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Application to add a Long Acting Muscarinic Agent (LAMA) inhaler

to the Essential Medicines List

1. Summary statement of the proposal for inclusion

The successful control of COPD requires reliever and maintenance medicines,

including bronchodilators that relax airway smooth muscle. Currently the WHO List

of Essential Medicines for COPD contains two bronchodilators, salbutamol and

ipratropium, both being short-acting in nature.

Bronchodilators (BD) are central to COPD treatment (GOLD 2019). They reduce

symptoms, and risk and severity of exacerbations while also improving overall

health status and exercise tolerance.

Two classes of BD are available; beta agonists and anti-muscarinics. Both are

available in short and long acting formulations (Long acting beta agonists, LABA;

long acting anti-muscarinics, LAMA) (Barnes 1995).

Antimuscarinic drugs block the bronchoconstrictor effects of acetylcholine on M3

muscarinic receptors expressed in airway smooth muscle (Melani 2015). Long-

acting antimuscarinic antagonists (LAMAs), such as tiotropium, aclidinium,

glycopyrronium bromide and umeclidinium have prolonged binding to M3

muscarinic receptors, with faster dissociation from M2 muscarinic receptors, thus

prolonging the duration of bronchodilator effect.

There are data showing benefits of long over short acting formulations (eg

tiotropium vs ipratropium) (van Noord, Bantje et al. 2000, Cheyne, Irvin-Sellers et

al. 2013, Cheyne, Irvin-Sellers et al. 2015).

The benefits of LAMA medication on COPD have been shown with aclinidium

(Jones, Singh et al. 2012) and Tiotropium (Karner, Chong et al. 2012, Karner,

Chong et al. 2014). Large studies have shown improvement in lung function,

quality of life, exercise performance and reduced exacerbations with the use of

Tiotropium (Disse, Speck et al. 1999, Casaburi, Kukafka et al. 2005, Kesten,

Casaburi et al. 2008, Karner, Chong et al. 2012, Karner, Chong et al. 2014, Zhou,

Zhong et al. 2017).

There is also evidence on the effectiveness of anti-muscarinics when compared

with LABA agents (Appleton, Jones et al. 2006, Decramer, Chapman et al. 2013)

(Vogelmeier, Hederer et al. 2011, Karner and Cates 2012).

As briefly discussed here, LAMA medications with prolonged bronchodilator effect

are relevant and efficacious for the treatment of symptoms in moderate to severe

COPD patients. It is thus proposed to add this formulation to the EML.

2. Name of the WHO technical department supporting the application

Department of Non Communicable Diseases.

3. Name of the organisation(s) consulted and/or supporting the application

Forum of International Society (FIRS)

Contributors

Maria Victorina Lopez Varela

Universidad de la Republica. Montevideo, Uruguay

Kwun M Fong

University of Queensland Thoracic Research Centre at The Prince Charles Hospital

Dean Schraufnagel

Executive Director, FIRS

Asian-Pacific Society of Respirology (APSR)

Contributors

Kwun M Fong (President APSR)


Thoracic Medicine, The Prince Charles Hospital

Ian A Yang (APSR member)

Head, UQ Northside Clinical Unit and Professor, Faculty of Medicine, The University

of Queensland

Thoracic Program Medical Director, The Prince Charles Hospital


Supported by Global Initiative for Chronic Obstructive Lung Disease (GOLD)

Contributors

Maria Victorina Lopez Varela (BoD GOLD)

Universidad de la Republica. Montevideo, Uruguay

Alvar Agusti (Chair GOLD)

Respiratory Institute, Hospital Clinic, IDIBAPS Univ. Barcelona and Ciberes Barcelona, Spain

Claus Vogelmeir (Chair Science Committee GOLD)

University of Marburg, Germany

Dave Singh (Science Committee GOLD)

University of Manchester, UK

Rogelio Perez Padilla (ALAT)

INER, Ciudad de Mexico, Mexico

Alejandra Rey (ALAT)

Montevideo, Uruguay

4. International Nonproprietary Name (INN) and Anatomical Therapeutic Chemical

(ATC) code of the medicine

DIN (Drug Identification Number)

02246793 SPIRIVA 18µG Capsule


02435381 Spiriva Respimat 2.5 µg Oral inhalation


02394936 Seebri 50 µg Capsule for inhalation


02423596 Incruse Ellipta 62.5 mg/blister

5. Formulations and strengths proposed for inclusion; including adult and

paediatric

Tiotropium

Spiriva HandiHaler, Spiriva Respimat (Boehringer Ingelheim)

Adults

capsule (Spiriva Handihaler; powder for oral inhalation)

• 18mcg

solution for inhalation (Spiriva Respimat)

• 1.25mcg/actuation


Chronic Obstructive Pulmonary Disease

Maintenance treatment of bronchospasm associated with chronic obstructive

pulmonary disease (COPD); reduction of COPD exacerbations

Spiriva Handihaler: 2 PO inhalations of 1 capsule (18 mcg) qDay via HandiHaler

inhalation device

Spiriva Respimat: 5 mcg (2 actuations; 2.5 mcg/actuation) inhaled PO qDay

Glycopyrronium

Seebri Breezhaler (Novartis)

Adults

Capsule 50 µg of glycopyrronium


Available as a maintenance bronchodilator treatment to relieve symptoms in adult

patients with COPD. Once-daily Seebri Breezhaler is approved for use in over 90

countries, including countries within the EU and Latin America, Japan, Canada,

Switzerland and Australia.

Umeclidinium bromide

Incruse Ellipta (Glaxosmithkline)

Adults

Powder for inhalation



Indicated for the long-term, once-daily, maintenance treatment of airflow obstruction

in patients with chronic obstructive pulmonary disease (COPD), including chronic

bronchitis and/or emphysema

62.5 mcg (1 actuation) inhaled PO q Day

Availability of pharmacopoeial standards

The Pharmacopeia status of the LAMA drugs were verified from the European

Pharmacopoeia: https://www.edqm.eu/en/knowledge-database and the entries for

tiotropium and glycopyrronium are reproduced here:

6. Whether listing is requested as an individual medicine or as a representative

of a pharmacological class

The present application requests the inclusion of the LAMA inhaler as representative

of a pharmacological class i.e. LAMA.

7. Treatment details (requirements for diagnosis, treatment and monitoring)

Global Initiative for Chronic Obstructive Lung Disease (GOLD) Document

GOLD document (1) proposes the assessment of COPD based on the patient’s

level of symptoms, future risk of exacerbations, the extent of airflow limitation, the

spirometric abnormality, and the identification of comorbidities. The “ABCD”

assessment tool approaches pharmacologic management according to symptom

burden and exacerbation risk. LAMA medication is included in patients in groups B,

C and D alone or associated with other drugs. Only less symptomatic and non

exacerbating group A patients can be treated with “any BD”.

8. Information supporting the public health relevance

Chronic obstructive pulmonary disease (COPD) is currently the third leading cause

of death in the world and affects about 10% of the adult global population

The COPD burden will undoubtedly increase in the coming decades because of

continued exposure to risk factors tobacco, outdoor and indoor pollution an aging

population and increased childhood survival.

It is well known that there are wide disparities between countries in access to

healthcare however, access to spirometry and basic COPD medications show much

greater inequalities.

There is a need to raise awareness of COPD to emphasize the importance of

accurate diagnosis and ensure drugs with proven efficacy and safety are available

9. Review of benefits: summary of comparative effectiveness in a variety of

clinical settings

We searched systematic reviews, technology assessment reports, and meta-

analyses of controlled clinical trials involving LAMAs in the Database of Abstracts

of Reviews of Effectiveness.

We identified the following studies in DARE:

2014 DARE Cochrane Database of Systematic Reviews: Reviews

Aclidinium bromide for stable chronic obstructive pulmonary disease

[Abstract of a Cochrane Review]

2014 HTA Canadian Agency for Drugs and Technologies in Health (CADTH)

Aclidinium bromide (Tudorza Genuair - Almirall Canada Ltd.) indication: chronic obstructive pulmonary disease

Authors' conclusions: The Canadian Drug Expert Committee (CDEC) recommends that aclidinium bromide be listed for the treatment of chronic obstructive pulmonary disease (COPD) if the following conditions are met: • List in a manner similar to other long-acting antimuscarinic antagonists (LAMAs). • Drug plan costs for aclidinium bromide should not exceed the cost of any other LAMA.

2014 NHS EED

Respiratory Medicine

Cost-effectiveness of the LABA/LAMA dual bronchodilator indacaterol/glycopyrronium in a Swedish healthcare setting

Economic evaluation


Long-acting beta2-agonists and long-acting muscarinic antagonists in a combined inhaler versus either agent alone or placebo for chronic obstructive pulmonary disease



Long-acting inhaled therapy (beta-agonists, anticholinergics and steroids) for COPD: a network meta-analysis


Additional searches for relevant reviews were undertaken in PubMed which

identified relevant papers.

Furthermore, the Cochrane Database of Systematic Reviews was also

interrogated for additional evidence, which are summarized here:

• Oba et al (Oba, Keeney et al. 2018)

For this 2018 Cochrane review, Oba collected and analysed data from 99 studies,

including a total of 101,311 participants with advanced COPD, using a special

method called network meta-analysis, which enabled us to simultaneously compare

the four inhaler groups and 28 individual inhalers (4 LABAs, 5 LAMAs, 9 LABA/ICS

combinations, and 10 LABA/LAMA combinations). They found that LABA/LAMA

combination was the best treatment, followed by LAMA, in preventing flare-ups

although there was some uncertainty in the results. Combination inhalers

(LABA/LAMA and LABA/ICS), are more effective for controlling symptoms than

single-agent therapies (LAMA and LABA), in general. The LABA/LAMA combination

was better than LABA/ICS combination, especially in people with a prior episode of

flare-ups. The LABA/ICS combination had a higher incidence of severe pneumonia

compared to the others. They did not find a difference in benefits and harms,

including side effects, among individual inhalers within the same treatment groups.

Conclusions drawn were that the LABA/LAMA combination is likely the best

treatment in preventing COPD flare-ups. LAMA-containing inhalers appear to have

an advantage over those without LAMA for preventing flare-ups. Combination

inhalers (LABA/LAMA and LABA/ICS), appear more effective for controlling

symptoms than single-agent therapies (LAMA and LABA). Inhaled steroids carry an

increased risk of pneumonia.

Representative LABA examples from Oba et al

Figure 6.1 LAMA vs LABA for moderate to severe exacerbations, favouring LAMAs.

• Kew et al (Kew, Dias et al. 2014)

Kew conducted a Cochrane network meta-analysis in 2014 to assess the benefits of

each type of treatment (e.g. long-acting beta2-agonists) relative to the others for

quality of life and lung function. Kew also looked at how much individual treatments

varied (e.g. How different were the three inhaled steroids from one other?) and

whether particular treatments were more effective than others. Kew assessed the

data for six months and 12 months separately and reported six months as the primary

findings.

Kew found 71 relevant studies, but not all measured the outcomes we were

interested in. Forty-two studies were included in the quality of life analyses

(measured on St George's Respiratory Questionnaire), and 46 were included in the

lung function analyses. Evidence from good quality and similar trials supported

LABA/ICS combinations as the most likely treatment strategy to bring the greatest

improvement to quality of life and lung function. Combination therapy gave an

average benefit of 3.9 units over placebo at six months. LAMAs and LABAs were

ranked second and third at six months (-2.63 and -2.29 units, respectively), especially

when unreliable trials were not included, but a large degree of overlap in the

estimates was noted. Combination LABA/ICS was the highest ranked class for

trough forced expiratory volume in one second (FEV1), with mean improvement over

placebo of 133 mL at six months (95% credible Interval (CrI) 101 to 164). As was the

case for SGRQ, LAMAs (mean difference (MD) 104, 95% CrI 82 to 125) were ranked

just ahead of LABAs (MD 99, 95% CrI 72 to 128) at six months, and ICSs were the

lowest ranked class (MD 65, 95% CrI 33 to 97). For both outcomes, the effects of

LABA and ICS used alone appeared to increase when used together for six months,

but initial differences between the treatment classes were less obvious after a year

of treatment.

Kew concluded that quality of life and lung function were improved most on

combination inhalers (LABA and ICS) and least on ICS alone at 6 and 12 months.

Overall LAMA and LABA inhalers had similar effects, particularly at 12 months. The

network has demonstrated the benefit of ICS when added to LABA for these

outcomes in participants who largely had an FEV1 that was less than 50% predicted,

but the additional expense of combination inhalers and any potential for increased

adverse events (which has been shown by other reviews) require consideration.

• Ni et al (Ni, Soe et al. 2014)

Ni included 12 studies involving 9547 COPD patients in this 2014 Cochrane review

treated over a period of four to 52 weeks. These studies were sponsored by drug

companies and were well designed. Both patients and the people doing the research

did not know which treatment the patients were getting; although in one study one

treatment was known to both parties. More men than women took part, and they

were mostly Caucasians. They were in their 60s and had smoked a lot in their lives.

These people had moderate to severe symptoms when they started treatment.

Aclidinium did not reduce the number of people with flare-ups that need additional

drugs. There was little or no difference in deaths or serious side effects between

aclidinium and a dummy inhaler. Aclidinium inhalers improved quality of life more

than the dummy inhalers. People who took aclidinium had fewer hospital admissions

due to serious flare-ups. Based on our results, among 1000 COPD patients using a

dummy inhaler over four weeks to one year 37 would have severe flare-ups needing

hospital admission. Only 17 to 33 patients out of 1000 would require hospital

admission if they were using aclidinium inhalers. Ni also set out to compare this new

medication with tiotropium, which is already used to treat COPD. There were only

two studies for this comparison thus they could not be sure how aclidinium compared

to tiotropium. Ni also could not compare aclidinium with another well known inhaler

that contains the drug formoterol because of unreliable data. For the comparison of

aclidinium inhalers and dummy inhalers, the Investigators were confident that there

are benefits in terms of the number of hospitalisations and patients' quality of life; we

are less certain about the numbers of flare-ups needing additional drugs and serious

side effects. They did not have enough information to assess any effect on the

number of deaths nor enough information to reliably compare aclidinium with

tiotropium or formoterol.

They concluded that Aclidinium is associated with improved quality of life and

reduced hospitalisations due to severe exacerbations in patients with moderate to

severe stable COPD compared to placebo. Overall, aclidinium did not significantly

reduce mortality, serious adverse events or exacerbations requiring oral steroids or

antibiotics, or both.

• Ni et al 2018 (Ni, Moe et al. 2018)

In 2018, Ni also published a Cochrane review of studies on aclidinium and formoterol

combination and included seven studies involving 5921 people with COPD which

ranged from four weeks to one year long. Most participants were men in their 60s,

moderate-to-heavy smokers, around half of whom were current smokers. They had

moderate-to-severe symptoms of COPD when they started treatment. People in the

studies took either combined inhalers containing aclidinium and formoterol or

aclidinium or formoterol or placebo through a similar inhaler. People taking combined

inhaler and aclidinium inhaler were not different in terms of flare-ups that need

additional medicines, quality of life, hospitalisations, side effects or serious side

effects. However, they were less breathless than those taking aclidinium inhaler.

Fourteen people with COPD would need to be treated with combined inhalers to have

one additional person with a clinically significant improvement in breathlessness.

People on combined inhalers were likely to have fewer flare-ups, side effects and

symptoms and a better quality of life compared to those taking formoterol inhaler.

But, there was little or no difference in hospital admissions due to severe flare-ups,

serious side effects or the risk of dying. When compared to dummy inhalers, people

taking combined inhalers experienced less breathlessness and better quality of life.

Seven people with COPD would need to be treated with combined inhaler to achieve

a significant improvement in quality of life than dummy inhaler. For flare-ups, hospital

admissions, side effects, serious side effects and death, there was no difference

between combined and dummy inhalers. Ni had to interpret the results carefully as

all the included studies were sponsored by pharmaceutical companies, which could

have led to bias. However, the included studies were generally conducted in a

systematic and acceptable manner. The Investigators were confident that combined

inhalers are more effective than single or dummy inhalers at improving

breathlessness and lung function. However, they were less certain about its effects

on flare-ups, hospital admissions, quality of life and side effects.

Conclusions made stated that combined inhalers are more effective than individual

or dummy inhalers for relieving breathlessness and improving lung performance.

They also lead to better quality of life than formoterol or dummy inhalers. However,

they are not different from individual or dummy inhalers in terms of flare-ups or

hospital admissions. These combined inhalers have similar safety profiles as

individual or dummy inhalers in terms of death, side effects or serious side effects.

Combined inhalers probably had lesser side effects and moderate flare-ups than

formoterol, but further studies are needed to confidently support this finding. In

summary, the combined inhalers are an effective option for treatment of COPD and

appear to have a similar safety profile to individual or dummy inhalers.

• Farne et al 015 (Farne and Cates 2015)

In this 2015 Cochrane systematic review, the Investigators found 10 studies involving

10,894 participants comparing the long-term effectiveness and side effects of

combining tiotropium with a LABA. The combination of tiotropium plus LABA resulted,

on average, in a slightly better quality of life and lung function for the participants

compared to using only either tiotropium or a LABA alone, but did not show a

difference in hospital admissions or death. The combination treatment also reduced

the risk of episodes of acutely worse symptoms ('exacerbations'), compared to a

LABA alone but not tiotropium. There were not enough data to determine the risks

and benefits of the different types of LABA.

The conclusions were that this review indicated a small mean improvement in health-

related quality of life and FEV1 for participants on a combination of tiotropium and

LABA compared to either agent alone, and this translated into a small increase in the

number of responders on combination treatment. In addition, adding tiotropium to

LABA reduced exacerbations, although adding LABA to tiotropium did not. Hospital

admission and mortality were not altered by adding LABA to tiotropium, although

there may not be enough data. While it is possible that this is affected by higher

attrition in the tiotropium group, one would expect that participants withdrawn from

the study would have had less favourable outcomes; this means that the expected

direction of attrition bias would be to reduce the estimated benefit of the combination

treatment. The results were largely from studies of olodaterol and there was

insufficient information to assess whether the other LABAs were equivalent to

olodaterol or each other.

Lastly, we identified a recent NICE guideline (Chronic obstructive pulmonary

disease in over 16s: diagnosis and management. NICE guideline. Published: 5

December 2018. nice.org.uk/guidance/ng115). The recommendations are

reproduced here:

Inhaled combination therapy

Inhaled combination therapy refers to combinations of long-acting muscarinic antagonists (LAMA), long-acting beta2

agonists (LABA) and inhaled corticosteroids (ICS).

The evidence on triple therapy (LAMA+LABA+ICS) is being reviewed as part of the 2019 update to this guideline.

This update is expected to publish in June 2019.

1.2.10 Do not assess the effectiveness of bronchodilator therapy using lung function alone. Include a variety of

other measures such as improvement in symptoms, activities of daily living, exercise capacity, and rapidity of

symptom relief. [2004]

1.2.11 Offer LAMA+LABA[2] to people who:

• have spirometrically confirmed COPD and

• do not have asthmatic features/features suggesting steroid responsiveness and

• remain breathless or have exacerbations despite:

o having used or been offered treatment for tobacco dependence if they smoke and

o optimised non-pharmacological management and relevant vaccinations and

o using a short-acting bronchodilator. [2018]

https://www.nice.org.uk/guidance/indevelopment/gid-ng10128https://www.nice.org.uk/guidance/ng115/chapter/Recommendations#ftn.footnote_2https://www.nice.org.uk/guidance/ng115/chapter/recommendations#asthmatic-featuresfeatures-suggesting-steroid-responsiveness

Summary of comparative effectiveness evidence appraisal

Evidence appraisal for specific long-acting muscarinic antagonists (LAMAs) which

result in bronchodilation with a duration of action of 12 to 24 hours, depending on the

agent. A number of LAMAs are available, which are delivered via a range of devices;

aclidinium, glycopyrronium, tiotropium and umeclidinium (Ellipta).

Aclidinium: Aclidinium is a twice daily LAMA. A Cochrane systematic review of 12

RCTs (9,547 participants) showed that, compared to placebo, aclidinium resulted in

marginal improvements in quality of life and FEV1, and reduced the number of

patients with exacerbations requiring hospitalisation (NNT 77, 95% CI 51 to 233) (Ni,

Soe et al. 2014) [evidence level I]. Aclidinium has also been shown to reduce the

rate of moderate to severe exacerbations (OR 0.80) (Wedzicha, Agusti et al. 2016)

[evidence level I].

Glycopyrronium: Once daily glycopyrronium demonstrated significant improvement

in spirometry and a reduction in the rate of moderate to severe exacerbations, but no

difference in quality of life, compared with placebo (D'Urzo, Ferguson et al. 2011,

Kerwin, Hebert et al. 2012) [evidence level II]. In an RCT comparing glycopyrronium

to tiotropium, there was no difference in FEV1, dyspnoea, quality of life, exacerbation

rate or adverse effects (Chapman, Beeh et al. 2014) [evidence level II].

Tiotropium: Once daily tiotropium resulted in improved quality of life, and reduced

exacerbation rates (OR 0.78, 95% CI 0.70 to 0.87; NNT 16, 95% CI 10 to 36)

compared to placebo, in a Cochrane systematic review of 22 studies (23,309

participants) (Karner, Chong et al. 2014) [evidence level I]. Tiotropium improved

FEV1 (mean difference 119 mL, 95% CI 113 to 125), and there was no overall

difference in mortality. In a 2 year RCT of 841 COPD patients with post-

bronchodilator FEV1 >50% predicted, tiotropium resulted in a significantly higher

FEV1 (mean difference of 157 ml, 95% CI 123 to 192) and reduced annual decline in

post-bronchodilator FEV1 (mean difference 22 ml per year, 95% CI 6 to 37),

compared to placebo (Zhou, Zhong et al. 2017) [evidence level II]. However, there

was a high withdrawal rate and 40% were current smokers.

Compared to ipratropium, tiotropium had beneficial effects for quality of life,

dyspnoea and exacerbation rates (Yohannes, Willgoss et al. 2011) [evidence level

I]. Compared to LABAs, tiotropium reduced exacerbation rates (Vogelmeier, Hederer

et al. 2011, Decramer, Chapman et al. 2013) [evidence level II], whereas effects were

heterogeneous for quality of life, compared to various LABAs (Chong, Karner et al.

2012, Decramer, Chapman et al. 2013) [evidence level II]. A Cochrane meta-

analysis comparing treatment with tiotropium [HandiHaler or Respimat] with

ipratropium bromide (via MDI) for patients with stable COPD found that tiotropium

treatment, 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 signifiant 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

(Cheyne, Irvin-Sellers et al. 2015).

Umeclidinium: Once-daily umeclidinium significantly improved lung function,

dyspnoea and quality of life, compared with placebo (Trivedi, Richard et al. 2014)

[evidence level II]. Umeclidinium resulted in a greater improvement in FEV1 than

tiotropium, but there were no significant differences between umeclidinium and

tiotropium for dyspnoea, SGRQ or CAT scores (Feldman, Maltais et al. 2016)

[evidence level II].

Network meta-analyses of LAMAs: A network meta-analysis of LAMAs versus

placebo showed that there were no statistically significant differences among LAMAs

in preventing moderate-to-severe COPD exacerbations (Oba and Lone 2015)

[evidence level I]. Tiotropium HandiHaler was the only LAMA formulation which

reduced severe exacerbations (HR 0.73; 95% CrI 0.60– 0.86). Another network

meta-analysis showed that current LAMAs have similar efficacy for change in FEV1,

SGRQ, dyspnoea and rescue medication use (Ismaila, Huisman et al. 2015)

[evidence level I]. However, with few head to head comparisons of LAMAs available,

the choice of LAMA and inhaler device depends on patient and clinician preferences.

A meta-analysis of 9 studies of LAMA vs. LABA inhalers (17,120 COPD patients,

with tiotropium as the most common LAMA) showed that LAMAs had reduced

exacerbation rates (RR 0.88, 95% CI 0.84 to 0.93) and exacerbation-related

hospitalisations (RR 0.78, 95% CI 0.69 to 0.87), compared to LABAs (Maia, Pincelli

et al. 2017) [evidence level I].

10. Review on harms and toxicity: summary of evidence on safety

Adverse effects

Extensive use of this class of agents in a wide range of doses and clinical settings

has shown them to be very safe. Inhaled anticholinergic drugs are poorly absorbed

which limits the systemic effects observed with atropine (Tashkin 2010). The main

side effect is dryness of mouth (Disse, Speck et al. 1999, Tashkin 2010).

Although occasional urinary symptoms have been reported, there are no data to

prove a true causal relationship (Kesten, Jara et al. 2006). Some patients using

ipratropium report a bitter, metallic taste.

An unexpected small increase in cardiovascular events in COPD patients regularly

treated with ipratropium bromide has been reported (Michele, Pinheiro et al. 2010).

In a large, long-term clinical trial in COPD patients, tiotropium added to other

standard therapies had no effect on cardiovascular risk (Tashkin 2010).

Although there were some initial concerns regarding the safety of tiotropium delivery

via the Respimat® inhaler (Verhamme, Afonso et al. 2013), the findings of a large

trial observed no difference in mortality or exacerbation rates when comparing

tiotropium in a dry-powder inhaler and the Respimat® inhaler (Wise, Anzueto et al.

2013).

There are less safety data available for the other LAMAs, but the rate of anti-

cholinergic side effects for drugs in this class appears to be low and generally similar

(Jones, Singh et al. 2012). Use of solutions with a facemask can precipitate acute

glaucoma, probably as a direct result of the contact between the solution and the eye

(Mulpeter, Walsh et al. 1992, Karabis, Lindner et al. 2013).

Relevant available data on safety:

Adverse effects of LAMAs notably include dry mouth, constipation and urinary

retention (Halpin, Dahl et al. 2015) and as described above.

A safety study showed similar rates of death and exacerbations with tiotropium

HandiHaler and tiotropium Respimat (Wise, Anzueto et al. 2013) [evidence level II].

Summary of regulatory status of the medicine

LAMA is approved for use in various jurisdictions as follows:

EMA in the EU:

• Tiotropium - List of nationally authorised medicinal products.

EMA/356882/2017

Other LAMA medicines in the same class

• Aclidinium bromide (Bretaris Genuair) is indicated as a maintenance

bronchodilator treatment to relieve symptoms in adult patients with chronic

obstructive pulmonary disease (COPD).

• Glycopyrronium (Seebri Breezhaler) is indicated as a maintenance

bronchodilator treatment to relieve symptoms in adult patients with chronic

obstructive pulmonary disease (COPD).

• Umeclidinium bromide (Incruse Ellipta (previously Incruse)) Indicated as a

maintenance bronchodilator treatment to relieve symptoms in adult patients

with chronic obstructive pulmonary disease (COPD).

FDA in USA for Tiotropium:

• SPIRIVA (TIOTROPIUM BROMIDE) | NDA #021395 |

POWDER;INHALATION | Prescription | BOEHRINGER INGELHEIM

• SPIRIVA RESPIMAT (TIOTROPIUM BROMIDE) | NDA #021936 | SPRAY,

METERED;INHALATION | Prescription | BOEHRINGER INGELHEIM

• SPIRIVA RESPIMAT (TIOTROPIUM BROMIDE) | NDA #207070 |

SPRAY;INHALATION | Prescription | BOEHRINGER INGELHEIM

TGA in Australia for Tiotropium:

• ARTG ID 81525 - SPIRIVA is indicated for the long term maintenance

treatment of bronchospasm and dyspnoea associated with chronic obstructive

pulmonary disease

• (COPD). SPIRIVA is indicated for the prevention of COPD exacerbations.

• ARTG ID 132578 - COPD:

• SPIRIVA RESPIMAT is indicated for the long term maintenance treatment of

bronchospasm and dyspnoea associated with chronic obstructive pulmonary

disease (COPD). SPIRIVA RESPIMAT is indicated for the prevention of

COPD exacerbations.

To our knowledge, generics are not yet available.

11. Available data on cost-effectiveness within the pharmacological class or

therapeutic group

A Pubmed search with pearling identified applicable and non-applicable systematic

reviews and primary studies on pharmacoeconomic evaluation of LAMA medications

and comparison with other drugs used on COPD maintenance therapy (Naik, Kamal

et al. 2010, Hertel, Kotchie et al. 2012, Hettle, Wouters et al. 2012, Zaniolo, Iannazzo

et al. 2012, Hoogendoorn, Al et al. 2013, Nowak, Ehlken et al. 2013, Samyshkin,

Schlunegger et al. 2013, Price, Keininger et al. 2014, Thorlund, Zafari et al. 2014,

Eklund, Afzal et al. 2015, Punekar, Landis et al. 2015, Ramadan, Kabbara et al.

2015, Eklund, Afzal et al. 2016, Miravitlles, Galdiz et al. 2016, Ramos, Haughney et

al. 2016, Tebboth, Ternouth et al. 2016, Calzetta, Rogliani et al. 2017, Samp, Joo et

al. 2017, van der Schans, Goossens et al. 2017, Wilson, Patel et al. 2017, Chan, Tan

et al. 2018, Chapin, Mann et al. 2018, Driessen, Shah et al. 2018, Driessen, Whalen

et al. 2018, Kiff, Ruiz et al. 2018, Rajagopalan, Bloudek et al. 2018).

The synthesis of the current data is clearly summarised in a systematic literature

search of 18 recent pharmacoeconomic analyses of COPD maintenance treatments

(van der Schans, Goossens et al. 2017). The Investigators found 6 papers reporting

the cost effectiveness of LAMA monotherapy. Many studies were funded by the

manufacturer, and all studies indicated favourable cost effectiveness. Exacerbation

and mortality rates were found to be the main drivers of cost effectiveness. A

Bayesian comparison of Pair-wise Meta Analyses (PMA) and Network Meta

Analyses (NMA) of COPD treatments reported that at $40,000/QALY threshold, PMA

suggested LAMA had a 30% probability of being the most cost-effective whereas the

NMA suggested that LAMA had a 19% probability of being cost-effective (Thorlund,

Zafari et al. 2014).

It should be noted that the Investigators considered that the QALYs gained was small

and most studies poorly represented the cost effectiveness of real-life medication

use (van der Schans, Goossens et al. 2017). Others have noted potential issues

with adherence (Punekar, Landis et al. 2015).

Representative costs in Australia and USA for the examplar medication

Australia

Spiriva 18 mcg Handihaler: registered, May 2002, launched

• Ex-factory Price: 38,43 AUD monthly costs (30day pack).

Spiriva Respimat 2.5 mcg inhalation solution: Registered April 2008. Launched

• Ex-factory Price: 38,43 AUD (monthly costs 30 day pack)

USA

Spiriva 18 mcg Handihaler: registered, Jan 2004, launched

• WAC Price: $429.47 (as of Jan 2019) monthly costs (30day pack).

Spiriva Respimat 2.5 mcg inhalation solution: Registered Sept 2014. Launched

• WAC Price: $429.47 (as of Jan 2019) monthly costs (30day pack).

References

Appleton, S., T. Jones, P. Poole, L. Pilotto, R. Adams, T. J. Lasserson, B. Smith and J. Muhammad (2006).

"Ipratropium bromide versus long-acting beta-2 agonists for stable chronic obstructive pulmonary

disease." Cochrane Database Syst Rev(3): CD006101.

Barnes, P. J. (1995). "Bronchodilators: basic pharmacology. In: Calverley PMA, Pride NB, eds. Chronic

obstructive pulmonary disease. London: Chapman and Hall; 1995: 391-417. ."

Calzetta, L., P. Rogliani, J. Ora, E. Puxeddu, M. Cazzola and M. G. Matera (2017). "LABA/LAMA

combination in COPD: a meta-analysis on the duration of treatment." Eur Respir Rev 26(143).

Casaburi, R., D. Kukafka, C. B. Cooper, T. J. Witek, Jr. and S. Kesten (2005). "Improvement in exercise

tolerance with the combination of tiotropium and pulmonary rehabilitation in patients with COPD." Chest

127(3): 809-817.

Chan, M. C., E. C. Tan and M. C. Yang (2018). "Cost-effectiveness analysis of a fixed-dose combination

of indacaterol and glycopyrronium as maintenance treatment for COPD." Int J Chron Obstruct Pulmon

Dis 13: 1079-1088.

Chapin, T. W., M. A. Mann, G. L. Brown, T. L. Leitheiser, B. Anderson and D. D. Leedahl (2018).

"Effectiveness of Umeclidinium-Vilanterol for Protocolized Management of Chronic Obstructive

Pulmonary Disease Exacerbation in Hospitalized Patients: A Sequential Period Analysis." Chronic Obstr

Pulm Dis 5(1): 38-45.

Chapman, K. R., K. M. Beeh, J. Beier, E. D. Bateman, A. D'Urzo, R. Nutbrown, M. Henley, H. Chen, T.

Overend and P. D'Andrea (2014). "A blinded evaluation of the efficacy and safety of glycopyrronium, a

once-daily long-acting muscarinic antagonist, versus tiotropium, in patients with COPD: the GLOW5

study." BMC Pulm Med 14: 4.

Cheyne, L., M. J. Irvin-Sellers and J. White (2013). "Tiotropium versus ipratropium bromide for chronic

obstructive pulmonary disease." Cochrane Database Syst Rev(9): CD009552.


obstructive pulmonary disease." Cochrane Database Syst Rev 9: CD009552.


obstructive pulmonary disease." Cochrane Database Syst Rev(9): CD009552.

Chong, J., C. Karner and P. Poole (2012). "Tiotropium versus long-acting beta-agonists for stable chronic

obstructive pulmonary disease." Cochrane Database Syst Rev 9: CD009157.

D'Urzo, A., G. T. Ferguson, J. A. van Noord, K. Hirata, C. Martin, R. Horton, Y. Lu, D. Banerji and T.

Overend (2011). "Efficacy and safety of once-daily NVA237 in patients with moderate-to-severe COPD:

the GLOW1 trial." Respir Res 12: 156.

Decramer, M. L., K. R. Chapman, R. Dahl, P. Frith, G. Devouassoux, C. Fritscher, R. Cameron, M.

Shoaib, D. Lawrence, D. Young, D. McBryan and I. investigators (2013). "Once-daily indacaterol versus

tiotropium for patients with severe chronic obstructive pulmonary disease (INVIGORATE): a

randomised, blinded, parallel-group study." Lancet Respir Med 1(7): 524-533.

Disse, B., G. A. Speck, K. L. Rominger, T. J. Witek, Jr. and R. Hammer (1999). "Tiotropium (Spiriva):

mechanistical considerations and clinical profile in obstructive lung disease." Life Sci 64(6-7): 457-464.

Driessen, M., D. Shah, N. Risebrough, T. Baker, I. Naya, A. Briggs and A. S. Ismaila (2018). "Cost-

effectiveness of umeclidinium as add-on to ICS/LABA therapy in COPD: A UK perspective." Respir Med

145: 130-137.

Driessen, M. T., J. Whalen, B. Seewoodharry Buguth, L. A. Vallejo-Aparicio, I. P. Naya, Y. Asukai, B.

Alcazar-Navarrete, M. Miravitlles, F. Garcia-Rio and N. A. Risebrough (2018). "Cost-effectiveness

analysis of umeclidinium bromide/vilanterol 62.5/25 mcg versus tiotropium/olodaterol 5/5 mcg in

symptomatic patients with chronic obstructive pulmonary disease: a Spanish National Healthcare System

perspective." Respir Res 19(1): 224.

Eklund, O., F. Afzal and F. Borgstrom (2015). "Cost-effectiveness of tiotropium versus usual care and

glycopyrronium in the treatment of chronic obstructive pulmonary disease in Sweden." Cost Eff Resour

Alloc 13: 13.

Eklund, O., F. Afzal, F. Borgstrom, J. Flavin, A. Ternouth, M. E. Ojanguren, C. Crespo and M. Baldwin

(2016). "Cost-effectiveness of tiotropium versus glycopyrronium in moderate to very severe chronic

obstructive pulmonary disease in Canada, Spain, Sweden, and the UK." Clinicoecon Outcomes Res 8:

243-252.

Farne, H. A. and C. J. Cates (2015). "Long-acting beta2-agonist in addition to tiotropium versus either

tiotropium or long-acting beta2-agonist alone for chronic obstructive pulmonary disease." Cochrane

Database Syst Rev(10): Cd008989.

Feldman, G., F. Maltais, S. Khindri, M. Vahdati-Bolouri, A. Church, W. A. Fahy and R. Trivedi (2016).

"A randomized, blinded study to evaluate the efficacy and safety of umeclidinium 62.5 mug compared

with tiotropium 18 mug in patients with COPD." Int J Chron Obstruct Pulmon Dis 11: 719-730.

GOLD (2019). "Global strategy for the diagnosis, management, and prevention of chronic obstructive

pulmonary disease. 2019 report. Available from: http://goldcopd.org."

Halpin, D. M., R. Dahl, C. Hallmann, A. Mueller and D. Tashkin (2015). "Tiotropium HandiHaler((R))

and Respimat((R)) in COPD: a pooled safety analysis." Int J Chron Obstruct Pulmon Dis 10: 239-259.

Hertel, N., R. W. Kotchie, Y. Samyshkin, M. Radford, S. Humphreys and K. Jameson (2012). "Cost-

effectiveness of available treatment options for patients suffering from severe COPD in the UK: a fully

incremental analysis." Int J Chron Obstruct Pulmon Dis 7: 183-199.

Hettle, R., H. Wouters, J. Ayres, R. Gani, S. Kelly, M. Lion and M. Decramer (2012). "Cost-utility analysis

of tiotropium versus usual care in patients with COPD in the UK and Belgium." Respir Med 106(12):

1722-1733.

Hoogendoorn, M., M. J. Al, K. M. Beeh, D. Bowles, J. M. Graf von der Schulenburg, J. Lungershausen,

B. U. Monz, H. Schmidt, C. Vogelmeier and M. P. Rutten-van Molken (2013). "Cost-effectiveness of

tiotropium versus salmeterol: the POET-COPD trial." Eur Respir J 41(3): 556-564.

Ismaila, A. S., E. L. Huisman, Y. S. Punekar and A. Karabis (2015). "Comparative efficacy of long-acting

muscarinic antagonist monotherapies in COPD: a systematic review and network meta-analysis." Int J

Chron Obstruct Pulmon Dis 10: 2495-2517.

Jones, P. W., D. Singh, E. D. Bateman, A. Agusti, R. Lamarca, G. de Miquel, R. Segarra, C. Caracta and

E. Garcia Gil (2012). "Efficacy and safety of twice-daily aclidinium bromide in COPD patients: the

ATTAIN study." Eur Respir J 40(4): 830-836.

Karabis, A., L. Lindner, M. Mocarski, E. Huisman and A. Greening (2013). "Comparative efficacy of

aclidinium versus glycopyrronium and tiotropium, as maintenance treatment of moderate to severe COPD

patients: a systematic review and network meta-analysis." Int J Chron Obstruct Pulmon Dis 8: 405-423.

Karner, C. and C. J. Cates (2012). "Long-acting beta(2)-agonist in addition to tiotropium versus either

tiotropium or long-acting beta(2)-agonist alone for chronic obstructive pulmonary disease." Cochrane

Database Syst Rev(4): CD008989.

Karner, C., J. Chong and P. Poole (2012). "Tiotropium versus placebo for chronic obstructive pulmonary





disease." Cochrane Database Syst Rev 7: CD009285.

Kerwin, E., J. Hebert, N. Gallagher, C. Martin, T. Overend, V. K. Alagappan, Y. Lu and D. Banerji (2012).

"Efficacy and safety of NVA237 versus placebo and tiotropium in patients with COPD: the GLOW2

study." Eur Respir J 40(5): 1106-1114.

Kesten, S., R. Casaburi, D. Kukafka and C. B. Cooper (2008). "Improvement in self-reported exercise

participation with the combination of tiotropium and rehabilitative exercise training in COPD patients."

Int J Chron Obstruct Pulmon Dis 3(1): 127-136.

Kesten, S., M. Jara, C. Wentworth and S. Lanes (2006). "Pooled clinical trial analysis of tiotropium

safety." Chest 130(6): 1695-1703.

Kew, K. M., S. Dias and C. J. Cates (2014). "Long-acting inhaled therapy (beta-agonists, anticholinergics

and steroids) for COPD: a network meta-analysis." Cochrane Database Syst Rev(3): Cd010844.

Kiff, C., S. Ruiz, N. Varol, D. Gibson, A. Davies and D. Purkayastha (2018). "Cost-effectiveness of

roflumilast as an add-on to triple inhaled therapy vs triple inhaled therapy in patients with severe and very

severe COPD associated with chronic bronchitis in the UK." Int J Chron Obstruct Pulmon Dis 13: 2707-

2720.

Maia, I. S., M. P. Pincelli, V. F. Leite, J. Amadera and A. M. Buehler (2017). "Long-acting muscarinic

antagonists vs. long-acting beta 2 agonists in COPD exacerbations: a systematic review and meta-

analysis." J Bras Pneumol 43(4): 302-312.

http://goldcopd.org./

Melani, A. S. (2015). "Long-acting muscarinic antagonists." Expert Rev Clin Pharmacol 8(4): 479-501.

Michele, T. M., S. Pinheiro and S. Iyasu (2010). "The safety of tiotropium--the FDA's conclusions." N

Engl J Med 363(12): 1097-1099.

Miravitlles, M., J. B. Galdiz, A. Huerta, A. Villacampa, D. Carcedo and F. Garcia-Rio (2016). "Cost-

effectiveness of combination therapy umeclidinium/vilanterol versus tiotropium in symptomatic COPD

Spanish patients." Int J Chron Obstruct Pulmon Dis 11: 123-132.

Mulpeter, K. M., J. B. Walsh, M. O'Connor, F. O'Connell and C. Burke (1992). "Ocular hazards of

nebulized bronchodilators." Postgrad Med J 68(796): 132-133.

Naik, S., K. M. Kamal, P. A. Keys and T. J. Mattei (2010). "Evaluating the cost-effectiveness of tiotropium

versus salmeterol in the treatment of chronic obstructive pulmonary disease." Clinicoecon Outcomes Res

2: 25-36.

Ni, H., S. Moe, Z. Soe, K. T. Myint and K. N. Viswanathan (2018). "Combined aclidinium bromide and

long-acting beta2-agonist for chronic obstructive pulmonary disease (COPD)." Cochrane Database Syst

Rev 12: Cd011594.

Ni, H., Z. Soe and S. Moe (2014). "Aclidinium bromide for stable chronic obstructive pulmonary disease."

Cochrane Database Syst Rev 9: CD010509.

Ni, H., Z. Soe and S. Moe (2014). "Aclidinium bromide for stable chronic obstructive pulmonary disease."

Cochrane Database Syst Rev(9): Cd010509.

Nowak, D., B. Ehlken, R. Kotchie, S. Wecht and H. Magnussen (2013). "[Roflumilast in combination

with long-acting bronchodilators in the management of patients with severe and very severe COPD. A

cost-effectiveness analysis for Germany]." Dtsch Med Wochenschr 138(4): 119-125.

Oba, Y., E. Keeney, N. Ghatehorde and S. Dias (2018). "Dual combination therapy versus long-acting

bronchodilators alone for chronic obstructive pulmonary disease (COPD): a systematic review and

network meta-analysis." Cochrane Database Syst Rev 12: Cd012620.

Oba, Y. and N. A. Lone (2015). "Comparative efficacy of long-acting muscarinic antagonists in preventing

COPD exacerbations: a network meta-analysis and meta-regression." Ther Adv Respir Dis 9(1): 3-15.

Price, D., D. Keininger, M. Costa-Scharplatz, K. Mezzi, M. Dimova, Y. Asukai and B. Stallberg (2014).

"Cost-effectiveness of the LABA/LAMA dual bronchodilator indacaterol/glycopyrronium in a Swedish

healthcare setting." Respir Med 108(12): 1786-1793.

Punekar, Y. S., S. H. Landis, K. Wurst and H. Le (2015). "Characteristics, disease burden and costs of

COPD patients in the two years following initiation of long-acting bronchodilators in UK primary care."

Respir Res 16: 141.

Rajagopalan, K., L. Bloudek, J. Marvel, C. Dembek and A. Kavati (2018). "Cost-effectiveness of twice-

daily indacaterol/glycopyrrolate inhalation powder for the treatment of moderate to severe COPD in the

US." Int J Chron Obstruct Pulmon Dis 13: 3867-3877.

Ramadan, W. H., W. K. Kabbara, G. M. El Khoury and S. A. Al Assir (2015). "Combined bronchodilators

(tiotropium plus olodaterol) for patients with chronic obstructive pulmonary disease." Int J Chron Obstruct

Pulmon Dis 10: 2347-2356.

Ramos, M., J. Haughney, N. Henry, L. Lindner and M. Lamotte (2016). "Cost versus utility of aclidinium

bromide 400 microg plus formoterol fumarate dihydrate 12 microg compared to aclidinium bromide 400

microg alone in the management of moderate-to-severe COPD." Clinicoecon Outcomes Res 8: 445-456.

Samp, J. C., M. J. Joo, G. T. Schumock, G. S. Calip, A. S. Pickard and T. A. Lee (2017). "Comparative

Effectiveness of Long-Acting Beta2 -Agonist Combined with a Long-Acting Muscarinic Antagonist or

Inhaled Corticosteroid in Chronic Obstructive Pulmonary Disease." Pharmacotherapy 37(4): 447-455.

Samyshkin, Y., M. Schlunegger, S. Haefliger, S. Ledderhose and M. Radford (2013). "Cost-effectiveness

of roflumilast in combination with bronchodilator therapies in patients with severe and very severe COPD

in Switzerland." Int J Chron Obstruct Pulmon Dis 8: 79-87.

Tashkin, D. P. (2010). "Long-acting anticholinergic use in chronic obstructive pulmonary disease: efficacy

and safety." Curr Opin Pulm Med 16(2): 97-105.

Tebboth, A., A. Ternouth and N. Gonzalez-Rojas (2016). "UK-specific cost-effectiveness of tiotropium +

olodaterol fixed-dose combination versus other LAMA + LABA combinations in patients with COPD."

Clinicoecon Outcomes Res 8: 667-674.

Thorlund, K., Z. Zafari, E. Druyts, E. J. Mills and M. Sadatsafavi (2014). "The impact of incorporating

Bayesian network meta-analysis in cost-effectiveness analysis - a case study of pharmacotherapies for

moderate to severe COPD." Cost Eff Resour Alloc 12(1): 8.

Trivedi, R., N. Richard, R. Mehta and A. Church (2014). "Umeclidinium in patients with COPD: a

randomised, placebo-controlled study." Eur Respir J 43(1): 72-81.

van der Schans, S., L. M. A. Goossens, M. R. S. Boland, J. W. H. Kocks, M. J. Postma, J. F. M. van Boven

and M. Rutten-van Molken (2017). "Systematic Review and Quality Appraisal of Cost-Effectiveness

Analyses of Pharmacologic Maintenance Treatment for Chronic Obstructive Pulmonary Disease:

Methodological Considerations and Recommendations." Pharmacoeconomics 35(1): 43-63.

van Noord, J. A., T. A. Bantje, M. E. Eland, L. Korducki and P. J. Cornelissen (2000). "A randomised

controlled comparison of tiotropium nd ipratropium in the treatment of chronic obstructive pulmonary

disease. The Dutch Tiotropium Study Group." Thorax 55(4): 289-294.

Verhamme, K. M., A. Afonso, S. Romio, B. C. Stricker, G. G. Brusselle and M. C. Sturkenboom (2013).

"Use of tiotropium Respimat Soft Mist Inhaler versus HandiHaler and mortality in patients with COPD."

Eur Respir J 42(3): 606-615.

Vogelmeier, C., B. Hederer, T. Glaab, H. Schmidt, M. P. Rutten-van Molken, K. M. Beeh, K. F. Rabe, L.

M. Fabbri and P.-C. Investigators (2011). "Tiotropium versus salmeterol for the prevention of

exacerbations of COPD." N Engl J Med 364(12): 1093-1103.

Wedzicha, J. A., A. Agusti, G. Donaldson, F. Chuecos, R. Lamarca and E. Garcia Gil (2016). "Effect of

Aclidinium Bromide on Exacerbations in Patients with Moderate-to-Severe COPD: A Pooled Analysis of

Five Phase III, Randomized, Placebo-Controlled Studies." Copd 13(6): 669-676.

Wilson, M. R., J. G. Patel, A. Coleman, C. L. McDade, R. H. Stanford and S. R. Earnshaw (2017). "Cost-

effectiveness analysis of umeclidinium/vilanterol for the management of patients with moderate to very

severe COPD using an economic model." Int J Chron Obstruct Pulmon Dis 12: 997-1008.

Wise, R. A., A. Anzueto, D. Cotton, R. Dahl, T. Devins, B. Disse, D. Dusser, E. Joseph, S. Kattenbeck,

M. Koenen-Bergmann, G. Pledger, P. Calverley and T. Investigators (2013). "Tiotropium Respimat

inhaler and the risk of death in COPD." N Engl J Med 369(16): 1491-1501.

Yohannes, A. M., T. G. Willgoss and J. Vestbo (2011). "Tiotropium for treatment of stable COPD: a meta-

analysis of clinically relevant outcomes." Respir Care 56(4): 477-487.

Zaniolo, O., S. Iannazzo, L. Pradelli and M. Miravitlles (2012). "Pharmacoeconomic evaluation of

tiotropium bromide in the long-term treatment of chronic obstructive pulmonary disease (COPD) in Italy."

Eur J Health Econ 13(1): 71-80.

Zhou, Y., N. S. Zhong, X. Li, S. Chen, J. Zheng, D. Zhao, W. Yao, R. Zhi, L. Wei, B. He, X. Zhang, C.

Yang, Y. Li, F. Li, J. Du, J. Gui, B. Hu, C. Bai, P. Huang, G. Chen, Y. Xu, C. Wang, B. Liang, Y. Li, G.

Hu, H. Tan, X. Ye, X. Ma, Y. Chen, X. Hu, J. Tian, X. Zhu, Z. Shi, X. Du, M. Li, S. Liu, R. Yu, J. Zhao,

Q. Ma, C. Xie, X. Li, T. Chen, Y. Lin, L. Zeng, C. Ye, W. Ye, X. Luo, L. Zeng, S. Yu, W. J. Guan and P.

Ran (2017). "Tiotropium in Early-Stage Chronic Obstructive Pulmonary Disease." N Engl J Med 377(10):

923-935.

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