaler are required before firm conclusions can be drawn concern-

ing the difference in mortality rates between the inhalers. Hope-

fully the ongoing head-to-head two-year trial NCT01126437 will

be able to clarify the uncertainty.

A C K N O W L E D G E M E N T S

We are grateful to Elizabeth Stovold for help in designing our

search strategy.

We are deeply grateful to Dr Emma Welsh and Chris Cates for all

their help and support whilst producing this review.

Boehringer Ingleheim have been helpful clarifying and supplying

additional information about studies sponsored by them.



R E F E R E N C E S

References to studies included in this review

Vincken 2002 {published data only}

Oostenbrink JB, Rutten-van Molken MP, Al MJ, Van Noord

JA, Vincken W. One-year cost-effectiveness of tiotropium

versus ipratropium to treat chronic obstructive pulmonary

disease. European Respiratory Journal 2004;23(2):241–9.

Van Noord JA, Bantje TA, Eland ME, Korducki L,

Cornelissen PJG. A randomised controlled comparison of

tiotropium and ipratropium in the treatment of chronic

obstructive pulmonary disease. Thorax 2000;55(4):289–94.∗ Vincken W, van Noord JA, Greefhorst A, Bantje TA,

Kesten S, Korducki L, et al.Improved health outcomes

in patients with COPD during 1 yr’s treatment with

tiotropium. European Respiratory Journal 2002;19(2):

209–16.

Voshaar 2008 {published data only}

Clinical trial 205.251. Boehringer Ingelheim.

Clinical trial 205.252. Boehringer Ingelheim.∗ Voshaar T, Lapidus R, Maleki-Yazdi R, Timmer W,

Rubin E, Lowe L, et al.A randomized study of tiotropium

Respimats Soft MistTM Inhaler vs. ipratropium pMDI in

COPD. Respiratory Medicine 2008;102:32–41.

References to studies excluded from this review

Kim 2005 {published data only}

Kim SJ, Kim MS, Lee SH, Kim YK, Moon HS, Park

SH, et al.A comparison of tiotropium 18mug, once daily

and ipratropium 40mug, 4 times daily in a double-blind,

double-dummy, efficacy and safety study in adults with

chronic obstructive pulmonary disease. Tuberculosis and

Respiratory Diseases 2005;58(5):498–506.

Niewoehner 2009 {published data only}

Niewoehner DE, Lapidus R, Cote C, Sharafkhaneh A,

Plautz M, Johnson P, et al.Therapeutic conversion of the

combination of ipratropium and albuterol to tiotropium

in patients with chronic obstructive pulmonary disease.

Pulmonary Pharmacology and Therapeutics 2009;22(6):

587–92.

Serby 2002 {published data only}

Serby CW, Schwartzstein RM, Jones PW, Ries AL, Killian

KJ. Tiotropium: 1-Yr studies versus placebo/ipratropium.

European Respiratory Review 2002;12(82):40–2.

Wang 2007 {published data only}

Wang HY, Xiao Y, Shi LL, Gong Q, Wen ZG. Study on

efficacy and safety of tiotropium powder in patients with

stable COPD. Chinese Journal of New Drugs 2007;16(14):

1119–22.

Zheng 2006 {published data only}

Zheng JP, Kang J, Cai BQ, Zhou X, Cao ZL, Bai CX,

et al.Comparison of tiotropium inhalation capsules and

ipratropium metered dose inhaler in a randomized, double-

blind, double-dummy, efficacy and safety study in patients

with chronic obstructive pulmonary disease. Chinese Journal

of Tuberculosis and Respiratory Diseases 2006;29(6):363–7.

Additional references

Barnes 2000

Barnes P. The pharmacological properties of tiotropium.

Chest 2000;117:63S.

Barr 2005

Barr RG, Bourbeau J, Camargo Carlos A. Tiotropium for

stable chronic obstructive pulmonary disease. Cochrane

Database of Systematic Reviews. Chichester, UK: John

Wiley & Sons, Ltd, 2005, issue 2. [DOI: 10.1002/

14651858.CD002876.pub2]

BNF

British National Formulary. www.bnf.org (accessed 1

November 2011).

Cates 2011

Cates CJ. Safety of tiotropium. BMJ June 2011;14:342.

Celli 2010

Celli B, Decramer M, Leimer I, Vogel U, Kesten S, Tashkin

DP. Cardiovascular safety of tiotropium in patients with

COPD. Chest 2010;137(1):20–30.

Dong 2013

Dong YH, Lin HH, Shau WY, Wu YC, Chang CH, Lai

MS. Comparative safety of inhaled medications in patients

with chronic obstructive pulmonary disease: systematic

review and mixed treatment comparison meta-analysis of

randomised controlled trials. Thorax 2013;68(1):48–56.

GOLD 2010

GOLD. Global strategy for the diagnosis, management,

and prevention of chronic obstructive pulmonary disease.

GOLD 2010.

Healthcare Commission 2006

Healthcare Commission. Clearing the air: A national

study of chronic obstructive pulmonary disease. Healthcare

Commission 2006.

Higgins 2008

Higgins JPT, Green S, editors. Cochrane Handbook for

Systematic Reviews of Interventions Version 5.0.1 [updated

September 2008]. The Cochrane Collaboration, Available

from www.cochrane-handbook.org, 2008.

Karner 2011

Karner C, Cates CJ. The added effect of inhaled

corticosteroids to tiotropium and long-acting beta2-agonists

for chronic obstructive pulmonary disease. Cochrane

Database of Systematic Reviews 2011, Issue 3. [DOI:

10.1002/14651858.CD009039]

Karner 2011a

Karner C, Cates CJ. Combination inhaled steroid and

long-acting beta2-agonist in addition to tiotropium

versus tiotropium or combination alone for chronic

obstructive pulmonary disease. Cochrane Database of

Systematic Reviews 2011, Issue 3. [DOI: 10.1002/

14651858.CD008532.pub2]



Karner 2011b

Karner C, Cates CJ. Long-acting beta2-agonist in addition

to tiotropium versus either tiotropium or long-acting beta2-

agonist alone for chronic obstructive pulmonary disease.

Cochrane Database of Systematic Reviews 2011, Issue 2.

[DOI: 10.1002/14651858.CD008989]

Karner 2012

Karner C, Chong J, Poole P. Tiotropium versus placebo for

chronic obstructive pulmonary disease. Cochrane Database

of Systematic Reviews 2012, Issue 7. [DOI: 10.1002/

14651858.CD009285.pub2]

Kesten 2009

Kesten S, Celli B, Decramer M, Leimer I, Tashkin D.

Tiotropium HandiHaler® in the treatment of COPD: A

safety review. International Journal of Chronic Obstructive

Pulmonary Disease 2009;4:397–409.

Lubinski 2004

Lubinski W. Tiotropium as a controller of

bronchoconstriction. Polski Merkuriusz Lekarski 2004;16:

75-76, 78.

NICE 2010

NICE. Chronic Obstructive Pulmonary Disease: full

guideline. NICE guidelines June 2010.

Ogale 2010

Ogale SS, Lee TA, Au DH, Boudreau DM, Sullivan

SD. Cardiovascular events associated with ipratropium

bromide in COPD. Chest 2010; Vol. 137, issue 1:13–9. [:

0012–3692]

Ram 2011

Ram FS. Tiotropium mist inhaler for COPD increases

risk of mortality compared with placebo. Evidence Based

Medicine 2011;16(6):189–90.

RevMan 5

The Nordic Cochrane Centre, The Cochrane Collaboration.

Review Manager (RevMan). 5.2. Copenhagen: The Nordic

Cochrane Centre, The Cochrane Collaboration, 2008.

Salpeter 2006

Salpeter R, Buckley N, Salpeter E. Meta-analysis:

Anticholinergics, but not beta agonists, reduce severe

exacerbations and respiratory mortality in COPD. Journal

of General Internal Medicine 2006;21(10):1011–9.

Sears 2008

Sears M, Hamilton M. Long-acting bronchodilators in

COPD. Chest 2008;133(5):1057–8.

Singh 2008

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.

Singh 2013

Singh S, Loke YK, Enright P, Furberg CD. Pro-arrhythmic

and pro-ischaemic effects of inhaled anticholinergic

medications. Thorax 2013;68(1):114–6.

Welsh 2010

Welsh EJ, Cates CJ, Poole P. Combination inhaled steroid

and long-acting beta2-agonist versus tiotropium for

chronic obstructive pulmonary disease. Cochrane Database

of Systematic Reviews 2010, Issue 5. [DOI: 10.1002/

14651858.CD007891.pub2]

Yohannes 2011

Yohannes AW, Willgoss TG, Vestbo J. Tiotropium for

treatment of stable COPD: A meta-analysis of clinically

relevant outcomes. Respiratory Care 2011;56(4):477–87.∗ Indicates the major publication for the study



C H A R A C T E R I S T I C S O F S T U D I E S

Characteristics of included studies [ordered by study ID]

Vincken 2002

Methods Randomised, double-blind, double-dummy, parallel group study (2 separate RCTs re-

ported as one study) in 29 centres in the Netherlands (85%) and Belgium (15%) between

October 1996 and June 1998. 12 months

Participants Participants: n= 356 (tiotropium), n= 179 (ipratropium bromide)

Baseline characteristics: mean age (tiotropium 63.6, ipratropium bromide 64.5: gen-

der (tiotropium 84% male, ipratropium bromide 86% male: mean % predicted

FEV1 (tiotropium 41.9, ipratropium bromide 39.4): mean smoking pack year history

(tiotropium 34.3, ipratropium bromide 33.2). Mean baseline FEV1 40% predicted

Diagnostic criteria: as inclusion criteria

COPD severity: moderate to severe

Inclusion criteria: clinical diagnosis of COPD according to ATS criteria and stable airways

obstruction with FEV1 of ≤ 65% predicted and a FEV1/FVC ratio of ≤ 70%. They had

to be at least 40 years of age and all had to be current or previous smoker (≥ 10 pack

years)

Exclusion criteria: patients were excluded if they had a history of asthma, allergic rhinitis,

atopy, or an increased total blood eosinophil count, a significant disease other than

COPD. In addition, patients were excluded if they were on oxygen therapy or had had

a recent upper respiratory tract infection

Interventions Run-in period: 2-week run-in period, ITT

Intervenions: 1st group: tiotropium 18 mcg once daily (Spiriva HandiHaler taken be-

tween 8 am and 10 am) and ipratropium matched placebo four times daily. Two thirds

of patients in this group

2nd group: tiotropium matched placebo once daily and ipratropium 40 mcg four times

daily (Atrovent taken between 8am and 10am firstly, lunch, dinner and when going to

bed). One third of patients in this group

Concominat medication: patients were permitted salbutamol MDI (100 mcg per actua-

tion) as needed for acute symptom relief. Other beta2-agonists (long- and short-acting)

and inhaled anticholinergic medications (other than study drugs) were not permitted.

Concomitant use of theophylline, inhaled steroids and oral steroids (at a dose of ≤ 10

mg/day prednisolone or equivalent) was allowed if the dosage was stable for ≥ 6 weeks

before screening

Outcomes Collected outcomes:

Spirometry was conducted in the outpatient clinic at screening and on day 1 (randomi-

sation) as well as after 1, 7, 13, 26, 39 and 52weeks of therapy. Testing was performed

1h before drug administration, immediately before drug administration, and at 30, 60,

120 and 180min after dosing (and at 240, 300 and 360min on day 1 and at 1, 7 and

13weeks). The highest FEV1 and FVC from three technically adequate measurements

were retained. Peak expiratory flow rates (PEFRs) were self-measured by patients twice

daily (upon arising and at bedtime) using a Mini-Wright Peak Flow Meter (Clement

Clarke International, Harlow, UK). Patients were requested to record the best of three

efforts. Patients also recorded the number of puffs of ’as needed’ salbutamol used



Vincken 2002 (Continued)

Dyspnoea was evaluated using the Baseline Dyspnea Index (BDI) and the Transition

Dyspnea Index (TDI). HRQOL was determined using the St George’s Respiratory Ques-

tionnaire (SGRQ) and the Medical Outcomes Study 36-Item Short-Form Health Survey

(SF-36)

No primary endpoint identified

Reported outcomes:

Trough FEV1 and FVC at 1 year

FEV1 at day 1, and after 1 and 52weeks

FVC at day 1 and after 1, 7, 13, 26, 39 and 52weeks of therapy

Baseline morning and evening PEFR and comparable values throughout the 1 year period

Mean BDI and TDI on all test days

Mean SGRQ and SF-36 on all test days

COPD exacerbations and adverse events

Concomitant use of medication during the treatment period

Notes Safety assessments included a complete blood count, biochemistry, urinalysis and elec-

trocardiogram on entry and upon completion of the study

Risk of bias

Bias Authors’ judgement Support for judgement

Random sequence generation (selection

bias)

Low risk Each patient within each centre was ran-

domly assigned to one of the two treat-

ment groups with two thirds of the pa-

tients assigned to the tiotropium group

and one third to the ipratropium group.

Boehringer Ingelheim Pharma KG gener-

ated the randomisation list using the inter-

nal programme BEA 01 running on a HP

1000 computer. The randomised list was

based on a block size of three

Allocation concealment (selection bias) Unclear risk Not described

Blinding of participants and personnel

(performance bias)

All outcomes

Low risk The double-dummy feature prevented

both investigators and patients from differ-

entiating active drug from placebo. Both

arms used both inhaler devices and there-

fore were completely blinded

Blinding of outcome assessment (detection

bias)

All outcomes

Unclear risk Not described

Incomplete outcome data (attrition bias)

All outcomes

Low risk When a patient could not continue in the

study because of deterioration of COPD,

the missing efficacy data were estimated

using the least favourable data observed



Vincken 2002 (Continued)

prior to withdrawal from the study. For

patients who missed study visits for other

reasons, missing data were estimated using

the patient’s last observed data. For patients

who did not complete all the pulmonary

function measurements on a specific pul-

monary function test day, linear interpola-

tion was used to estimate random, missing,

or middle spirometric measurements. Like-

wise, the minimum observed spirometric

measurements on a specific test day were

used to estimate values at the end of pro-

files that were missing because rescue med-

ication was taken. Finally, the last available

spirometric measurements were used to es-

timate values at the end of the profiles that

were missing for reasons unrelated to the

patient’s treatment response

The withdrawal rates were relatively

low and were balanced between arms

(tiotropium 18 mcg 10% and ipratropium

11%)

Selective reporting (reporting bias) Low risk All specified outcomes reported

Voshaar 2008

Methods Randomized, double-blind, double-dummy, placebo- and active-controlled, parallel

group studies in 39 centres across Germany, Italy, South Africa and Switzerland and

in 25 centres across the USA and Canada from November 2002 to December 2003. 2

identical 12 week trials

Participants Participants: n= 180 (tiotropium 5 mcg), n=180 (tiotropium 10 mcg), n= 178 (iprat-

ropium bromide 36 mcg)

Baseline characteristics: mean age (tiotropium 5 mcg 64, tiotropium 10 mcg 64, ipra-

tropium bromide 65: gender (tiotropium 5 mcg 69% male, tiotropium 10 mcg 72%

male, ipratropium bromide 67% male: mean %predicted FEV1 (tiotropium mcg 40,

tiotropium 10 mcg 39, ipratropium bromide 41): mean smoking pack year history

(tiotropium 5 mcg 52, tiotropium 10 mcg 53 ipratropium bromide 48). Mean baseline

FEV1 40% predicted

Diagnostic criteria: as inclusion criteria

COPD severity: moderate to severe

Inclusion criteria: clinical diagnosis of COPD according to ATS criteria and stable airways

obstruction with FEV1 of ≤ 65% predicted and a FEV1/FVC ratio of ≤ 70%. They had

to be at least 40 years of age and all had to be current or previous smokers (≥10 pack

years)

Exclusion criteria: patients were excluded if they had a history of asthma, allergic rhinitis,

atopy, or an increased total blood eosinophil count, a significant disease other than

COPD. In addition, patients were excluded if they were on oxygen therapy or had had



Voshaar 2008 (Continued)

a recent upper respiratory tract infection

Interventions Run-in period: 2 week run-in period

Interventions:

Group 1: tiotropium 5 mcg delivered via SPIRIVA Respimat SMI once daily and placebo

delivered via pMDI four times daily

Group 2: tiotropium 10 mcg delivered via SPIRIVA Respimat SMI once daily and

placebo delivered via pMDI four times daily

Group 3: ipratropium bromide 36 mcg, delivered via pMDI four times daily and 2

inhalations of placebo Respimat

Group 4: placebo delivered via pMDI four times daily and via Respimats SMI once daily

Concomitant medication: rescue medication (salbutamol pMDI) was permitted as

needed during the study. Oral corticosteroids (equivalent of < 10 mg prednisone per day)

, orally inhaled corticosteroids, theophylline and mucolytics were allowed if stabilized

for at least 6 weeks prior to and throughout the study. Oral beta2-adrenergics and other

investigational drugs were not allowed for at least 1 month prior to run-in. Cromolyn

sodium and nedocromil sodium were not allowed for at least 3 months prior to run-in.

Anticholinergics, inhaled beta2-adrenergics other than salbutamol or fixed combination

inhalers were also not allowed during the treatment period

Outcomes Collected outcomes:

The primary endpoint was the change in trough (i.e. morning pre-dose) FEV1 after 12

weeks of treatment

Secondary spirometry endpoints included FVC, peak expiratory flow rate (PEFR) and

the number of patients achieving a 15% increase above baseline (i.e. pre-dose on test Day

1) in FEV1. Spirometry measures were performed (75) min pre-dose and up to 6 h post-

dose. PEFR was recorded in patient diary cards. Other secondary endpoints included

the weekly mean number of occasions per day that rescue medication (salbutamol) was

used; the severity of COPD symptoms (i.e., wheezing, shortness of breath, coughing

and tightness of chest), which was based on the physician’s assessment of the patient’s

condition during the week prior to a clinic visit, and was rated from 0 (not present) to 3

(severe); the physician’s global evaluation of the patient’s condition, which was rated on

an 8-point scale from poor (1-2) to excellent

Reported outcomes:

Trough FEV1

Post-dose FEV1 AUC 0-6 h

Post-dose FEV1 peak 0-6 h

FVC

PEFR

Rescue medication use

COPD symptoms

Safety assessments

≥15% increase in FEV1 above baseline from 2 h of dosing

Notes Safety was assessed by adverse events, vital signs, 12-lead electrocardiograms (ECG),

routine laboratory tests and physical examination

Funding BI

Risk of bias



Voshaar 2008 (Continued)

Bias Authors’ judgement Support for judgement

Random sequence generation (selection

bias)

Low risk The randomisation list was generated by BI

using a validated system, which involved a

pseudo-random number generator so that

the resulting treatment sequence was both

reproducible and non-predictable

Allocation concealment (selection bias) Low risk All investigational medication for each pa-

tient was identified by a unique medication

number. Each eligible patient was assigned

the lowest medication number available to

the investigator at the time of randomisa-

tion

Blinding of participants and personnel

(performance bias)

All outcomes

Low risk The double-dummy feature prevented

both investigators and patients from differ-

entiating active drug from placebo, despite

the different inhaler devices, which could

otherwise not be blinded

Blinding of outcome assessment (detection

bias)

All outcomes

Low risk In all studies, a selection of standard respi-

ratory endpoints like pulmonary function,

SGRQ, TDI, treadmill, exacerbations, etc.

were used. Outcome assessors remained

blinded with regard to the treatment as-

signments up to database lock

Incomplete outcome data (attrition bias)

All outcomes

Low risk The withdrawal rates were relatively low

(tiotropium 5 mcg 8.9%, tiotropium 10

mcg 10%, and placebo 12.2%)

Selective reporting (reporting bias) Low risk All specified outcomes reported

Characteristics of excluded studies [ordered by study ID]

Study Reason for exclusion

Kim 2005 Less than 12 weeks duration

Niewoehner 2009 Combined ipratropium and albuterol

Serby 2002 Not an RCT

Wang 2007 Less than 12 weeks duration



(Continued)

Zheng 2006 Less than 12 weeks duration



D A T A A N D A N A L Y S E S

Comparison 1. Tiotropium versus ipratropium

Outcome or subgroup titleNo. of

studies

No. of

participants Statistical method Effect size

1 Change in baseline trough FEV1

at 3 months

2 Mean Difference (Fixed, 95% CI) 108.87 [80.37, 137.

37]

1.1 Tiotropium Handihaler 1 Mean Difference (Fixed, 95% CI) 142.0 [100.42, 183.

58]

1.2 Tiotropium Respimat 5 1 Mean Difference (Fixed, 95% CI) 64.0 [8.63, 119.37]

1.3 Tiotropium Respimat 10 1 Mean Difference (Fixed, 95% CI) 95.0 [39.63, 150.37]

2 Change in baseline trough FEV1

at 12 months

1 Mean Difference (IV, Fixed, 95% CI) Totals not selected

2.1 Tiotropium18 1 Mean Difference (IV, Fixed, 95% CI) 0.0 [0.0, 0.0]

3 Patients with at least one serious

adverse event

2 1073 Odds Ratio (M-H, Fixed, 95% CI) 0.50 [0.34, 0.73]

3.1 Tiotropium18 1 535 Odds Ratio (M-H, Fixed, 95% CI) 0.55 [0.36, 0.85]



4 Patients with at least one disease

specific adverse event (=COPD

exac)

1 Odds Ratio (M-H, Fixed, 95% CI) Totals not selected

5 Patients with at least one hospital

admission (all cause)




6 Patients with at least one

exacerbation requiring

hospitalisation





7 All cause mortality 2 1073 Odds Ratio (M-H, Fixed, 95% CI) 1.39 [0.44, 4.39]


7.2 Tiotropium5+10 1 538 Odds Ratio (M-H, Fixed, 95% CI) 0.99 [0.09, 10.98]

8 SGRQ 1 Mean Difference (IV, Fixed, 95% CI) Totals not selected

9 Withdrawals 2 1073 Odds Ratio (M-H, Fixed, 95% CI) 0.58 [0.41, 0.83]




10 Patients with one or more

exacerbations





11 Mean number of exacerbations

per patient per year

1 Mean Difference (Fixed, 95% CI) Totals not selected

12 BDI 1 Mean Difference (IV, Fixed, 95% CI) Totals not selected



13 TDI 1 Mean Difference (IV, Fixed, 95% CI) Totals not selected

14 Change from baseline in total

SGRQ score

1 Mean Difference (Fixed, 95% CI) Totals not selected

Analysis 1.1. Comparison 1 Tiotropium versus ipratropium, Outcome 1 Change in baseline trough FEV1 at

3 months.

Review: Tiotropium versus ipratropium bromide for chronic obstructive pulmonary disease

Comparison: 1 Tiotropium versus ipratropium

Outcome: 1 Change in baseline trough FEV1 at 3 months

Study or subgroup Mean Difference (SE)Mean

Difference WeightMean

Difference

IV,Fixed,95% CI IV,Fixed,95% CI

1 Tiotropium Handihaler

Vincken 2002 142 (21.2147) 47.0 % 142.00 [ 100.42, 183.58 ]

Subtotal (95% CI) 47.0 % 142.00 [ 100.42, 183.58 ]

Heterogeneity: not applicable

Test for overall effect: Z = 6.69 (P < 0.00001)

2 Tiotropium Respimat 5

Voshaar 2008 64 (28.2489) 26.5 % 64.00 [ 8.63, 119.37 ]

Subtotal (95% CI) 26.5 % 64.00 [ 8.63, 119.37 ]


Test for overall effect: Z = 2.27 (P = 0.023)

3 Tiotropium Respimat 10

Voshaar 2008 95 (28.2489) 26.5 % 95.00 [ 39.63, 150.37 ]

Subtotal (95% CI) 26.5 % 95.00 [ 39.63, 150.37 ]



Total (95% CI) 100.0 % 108.87 [ 80.37, 137.37 ]

Heterogeneity: Chi2 = 5.20, df = 2 (P = 0.07); I2 =62%

Test for overall effect: Z = 7.49 (P < 0.00001)

Test for subgroup differences: Chi2 = 5.20, df = 2 (P = 0.07), I2 =62%

-200 -100 0 100 200

Favours ipratropium Favours tiotropium



Analysis 1.2. Comparison 1 Tiotropium versus ipratropium, Outcome 2 Change in baseline trough FEV1 at

12 months.



Outcome: 2 Change in baseline trough FEV1 at 12 months

Study or subgroup tiotropium ipratropiumMean

DifferenceMean

Difference

N Mean(SD) N Mean(SD) IV,Fixed,95% CI IV,Fixed,95% CI

1 Tiotropium18

Vincken 2002 356 120 (220) 179 -30 (220) 150.00 [ 110.49, 189.51 ]

-200 -100 0 100 200


Analysis 1.3. Comparison 1 Tiotropium versus ipratropium, Outcome 3 Patients with at least one serious

adverse event.



Outcome: 3 Patients with at least one serious adverse event

Study or subgroup tiotropium ipratropium Odds Ratio Weight Odds Ratio

n/N n/N M-H,Fixed,95% CI M-H,Fixed,95% CI

1 Tiotropium18

Vincken 2002 57/356 46/179 70.2 % 0.55 [ 0.36, 0.85 ]

Subtotal (95% CI) 356 179 70.2 % 0.55 [ 0.36, 0.85 ]

Total events: 57 (tiotropium), 46 (ipratropium)



2 Tiotropium5

Voshaar 2008 4/180 8/89 14.3 % 0.23 [ 0.07, 0.79 ]

Subtotal (95% CI) 180 89 14.3 % 0.23 [ 0.07, 0.79 ]



0.01 0.1 1 10 100

Favours tiotropium Favours ipratropium

(Continued . . . )



(. . . Continued)Study or subgroup tiotropium ipratropium Odds Ratio Weight Odds Ratio



3 Tiotropium10

Voshaar 2008 10/180 9/89 15.5 % 0.52 [ 0.20, 1.34 ]

Subtotal (95% CI) 180 89 15.5 % 0.52 [ 0.20, 1.34 ]




Total (95% CI) 716 357 100.0 % 0.50 [ 0.34, 0.73 ]


Heterogeneity: Chi2 = 1.73, df = 2 (P = 0.42); I2 =0.0%


Test for subgroup differences: Chi2 = 1.73, df = 2 (P = 0.42), I2 =0.0%

0.01 0.1 1 10 100


Analysis 1.4. Comparison 1 Tiotropium versus ipratropium, Outcome 4 Patients with at least one disease

specific adverse event (=COPD exac).



Outcome: 4 Patients with at least one disease specific adverse event (=COPD exac)

Study or subgroup tiotropium ipratropium Odds Ratio Odds Ratio


Vincken 2002 124/356 85/179 0.59 [ 0.41, 0.85 ]

0.5 0.7 1 1.5 2




Analysis 1.5. Comparison 1 Tiotropium versus ipratropium, Outcome 5 Patients with at least one hospital

admission (all cause).



Outcome: 5 Patients with at least one hospital admission (all cause)



1 Tiotropium5

Voshaar 2008 3/180 7/89 47.4 % 0.20 [ 0.05, 0.79 ]

Subtotal (95% CI) 180 89 47.4 % 0.20 [ 0.05, 0.79 ]




2 Tiotropium10

Voshaar 2008 8/180 8/89 52.6 % 0.47 [ 0.17, 1.30 ]

Subtotal (95% CI) 180 89 52.6 % 0.47 [ 0.17, 1.30 ]




Total (95% CI) 360 178 100.0 % 0.34 [ 0.15, 0.76 ]





0.01 0.1 1 10 100




Analysis 1.6. Comparison 1 Tiotropium versus ipratropium, Outcome 6 Patients with at least one

exacerbation requiring hospitalisation.



Outcome: 6 Patients with at least one exacerbation requiring hospitalisation



1 Tiotropium5

Voshaar 2008 1/180 1/89 4.5 % 0.49 [ 0.03, 7.95 ]

Subtotal (95% CI) 180 89 4.5 % 0.49 [ 0.03, 7.95 ]




2 Tiotropium18

Vincken 2002 26/356 21/179 86.6 % 0.59 [ 0.32, 1.09 ]

Subtotal (95% CI) 356 179 86.6 % 0.59 [ 0.32, 1.09 ]




3 Tiotropium10

Voshaar 2008 1/180 2/89 8.9 % 0.24 [ 0.02, 2.72 ]

Subtotal (95% CI) 180 89 8.9 % 0.24 [ 0.02, 2.72 ]




Total (95% CI) 716 357 100.0 % 0.56 [ 0.31, 0.99 ]





0.01 0.1 1 10 100




Analysis 1.7. Comparison 1 Tiotropium versus ipratropium, Outcome 7 All cause mortality.



Outcome: 7 All cause mortality



1 Tiotropium18

Vincken 2002 9/356 3/179 74.5 % 1.52 [ 0.41, 5.69 ]

Subtotal (95% CI) 356 179 74.5 % 1.52 [ 0.41, 5.69 ]




2 Tiotropium5+10

Voshaar 2008 2/360 1/178 25.5 % 0.99 [ 0.09, 10.98 ]

Subtotal (95% CI) 360 178 25.5 % 0.99 [ 0.09, 10.98 ]




Total (95% CI) 716 357 100.0 % 1.39 [ 0.44, 4.39 ]





0.01 0.1 1 10 100




Analysis 1.8. Comparison 1 Tiotropium versus ipratropium, Outcome 8 SGRQ.



Outcome: 8 SGRQ


DifferenceMean

Difference


Vincken 2002 356 40.9 (13.0189) 179 44.2 (12.9777) -3.30 [ -5.63, -0.97 ]

-4 -2 0 2 4


Analysis 1.9. Comparison 1 Tiotropium versus ipratropium, Outcome 9 Withdrawals.



Outcome: 9 Withdrawals



1 Tiotropium18

Vincken 2002 54/356 38/179 53.3 % 0.66 [ 0.42, 1.05 ]

Subtotal (95% CI) 356 179 53.3 % 0.66 [ 0.42, 1.05 ]




2 Tiotropium5

Voshaar 2008 16/180 15/89 22.7 % 0.48 [ 0.23, 1.03 ]

Subtotal (95% CI) 180 89 22.7 % 0.48 [ 0.23, 1.03 ]




3 Tiotropium10

Voshaar 2008 18/180 16/89 24.0 % 0.51 [ 0.24, 1.05 ]

0.1 0.2 0.5 1 2 5 10


(Continued . . . )





Subtotal (95% CI) 180 89 24.0 % 0.51 [ 0.24, 1.05 ]




Total (95% CI) 716 357 100.0 % 0.58 [ 0.41, 0.83 ]





0.1 0.2 0.5 1 2 5 10


Analysis 1.10. Comparison 1 Tiotropium versus ipratropium, Outcome 10 Patients with one or more

exacerbations.



Outcome: 10 Patients with one or more exacerbations



1 Tiotropium18

Vincken 2002 125/356 82/179 71.5 % 0.64 [ 0.44, 0.92 ]

Subtotal (95% CI) 356 179 71.5 % 0.64 [ 0.44, 0.92 ]




2 Tiotropium5

Voshaar 2008 17/180 12/89 14.7 % 0.67 [ 0.30, 1.47 ]

Subtotal (95% CI) 180 89 14.7 % 0.67 [ 0.30, 1.47 ]




0.2 0.5 1 2 5


(Continued . . . )





3 Tiotropium10

Voshaar 2008 26/180 12/89 13.9 % 1.08 [ 0.52, 2.26 ]

Subtotal (95% CI) 180 89 13.9 % 1.08 [ 0.52, 2.26 ]




Total (95% CI) 716 357 100.0 % 0.71 [ 0.52, 0.95 ]





0.2 0.5 1 2 5


Analysis 1.11. Comparison 1 Tiotropium versus ipratropium, Outcome 11 Mean number of exacerbations

per patient per year.



Outcome: 11 Mean number of exacerbations per patient per year


DifferenceMean

Difference


Vincken 2002 -0.23 (0.08337) -0.23 [ -0.39, -0.07 ]

-0.5 -0.25 0 0.25 0.5




Analysis 1.12. Comparison 1 Tiotropium versus ipratropium, Outcome 12 BDI.



Outcome: 12 BDI


DifferenceMean

Difference


Vincken 2002 356 7.13 (2.6415) 179 7.41 (2.542) -0.28 [ -0.74, 0.18 ]

-1 -0.5 0 0.5 1


Analysis 1.13. Comparison 1 Tiotropium versus ipratropium, Outcome 13 TDI.



Outcome: 13 TDI


DifferenceMean

Difference


Vincken 2002 356 0.46 (2.8376) 179 -0.44 (2.8376) 0.90 [ 0.39, 1.41 ]

-1 -0.5 0 0.5 1




Analysis 1.14. Comparison 1 Tiotropium versus ipratropium, Outcome 14 Change from baseline in total

SGRQ score.



Outcome: 14 Change from baseline in total SGRQ score


DifferenceMean

Difference


Vincken 2002 -3.3 (1.19) -3.30 [ -5.63, -0.97 ]

-4 -2 0 2 4


A P P E N D I C E S

Appendix 1. Sources and search methods for the Cochrane Airways Group Specialised Register(CAGR)

Electronic searches: core databases

Database Frequency of search

MEDLINE (Ovid) Weekly

EMBASE (Ovid) Weekly

CENTRAL (The Cochrane Library) Quarterly

PSYCHINFO (Ovid) Monthly

CINAHL (EBSCO) Monthly

AMED (EBSCO) Monthly



Handsearches: core respiratory conference abstracts

Conference Years searched

American Academy of Allergy, Asthma and Immunology (AAAAI) 2001 onwards

American Thoracic Society (ATS) 2001 onwards

Asia Pacific Society of Respirology (APSR) 2004 onwards

British Thoracic Society Winter Meeting (BTS) 2000 onwards

Chest Meeting 2003 onwards

European Respiratory Society (ERS) 1992, 1994, 2000 onwards

International Primary Care Respiratory Group Congress (IPCRG) 2002 onwards

Thoracic Society of Australia and New Zealand (TSANZ) 1999 onwards

MEDLINE search strategy used to identify trials for the CAGR

COPD search

1. Lung Diseases, Obstructive/

2. exp Pulmonary Disease, Chronic Obstructive/

3. emphysema$.mp.

4. (chronic$ adj3 bronchiti$).mp.

5. (obstruct$ adj3 (pulmonary or lung$ or airway$ or airflow$ or bronch$ or respirat$)).mp.

6. COPD.mp.

7. COAD.mp.

8. COBD.mp.

9. AECB.mp.

10. or/1-9

Filter to identify RCTs

1. exp “clinical trial [publication type]”/

2. (randomised or randomised).ab,ti.

3. placebo.ab,ti.

4. dt.fs.

5. randomly.ab,ti.

6. trial.ab,ti.

7. groups.ab,ti.

8. or/1-7

9. Animals/

10. Humans/



11. 9 not (9 and 10)

12. 8 not 11

The MEDLINE strategy and RCT filter are adapted to identify trials in other electronic databases

C O N T R I B U T I O N S O F A U T H O R S

LC initiated the protocol. LC and MI drafted the protocol. LC wrote the review.

D E C L A R A T I O N S O F I N T E R E S T

LC and MI: none known.

JW has received funding from Boehringer Ingleheim and Pfizer to provide an educational session in primary care on the management

of respiratory conditions.

N O T E S

None



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