Tiotropium versus ipratropium bromide for chronic obstructive pulmonary disease

  • Review
  • Intervention

Authors


Abstract

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.

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.

Résumé scientifique

Tiotropium versus bromure d'ipratropium dans la maladie pulmonaire obstructive chronique

Contexte

Le tiotropium et le bromure d'ipratropium sont les deux traitements reconnus dans la prise en charge des personnes souffrant d'une maladie pulmonaire obstructive chronique (MPOC). De nouvelles études ont comparé le tiotropium avec le bromure d'ipratropium, une mise à jour est donc nécessaire.

Objectifs

Comparer les effets relatifs de tiotropium pour le bromure d'ipratropium sur les marqueurs de la qualité de vie, les exacerbations, les symptômes, la fonction pulmonaire et les effets indésirables graves chez les patients atteints de MPOC en utilisant les données disponibles d’essais contrôlés randomisés (ECR).

Stratégie de recherche documentaire

Nous avons identifié des ECR dans le registre spécialisé des essais du groupe Cochrane sur les voies respiratoires et ClinicalTrials.gov jusqu' à novembre 2012.

Critères de sélection

Nous avons inclus des ECR en groupes parallèles de 12 semaines ou plus comparant le traitement avec tiotropium par rapport au traitement avec le bromure d'ipratropium chez les patients atteints de MPOC stable.

Recueil et analyse des données

Deux auteurs de la revue ont indépendamment évalué les études à inclure et ont ensuite extrait les données sur la qualité des études et les résultats des critères de jugement. Nous avons contacté les sponsors des essais pour obtenir des informations supplémentaires. Nous avons analysé les données à l'aide de Cochrane Review Manager (RevMan 5,2).

Résultats principaux

Cette revue a inclut deux études de bonne qualité méthodologique, qui portait sur 1 073 participants atteints de MPOC. Les études utilisaient un plan d'étude et des critères d'inclusion similaires et duraient au moins 12 semaines; les participants présentaient un volume expiratoire maximum en une seconde (VEM S de 40% de la valeur prédite au départ. Une étude avait utilisé le tiotropium via l'HandiHaler (18 g) pendant 12 mois et l'autre via l’appareil Respimat (5 g et 10 g) pendant 12 semaines. Les groupes de traitement étaient généralement bien répartis au départ, mais les deux études ne rapportaient pas tous les critères de jugement. Dans l’ensemble, le risque de biais dans les ECR inclus était faible.

Pour les critères de jugement principaux, cette revue a découvert qu'à trois mois (niveau le plus faible mesuré avant le traitement) VEM S augmentait significativement avec le tiotropium par rapport au bromure d'ipratropium (différence moyenne (DM) de 109 ml; intervalle de confiance (IC) à 95% de 81 à 137, preuves de qualité modérée, I 2 =62%). Moins de patients ressentaient un ou plusieurs effets indésirables graves non mortels en utilisant le tiotropium par rapport à l'ipratropium (rapport des cotes (RC) de 0,5; IC à 95% de 0,34 à 0,73, preuves de haute qualité). Cela représente une réduction absolue du risque de 176 à 97 sur 1 000 patients sur une période de 3 à 12 mois. Concernant les effets indésirables spécifiques de la maladie, le groupe sous tiotropium étaient également moins susceptibles de présenter un effet indésirable grave lié à la MPOC par rapport au bromure d'ipratropium (RC 0,59; IC à 95% de 0,41 à 0,85, preuves de qualité modérée).

Pour les critères de jugement secondaires, les deux études rapportaient moins d'admissions à l'hôpital dans le groupe sous tiotropium (RC 0,34; IC à 95% de 0,15 à 0,70, preuves de qualité modérée). De même et dans les deux études, les patients sous tiotropium subissaient moins de crises entraînant une hospitalisation (RC 0,56; IC à 95%, entre 0,31 et 0,99, preuves de qualité modérée). Il n'y avait aucune différence significative en termes de mortalité entre les traitements (RC 1,39; IC à 95%, entre 0,44 et 4,39, preuves de qualité modérée). Une étude a mesuré la qualité de vie en utilisant le Questionnaire Respiratoire St George (QRSG); la moyenne du score du QRSG à 52 semaines était inférieure dans le groupe sous tiotropium que celui sous ipratropium (inférieure sur l'échelle signifie favorable) (DM de -3,30; IC à 95% de -5,63 à -0,97, preuves de qualité modérée).Moins de participants souffraient d’exacerbations dans le groupe sous tiotropium (RC 0,71; IC à 95% de 0,52 à 0,95, preuves de haute qualité) et une différence rapportée dans le nombre moyen d'exacerbations par patient et par année atteignait une signification statistique (DM -0,23; IC à 95%, entre -0,39 et -0,07, P =0,006, preuves de qualité modérée). D'après les 1 073 participants, il y avait significativement moins d'abandons dans le groupe sous tiotropium (RC 0,58; IC à 95% de 0,41 à 0,83, preuves de haute qualité).

Conclusions des auteurs

Cette revue montre que le traitement sous tiotropium, en comparaison avec le bromure d'ipratropium, était associé à une amélioration de la fonction pulmonaire, moins d'admissions à l'hôpital (y compris ceux pour les exacerbations de MPOC), moins d'exacerbations de MPOC et une amélioration de la qualité de vie. Il y avait moins d'effets indésirables graves et d’effets spécifiques de la maladie dans le groupe sous tiotropium, mais aucune différence significative en termes de décès avec le bromure d'ipratropium par rapport au tiotropium. Ainsi, le tiotropium semble être une option raisonnable (au lieu du bromure d'ipratropium) chez les patients atteints de MPOC stable, comme suggéré dans les directives. Nous conseillons une certaine prudence avec le tiotropium via l'inhalateur Respimat et suggérons d’attendre l’obtention d’informations supplémentaires issues d'un essai en cours comparant la mortalité en relation avec les appareils d’injection de tiotropium par rapport aux doses.

Plain language summary

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

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.

Résumé simplifié

Tiotropium versus bromure d'ipratropium dans la prise en charge de la MPOC

Contexte

La maladie pulmonaire obstructive chronique (MPOC) est une maladie pulmonaire qui inclut la bronchite chronique et de l'emphysème. La MPOC est principalement causée par le tabagisme ou l'inhalation de poussière, ce qui conduit à l'obstruction ou un rétrécissement des voies respiratoires. Les symptômes incluent un essoufflement et une toux chronique. Le tiotropium est un médicament inhalé, pris une fois par jour, pour aider à élargir les voies aériennes (bronchodilatateur) et est utilisé dans la prise en charge de la MPOC. Le bromure d'ipratropium est également un bronchodilatateur, mais il a une durée d'action plus courte et doit être pris plusieurs fois par jour.

Qu’avons-nous trouvé?

Nous avons trouvé deux études incluant 1 073 participants qui comparaient l'efficacité à long terme et les effets secondaires du tiotropium par rapport au bromure d'ipratropium. Un essai était de 12 semaines et l'autre était d’un an. Les patients inclus dans les études présentaient des MPOC modérées à sévères (la moyenne du volume expiratoire maximum en une seconde (VEM S était de 40% de la valeur prédite).

Par rapport au bromure d'ipratropium, le traitement au tiotropium a conduit à une amélioration de la fonction pulmonaire et du nombre d'exacerbations de MPOC, à une diminution d'admissions à l'hôpital (y compris ceux pour les exacerbations de MPOC) et à une amélioration la qualité de vie. Le tiotropium semble être plus sûr et avec moins d'effets indésirables, mais il n'y avait aucune différence significative en termes de décès avec le bromure d'ipratropium par rapport au tiotropium.

Qualité des preuves

Dans l'ensemble, les preuves étaient de qualité moyenne à élevée. Le tiotrpium est disponible dans deux différents inhalateurs, Respimat et Handihaler. Il existe certaines inquiétudes concernant l'innocuité de l'appareil Respimat, mais nous attendons la publication d'un essai, avant de pouvoir confirmer si c'est le cas. cela sera rapporté dans une autre revue Cochrane. .

Conclusions

D'après cette revue, le tiotropium apporte plus de bénéfices que le bromure d'ipratropium pour les patients présentant une MPOC modérée à sévère.

La revue était à jour en novembre 2012.

Notes de traduction

Translated by: French Cochrane Centre

Translation supported by: Financeurs pour le Canada : Instituts de Recherche en Sant� du Canada, Minist�re de la Sant� et des Services Sociaux du Qu�bec, Fonds de recherche du Qu�bec-Sant� et Institut National d'Excellence en Sant� et en Services Sociaux; pour la France : Minist�re en charge de la Sant�

Summary of findings(Explanation)

Summary of findings for the main comparison. Tiotropium versus ipratropium for chronic obstructive pulmonary disease
  1. 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

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
OutcomesIllustrative comparative risks* (95% CI)Relative effect
(95% CI)
No of Participants
(studies)
Quality of the evidence
(GRADE)
Comments
Assumed riskCorresponding 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 groupThe mean change from baseline in trough FEV1 in the tiotropium group was
109 mL better
(80 to 137 better)
 1073
(2)
Moderate1MCID = 150 mL

All-cause serious adverse 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)
Moderate2There were also fewer hospitalisation due to exacerbations in the tiotropium group OR 0.56 (95% CI 0.31 to 0.99)

Mortality (all-cause)

Follow-up: 12 weeks to 12 months

11 per 1000 15 per 1000
(5 to 47)
OR 1.39
(0.44 to 4.39)
1073
(2)
Moderate3 

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 ipratropiumThe mean SGRQ in the tiotropium group was
3.3 better
(0.97 to 5.63 better)
 535
(1)
Moderate2MCID = 4 points

Patients with one or more exacerbations

Follow-up: 12 weeks to 12 months

297 per 1000 231 per 1000
(180 to 286)
OR 0.71
(0.52 to 0.95)
1073
(2)
High 

Withdrawals

Follow-up: 12 weeks to 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.

Background

Description of the condition

Chronic obstructive pulmonary disease (COPD) is characterised by airflow obstruction in the lungs. The airflow obstruction is usually 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 estimated two million people have COPD which remains undiagnosed (Healthcare Commission 2006). COPD is usually a progressive disease and lung function can be expected to worsen over time, even with the best available care (GOLD 2010). Management of the disease includes reduction of risk factors, pharmacological treatments, education, pulmonary rehabilitation and exercise programmes (Karner 2011b).

Description of the intervention

Medications for COPD are used to decrease symptoms or complications, 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 anticholinergics 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 hyperinflation (NICE 2010). Long-acting bronchodilators are used to prevent and reduce symptoms in COPD. Inhaled anticholinergic agents, such as tiotropium, have been shown to improve symptoms, reduce exacerbations and improve quality of life in patients with COPD (Ogale 2010); they can be used alone or in combination 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) anticholinergic bronchodilator used in the management of COPD. Continuous treatment with tiotropium significantly reduces the number of exacerbations and the risk of hospitalisation due to exacerbations compared with placebo (Barr 2005; Karner 2012). Treatment trials in COPD show a greater benefit in symptom control and lung function obtained from tiotropium compared with either 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 exacerbations. 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 management 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. Activation of M3 receptors on airway smooth muscle leads to bronchoconstriction through stimulation of phospholipase C, which generates the formation of diacylglycol and inositol triphosphate. These in turn stimulate a number of intracellular signalling cascades leading to changes in intracellular calcium homeostasis and bronchoconstriction (Lubinski 2004).

Tiotropium exhibits pharmacological effects through the inhibition 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 recommended for the treatment of COPD (GOLD 2010; NICE 2010). They both work by blocking M3 receptors. The long-acting anticholinergic 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 compared 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).

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 data.

Methods

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), American 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 ipratropium bromide. Participants were allowed inhaled steroids and other co-medications provided they were not part of the randomised 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 because disease specific adverse events are at higher risk of ascertainment 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 Specialised Register of trials, which is derived from systematic searches of bibliographic databases including the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE, CINAHL, AMED and PsycINFO, and handsearching of respiratory 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 potential studies identified as a result of the search strategy for inclusion 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 information 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 Systematic 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 trials 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 ratios 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 standard 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.

Results

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 metered dose inhaler (MDI). Voshaar 2008 was technically two separate, identical RCTs, but the results were reported together. When results from these trials were meta-analysed, we halved the number 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 participants 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 moderate-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 anticholinergic 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 obtained 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 described 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 subgrouped by tiotropium inhaler type and dose, due to possible differences in the dose received, we did not perform any further subgroup 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 heterogeneity (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 baseline 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 participants). There were fewer people experiencing one or more non-fatal serious adverse events on tiotropium compared to ipratropium (odds ratio (OR) 0.50; 95% CI 0.34 to 0.73; Analysis 1.3). Specific 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 specific adverse events (described as COPD exacerbations) in the tiotropium group (OR 0.59; 95% CI 0.41 to 0.85, moderate quality evidence; Analysis 1.4).

Secondary outcome: hospital admissions, all-cause and due to exacerbations

There were fewer people experiencing one or more hospital admissions 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 exacerbations 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 participants). 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 difference 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 exacerbations 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 significance (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).

Discussion

Summary of main results

This systematic review set out to investigate the medium to long-term (three months or longer) effects of tiotropium when compared to ipratropium bromide. We identified two eligible randomised, 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 manufacturer of tiotropium) and both studies had participants with a mean FEV1 of 40% predicted at baseline. The studies were of high methodical 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 significant increase in trough FEV1 at three months. On one hand this is not surprising given that tiotropium is a long-acting bronchodilator and ipratropium is not, however trough FEV1 is the best measure for long-acting bronchodilators because other outcome 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 requiring 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 clinical 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 of evidence

Tiotropium has been on the market for several years. It was approved in Europe in 2002 and the United States in 2004. To date, numerous trials on tiotropium have been completed. Despite this there have only been two good quality studies comparing tiotropium and ipratropium. Both trials are described in this review and are of high methodological standard, giving good evidence regarding the relative risks and benefits of tiotropium treatment. 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 advantages over ipratropium bromide, and that it would be suitable for those patients diagnosed with COPD who have exertional breathlessness, frequent infections and worsening lung function.

This review does not show any significant difference in mortality 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 recent systematic review, including 19,545 randomised patients in studies of four weeks or longer, showed that tiotropium was associated 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 significant difference between the tiotropium dry powder and soft mist inhaler. Based on the limited data available from the two studies 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 findings are applicable to patients with moderate to severe COPD.

The review supports that fewer hospital admissions and COPD exacerbations 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.

Quality of the evidence

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 studies. We contacted Boehringer Ingelheim to supply missing data. They supplied the majority of the missing data requested, where available.

Agreements and disagreements with other studies 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 effectiveness of tiotropium versus placebo, ipratropium or LABA. The review had similar selection criteria to our review and identified the same two studies. The review reported comparable results with improved 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 studies comparing tiotropium to placebo and therefore did not include any studies from this review. The pooled result showed a significant 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 (fatal 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 between 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 inhaler. These were short-term (three to four weeks) cross-over or parallel group trials. They showed no statistically significant difference 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).

Authors' conclusions

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 concerning the difference in mortality rates between the inhalers. Hopefully the ongoing head-to-head two-year trial NCT01126437 will be able to clarify the uncertainty.

Acknowledgements

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.

Data and analyses

Download statistical data

Comparison 1. Tiotropium versus ipratropium
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Change in baseline trough FEV1 at 3 months2 Mean Difference (Fixed, 95% CI)108.87 [80.37, 137.37]
1.1 Tiotropium Handihaler1 Mean Difference (Fixed, 95% CI)142.0 [100.42, 183.58]
1.2 Tiotropium Respimat 51 Mean Difference (Fixed, 95% CI)64.0 [8.63, 119.37]
1.3 Tiotropium Respimat 101 Mean Difference (Fixed, 95% CI)95.0 [39.63, 150.37]
2 Change in baseline trough FEV1 at 12 months1 Mean Difference (IV, Fixed, 95% CI)Totals not selected
2.1 Tiotropium181 Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]
3 Patients with at least one serious adverse event21073Odds Ratio (M-H, Fixed, 95% CI)0.50 [0.34, 0.73]
3.1 Tiotropium181535Odds Ratio (M-H, Fixed, 95% CI)0.55 [0.36, 0.85]
3.2 Tiotropium51269Odds Ratio (M-H, Fixed, 95% CI)0.23 [0.07, 0.79]
3.3 Tiotropium101269Odds Ratio (M-H, Fixed, 95% CI)0.52 [0.20, 1.34]
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)1538Odds Ratio (M-H, Fixed, 95% CI)0.34 [0.15, 0.76]
5.1 Tiotropium51269Odds Ratio (M-H, Fixed, 95% CI)0.20 [0.05, 0.79]
5.2 Tiotropium101269Odds Ratio (M-H, Fixed, 95% CI)0.47 [0.17, 1.30]
6 Patients with at least one exacerbation requiring hospitalisation21073Odds Ratio (M-H, Fixed, 95% CI)0.56 [0.31, 0.99]
6.1 Tiotropium51269Odds Ratio (M-H, Fixed, 95% CI)0.49 [0.03, 7.95]
6.2 Tiotropium181535Odds Ratio (M-H, Fixed, 95% CI)0.59 [0.32, 1.09]
6.3 Tiotropium101269Odds Ratio (M-H, Fixed, 95% CI)0.24 [0.02, 2.72]
7 All cause mortality21073Odds Ratio (M-H, Fixed, 95% CI)1.39 [0.44, 4.39]
7.1 Tiotropium181535Odds Ratio (M-H, Fixed, 95% CI)1.52 [0.41, 5.69]
7.2 Tiotropium5+101538Odds Ratio (M-H, Fixed, 95% CI)0.99 [0.09, 10.98]
8 SGRQ1 Mean Difference (IV, Fixed, 95% CI)Totals not selected
9 Withdrawals21073Odds Ratio (M-H, Fixed, 95% CI)0.58 [0.41, 0.83]
9.1 Tiotropium181535Odds Ratio (M-H, Fixed, 95% CI)0.66 [0.42, 1.05]
9.2 Tiotropium51269Odds Ratio (M-H, Fixed, 95% CI)0.48 [0.23, 1.03]
9.3 Tiotropium101269Odds Ratio (M-H, Fixed, 95% CI)0.51 [0.24, 1.05]
10 Patients with one or more exacerbations21073Odds Ratio (M-H, Fixed, 95% CI)0.71 [0.52, 0.95]
10.1 Tiotropium181535Odds Ratio (M-H, Fixed, 95% CI)0.64 [0.44, 0.92]
10.2 Tiotropium51269Odds Ratio (M-H, Fixed, 95% CI)0.67 [0.30, 1.47]
10.3 Tiotropium101269Odds Ratio (M-H, Fixed, 95% CI)1.08 [0.52, 2.26]
11 Mean number of exacerbations per patient per year1 Mean Difference (Fixed, 95% CI)Totals not selected
12 BDI1 Mean Difference (IV, Fixed, 95% CI)Totals not selected
13 TDI1 Mean Difference (IV, Fixed, 95% CI)Totals not selected
14 Change from baseline in total SGRQ score1 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.

Analysis 1.2.

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

Analysis 1.3.

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

Analysis 1.4.

Comparison 1 Tiotropium versus ipratropium, Outcome 4 Patients with at least one disease specific adverse event (=COPD exac).

Analysis 1.5.

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

Analysis 1.6.

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

Analysis 1.7.

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

Analysis 1.8.

Comparison 1 Tiotropium versus ipratropium, Outcome 8 SGRQ.

Analysis 1.9.

Comparison 1 Tiotropium versus ipratropium, Outcome 9 Withdrawals.

Analysis 1.10.

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

Analysis 1.11.

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

Analysis 1.12.

Comparison 1 Tiotropium versus ipratropium, Outcome 12 BDI.

Analysis 1.13.

Comparison 1 Tiotropium versus ipratropium, Outcome 13 TDI.

Analysis 1.14.

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

Appendices

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 Meeting2003 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

Contributions of authors

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

Declarations of interest

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.

Notes

None

Characteristics of studies

Characteristics of included studies [ordered by study ID]

Vincken 2002

MethodsRandomised, double-blind, double-dummy, parallel group study (2 separate RCTs reported 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: gender (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 between 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 actuation) 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 (randomisation) as well as after 1, 7, 13, 26, 39 and 52 weeks of therapy. Testing was performed 1h before drug administration, immediately before drug administration, and at 30, 60, 120 and 180 min after dosing (and at 240, 300 and 360 min on day 1 and at 1, 7 and 13 weeks). 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.

Dyspnoea was evaluated using the Baseline Dyspnea Index (BDI) and the Transition Dyspnea Index (TDI). HRQOL was determined using the St George's Respiratory Questionnaire (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 52 weeks

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

NotesSafety assessments included a complete blood count, biochemistry, urinalysis and electrocardiogram on entry and upon completion of the study.
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskEach patient within each centre was randomly assigned to one of the two treatment groups with two thirds of the patients assigned to the tiotropium group and one third to the ipratropium group. Boehringer Ingelheim Pharma KG generated the randomisation list using the internal 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 riskNot described
Blinding of participants and personnel (performance bias)
All outcomes
Low riskThe double-dummy feature prevented both investigators and patients from differentiating active drug from placebo. Both arms used both inhaler devices and therefore were completely blinded
Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskNot 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 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 pulmonary function test day, linear interpolation was used to estimate random, missing, or middle spirometric measurements. Likewise, the minimum observed spirometric measurements on a specific test day were used to estimate values at the end of profiles that were missing because rescue medication was taken. Finally, the last available spirometric measurements were used to estimate 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 riskAll specified outcomes reported

Voshaar 2008

MethodsRandomized, 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 (ipratropium bromide 36 mcg)

Baseline characteristics: mean age (tiotropium 5 mcg 64, tiotropium 10 mcg 64, ipratropium 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 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
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskThe 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 riskAll investigational medication for each patient was identified by a unique medication number. Each eligible patient was assigned the lowest medication number available to the investigator at the time of randomisation
Blinding of participants and personnel (performance bias)
All outcomes
Low riskThe double-dummy feature prevented both investigators and patients from differentiating active drug from placebo, despite the different inhaler devices, which could otherwise not be blinded
Blinding of outcome assessment (detection bias)
All outcomes
Low riskIn all studies, a selection of standard respiratory endpoints like pulmonary function, SGRQ, TDI, treadmill, exacerbations, etc. were used. Outcome assessors remained blinded with regard to the treatment assignments up to database lock
Incomplete outcome data (attrition bias)
All outcomes
Low riskThe withdrawal rates were relatively low (tiotropium 5 mcg 8.9%, tiotropium 10 mcg 10%, and placebo 12.2%)
Selective reporting (reporting bias)Low riskAll specified outcomes reported

Characteristics of excluded studies [ordered by study ID]

StudyReason for exclusion
Kim 2005Less than 12 weeks duration
Niewoehner 2009Combined ipratropium and albuterol
Serby 2002Not an RCT
Wang 2007Less than 12 weeks duration
Zheng 2006Less than 12 weeks duration

Ancillary