Tiotropium and chronic obstructive pulmonary diseaseBMJ 2010; 340 doi: https://doi.org/10.1136/bmj.c833 (Published 19 February 2010) Cite this as: BMJ 2010;340:c833
- R Andrew McIvor, professor of medicine
- 1McMaster University, Firestone Institute for Respiratory Health, 50 Charlton Avenue East, Hamilton ON, Canada L8N 4A6
Tiotropium is a once daily, inhaled, long acting anticholinergic drug that provides at least 24 hour improvement in airflow and hyperinflation in patients with chronic obstructive pulmonary disease (COPD). Clinical trials have consistently shown that these physiological effects translate into improvements in lung function, exercise tolerance, and health related quality of life, in addition to fewer exacerbations.1
Many national and international guidelines suggest using either a long acting β2 agonist or long acting anticholinergic to treat COPD, but because both are effective and convenient no guidance has been given on which one to choose if short acting agents fail to improve dyspnoea.2
Over the past two decades, the short acting anticholinergic, ipratropium, has been widely prescribed for maintenance treatment, at two inhalations of 20 mg four times a day via a metered dose inhaler. This dosage has also been used as the standard comparison in registration clinical trials. However, this dosage is not ideal, and most doctors commonly prescribe much higher doses in an attempt to improve efficacy. Yet boosting the dosage cannot overcome the short lived activity of ipratropium. Alternatively, a once daily long acting anticholinergic improves outcomes more than the standard dose of a short acting anticholinergic or a combination of ipratropium and salbutamol (short acting anticholinergic and short acting β2 agonist).3
Use of inhalers is not intuitive, so all patients need careful instruction, particularly if they are using a metered dose inhaler. Indeed, a common reason for lack of improvement of patients’ symptoms is poor inhaler technique and adherence. Dry powder inhalers are usually simpler to use, but the correct technique still needs to be carefully taught to the patient and checked at each visit.
The long acting anticholinergic, tiotropium, is most commonly delivered via the HandiHaler dry powder inhaler (18 μg/day) and more recently in some countries by a new propellant-free delivery system called the Respimat soft mist inhaler (2.5 μg two inhalations once a day). This last system is an effective alternative multi-dose delivery device for tiotropium.4
However, despite the widespread use of tiotropium and other anticholinergics in COPD over the years, two recent publications—a nested case-control study and a systematic review with meta-analysis5 6—have introduced uncertainty about the safety of these drugs. The studies reported an increased risk of all cause mortality and mortality from cardiovascular disease, myocardial infarction, and stroke in patients with COPD who received either tiotropium or short acting inhaled anticholinergics.
Thankfully this uncertainty has been promptly and adequately tackled by updating the clinical trial safety database for tiotropium, principally by adding data from the four year UPLIFT trial.7 The resulting database includes 30 trials in which 10 846 patients were randomised to tiotropium and 8699 to placebo. An analysis of these trials indicated that tiotropium was associated with a reduction in the risk of all cause mortality, mortality from cardiovascular disease, and cardiovascular events.8
Undoubtedly, the alternative choice of a long acting β2 agonist (salmeterol or formoterol) will also improve lung function in COPD. Monotherapy with a long acting β2 agonist must be avoided, however, if the clinical suspicion of COPD has not been confirmed by spirometry, because of the risk of increased mortality in undiagnosed asthma masquerading as COPD.9 In practice, many doctors avoid this by early introduction of treatment with an inhaled corticosteroid plus a long acting β2 agonist. However, this “asthma”-like approach is costly and puts patients at risk of the well known complications of inhaled steroids and pneumonia—which is specific to people with COPD.10
Screening spirometry is being advocated and adopted to increase the diagnosis of COPD.11 It helps identify patients with milder disease, for whom aggressive modification of risk factors can be successful. Recent subgroup analyses of the major COPD trials TORCH and UPLIFT have highlighted the importance earlier treatment.7 10
Primary care doctors need to reduce the risk of symptoms worsening after patients stop smoking, identify patients with COPD early, and support them in managing symptoms in accordance with current guidelines. Educating and vaccinating patients (annual influenza vaccination along with pneumococcal vaccination (at least once)), encouraging them to exercise, and introducing foundation therapy are appropriate goals for primary care doctors. Patients who do not respond to such an approach may need to be referred to a local COPD clinic for further investigation and individualised care.
Current guidelines favour a stepwise approach to pharmacotherapy.2 All patients should have a rescue short acting β agonist to prevent or reduce acute symptoms, along with tiotropium as initial maintenance or foundation treatment. This could be complemented by a long acting β2 agonist in patients with persistent dyspnoea (emphysema), and by a combination of drugs in those with frequent or recurrent exacerbations (chronic bronchitis).2 New drugs such as phosphodiesterase type-4 inhibitors may play an important role in patients with infrequent exacerbations before turning to a combination of inhaled corticosteroid and long acting β2 agonist.12
Tiotropium is not the “holy grail” of treatment for COPD because it does not slow the loss of lung function,9 but it does improve many patient centred outcomes. This supports its adoption as a safe and effective foundation treatment for all patients except those with mild COPD who need only an occasional short acting β2 agonist to be taken when needed.
Cite this as: BMJ 2010;340:c833
Competing interests: The author has completed the Unified Competing Interest form at www.icmje.org_disclosure.pdf (available on request from the corresponding author). He declares (1) no support from any company for the submitted work. (2) During the past three years he has been a consultant for AstraZeneca, GlaxoSmithKline, Nycomed, Merck, and Pfizer; he has received research funding through per case funding for studies contracted with drug companies including AstraZeneca, Boehringer Ingelheim, and Pfizer. He has received honoriums or been part of a speakers bureau for AstraZeneca, Boehringer Ingelheim, Merck, Nycomed, and Pfizer. He has also been a member of advisory boards for AstraZeneca, Merck, Novartis, Nycomed, and Pfizer. (3) His spouse and children have no financial relationships that may be relevant to the submitted work. (4) He has no non-financial interests that might be relevant to the submitted work.
Provenance and peer review: Commissioned; not externally peer reviewed.