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(Chest. 2004;126:1946-1953.)
© 2004 American College of Chest Physicians

Tiotropium Bromide*

Nicholas J. Gross, MD, PhD, FCCP

* From the Hines VA Hospital, Hines, IL.

Correspondence to: Nicholas J. Gross, MD, PhD, FCCP, PO Box 1485, Hines, IL 60141; e-mail: Nicholas.gross{at}med.va.gov


   Abstract
TOP
 Abstract
Introduction
 Pharmacology and Actions
 Clinical Efficacy
 Safety and Side Effects
 Clinical Recommendations
 References
 
Tiotropium bromide is a novel, inhaled, once-daily anticholinergic bronchodilator that has recently been approved in the United States for use in patients with COPD. Its unique feature is the persistence of bronchodilation for > 24 h due to prolonged M3 muscarinic receptor blockade. Tiotropium provides significant improvement in spirometry and lung volumes. Clinically relevant outcomes such as the relief of dyspnea, improvement in the quality of life (health status), and reductions in the frequency and severity of acute exacerbations have been consistently obtained with tiotropium in clinical trials. In head-to-head trials, tiotropium administered once daily resulted in bronchodilation (peak, trough, and area under the curve) that was statistically superior to ipratropium administered four times daily and salmeterol administered twice daily. Clinical outcomes (dyspnea, quality of life, exacerbation frequency) were numerically but not always statistically better with tiotropium than salmeterol. Long-term studies of the combination of tiotropium with adrenergic agents, methylxanthines, or inhaled corticosteroids have not been reported in full. Several 1-year studies demonstrate that the only significant side effect of tiotropium was dryness of the mouth, which occurred in approximately 10 to 16% of patients; it is well tolerated by patients and safe.

Key Words: acute exacerbations of COPD • adverse effects • anticholinergic agent • bronchodilators • COPD • quality of life • tiotropium bromide • transition dyspnea index


   Introduction
TOP
 Abstract
 Introduction
Pharmacology and Actions
 Clinical Efficacy
 Safety and Side Effects
 Clinical Recommendations
 References
 
Anticholinergic bronchodilators have become standard care in the treatment of COPD since the introduction of ipratropium bromide in the 1980s. The rationale for their use is that airway smooth muscle is under the control of autonomic activity, and that virtually all of the autonomic nerves in the human lung are derived from the cholinergic parasympathetic system via the vagus nerve. Inhibiting parasympathetic drive to the bronchial smooth muscle results in bronchodilation. Unlike asthma, in which airways obstruction is due to multiple factors, the inhibition of airway smooth-muscle tone may be the major if not the only pharmacologic means of increasing airflow in patients with COPD. There is also evidence that cholinergic tone of the airways may be increased in patients with COPD.12

Ipratropium is recommended in all current guidelines for the management of COPD.3 However, its duration of action is 4 to 6 h; for optimal effect, it must be taken at least every 6 h.4 This feature represents an opportunity for the development of an improved anticholinergic bronchodilator.

Tiotropium bromide is a synthetic quaternary anticholinergic agent that is closely related to ipratropium. It has two important features: it is functionally selective for specific muscarinic receptors that mediate airway smooth-muscle contraction, and it has an extremely long duration of action, making it well suited for once-daily therapy. This review summarizes the pharmacology, clinical efficacy, and safety profile of tiotropium, and suggests recommendations for its use in clinical practice.


   Pharmacology and Actions
TOP
 Abstract
 Introduction
 Pharmacology and Actions
Clinical Efficacy
 Safety and Side Effects
 Clinical Recommendations
 References
 
Parasympathetic activity in the airways induces bronchial smooth-muscle contraction, the release of mucus into the airway lumen, and possibly the stimulation of ciliary activity. These actions are mediated through the M1 and M3 subtypes of muscarinic receptors that are located on the above structures predominantly in large and medium-sized airways.5 In contrast, M2 receptors, which are located on the postganglionic parasympathetic nerves, are seen as autoreceptors that inhibit acetylcholine release from those nerve terminals, thereby providing feedback inhibition. In theory, therefore, optimal inhibition of parasympathetic activity would be achieved by selective antagonism of the M1 and M3 receptors, sparing the M2 receptors.

In both animal and human tissues, tiotropium binds to all three muscarinic receptor subtypes but dissociates rapidly from M2 receptors.6 The half-life of the receptor-drug complex, an index of the duration of action of the drug, is 35 h in the case of tiotropium on M3 receptors vs 0.3 h for ipratropium.67

Other laboratory studies89 in animal tissues indicate that tiotropium shows kinetic selectivity for the relevant muscarinic receptor subtypes in airways, is more potent, and has a substantially longer duration of action than ipratropium. The potential for inhibition of some airway inflammatory mechanisms by anticholinergic agents has been postulated by in vitro studies,1011 but the relevance of these to clinical practice is not known.

Tiotropium bromide has been available in several countries outside the United States since mid-2002, and was approved for use in the United States in January 2004. It is delivered as a dry powder via a novel single-dose device whose clinical use has been described.12 The dosage is 18 µg qd.


   Clinical Efficacy
TOP
 Abstract
 Introduction
 Pharmacology and Actions
 Clinical Efficacy
Safety and Side Effects
 Clinical Recommendations
 References
 
In all clinical studies reviewed here, tiotropium was administered as a dry powder in a random-assignment, double-blind, parallel-group, placebo or active-controlled, double-dummy format.

Bronchodilation
Onset and Duration of Bronchodilation:
Following inhalation of single doses of tiotropium, the FEV1 rises relatively slowly, reaching a peak after 1 to 3 h.1314 The peak response is followed by a plateau of long duration. Doses from 10 to 80 µg showed only slight differences from each other, all being significantly greater than placebo up to 32 h (Fig 1 ).14 The dip in FEV1 seen between 16 h and 24 h after dosing is due to the circadian nocturnal dip in airway function that is not entirely abolished by tiotropium.15



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  		Figure 1. Change in mean FEV1 from baseline. Adapted with permission from Maesen et al.14

 
An alternative and possibly more rigorous test of the duration of effect of a bronchodilator is to determine how long the agent can protect against a bronchospastic stimulus. In a study16 of 12 atopic, male, asthmatic patients, tiotropium in all doses from 10 to 80 µg provided significant protection against a methacholine challenge for 48 h. These data indicate that the effect of tiotropium on airways physiology persists for up to 48 h and possibly longer.

Following repeated daily use of tiotropium, the persistence of bronchodilation from the first day is evident as an increase in the baseline on the next day. The FEV1 23 to 24 h after a dose but before the next dose, its "trough" value, increases over the first few days of regular administration. Van Noord et al13 found that trough FEV1 increased by 0.19 L (18% above the initial baseline) after 8 days of daily administration, most of this increase having occurred by the second day. Trough FVC continued to rise daily during the first week, increasing by 0.67 L (27% above its initial baseline) by day 8.

The elevation in trough values is thought to be clinically important, as it signifies that, with regular daily use, bronchodilation will be maintained around the clock, and that repeated use results in progressive effects above those obtained on a single occasion. Carryover of bronchodilation from one dose to the next has also been observed with long acting ß-agonists17; however, these agents must be administered every 12 h.

Dose Response:
In the dose-response study of Maesen et al14 (Fig 1), effective bronchodilation was found following single administrations of tiotropium at each dose from 10 to 80 µg. To examine the steady state with regular daily dosing, Littner et al18 performed a dose-response study in which 169 patients with COPD received tiotropium in one of four doses (4.5 to 36 µg qd) or placebo for 28 days. In all treated groups, the trough FEV1 rose to a stable level approximately 0.1 L above the initial baseline value. In the 6 h following the final administration, the FEV1 rose a further 0.12 to 0.2 L above placebo, there being no significant difference between doses. All subsequent studies have used a daily dose of 18 µg. After the conclusion of the active phase of this study, and following withdrawal of tiotropium, the baseline (as measured by twice-daily peak expiratory flow rate) gradually returned to its prestudy level over a period of approximately 3 weeks, indicating the prolonged effect of the drug.

Long-term Studies:
The long-term efficacy of tiotropium has been studied in three, paired, multicentered trials.19202122 One 1-year paired trial19 was performed in the United States and compared tiotropium with placebo; another 1-year paired trial20 was performed in Europe, and compared tiotropium with ipratropium. Two 6-month trials2122 compared tiotropium with salmeterol and placebo.

In the 1-year studies, patients with moderate-to-severe COPD received tiotropium, 18 µg qd; the control agent was either placebo,19 or ipratropium, 40 µg qid.20 Enrollment numbers were 921 patients and 535 patients, respectively. In both studies, the primary outcome was trough FEV1 as described above; secondary outcomes included dyspnea scores, measures of health status, exacerbations of COPD, and adverse events. The primary outcome of each study is shown in Figure 2 . The baseline FEV1 values were very similar between treatment groups in both studies. Following 8 days of regular treatment, the trough FEV1 was 0.1 L higher than at baseline in the groups that received tiotropium. In both studies, the trough FEV1 of the group that received tiotropium remained at its 8-day level throughout the rest of the trial period, while the trough FEV1 of the control groups remained at or below baseline levels (intermediate data points have been omitted from Fig 2 for ease of viewing). By the end of both 1-year trials, the difference in trough FEV1 between tiotropium and control groups was 0.15 L.



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  		Figure 2. Mean FEV1 before and after administration of tiotropium or placebo (left panel), and tiotropium or ipratropium (right panel) on day 1, day 8, and after 1 year (p < 0.01 for tiotropium vs placebo at all time points on all test days; p < 0.05 for tiotropium vs ipratropium at all time points on all test days except for the first 2 h following the first dose and up to 1 h after the dose 1 week later). Adapted with permission from Casaburi et al19 and Vincken et al.20

 
Also seen in Figure 2 are the increases in FEV1 in the first 3 h following administration of agents; these were approximately 0.15 L above trough levels in the case of tiotropium. The results of FVC measurements (not shown) paralleled those of FEV1, with trough levels increasing by 0.26 to 0.32 L with tiotropium. The use of open-label albuterol as "rescue" for breakthrough dyspnea was statistically less in the tiotropium group than in the control group.1920 A post hoc analysis23 of one of these reports19 concluded that the spirometric response to tiotropium on the first day of treatment did not predict the ability of patients to benefit from long-term treatment with tiotropium.

The two 6-month trials2122 employed protocols that were very similar to each other and those of the 1-year studies described above, except that they included an additional patient group that received salmeterol, 50 µg bid, by metered-dose inhaler. The report by Brusasco and colleagues22 represents an analysis of the two studies combined, and includes 1,207 subjects. In the combined trials, after 6 months of regular treatment, the trough FEV1 values had increased by 0.12 L over the day-1 baseline values with tiotropium (last administered 23 to 24 h previously), and 0.09 L with salmeterol (last administered 11 to 12 h previously), the differences between these two treatments being statistically significant in the pooled analysis.22 Both the peak and mean FEV1 over the first 3 h after drug administration were statistically greater with tiotropium than with salmeterol, being 83 and 77 mL, respectively (both p < 0.001), in one study,21 and stated as statistically significant (p < 0.05) in the other study,22 although numerical values were not provided.

The results of these large long-term trials therefore indicate that tiotropium administered once daily raises the trough FEV1 by 0.1 to 0.15 L, and raises the peak FEV1 by a further 0.15 to 0.2 L. In both respects, tiotropium is statistically superior to either ipratropium administered four times daily or salmeterol administered twice daily. No loss of efficacy (tachyphylaxis) was seen over the course of 1 year of regular treatment with tiotropium.

Static Lung Volumes and Other Physiologic Effects
Airways obstruction, particularly in COPD, is typically accompanied by hyperinflation as signified by an increase in static lung volumes. In COPD, dyspnea correlates more closely with hyperinflation than with FEV1.2425 Conversely, effective bronchodilation and reduction of dyspnea in COPD are typically associated with a reduction in lung volumes.26 A parameter of lung volumes that is of special interest in COPD is the inspiratory capacity (IC), as it can be measured by spirometry and its increase reflects a decrease in hyperinflation.2427 Two studies have examined the effect of tiotropium on lung volumes including IC.2829 Celli et al28 reported the effects of 4 weeks of treatment with tiotropium or placebo in patients with COPD. The results (Fig 3 ) show that, in patients who received tiotropium, functional residual capacity was substantially reduced and IC was accordingly increased, indicating a reduction in hyperinflation.28 These changes in resting lung volumes could be expected to result in an improvement in dyspnea.



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  		Figure 3. Changes in lung volumes and spirometry following treatment with tiotropium or placebo after 4 weeks. All differences between treatments were significant (p < 0.01). From Celli et al.28 FRC = functional residual capacity; SVC = slow vital capacity.

 
In a double-blind, controlled, clinical trial of tiotropium in 187 patients with COPD, O’Donnell et al29 found that the reduction in hyperinflation resulted in increases in tidal volume during constant work-rate cycle ergometry, with improvements in endurance time and dyspnea index. Endurance time improved by approximately 21% after 6 weeks of treatment. Other studies of the effects of tiotropium on static lung volumes have not been published to my knowledge, nor have studies on recoil pressures or diffusion capacity.

The acute effects of tiotropium on arterial blood gases have been compared with those of salmeterol after 4 weeks of regular therapy with each agent.30 The results indicate that tiotropium had less tendency (although not statistically significant) to produce transient lowering of the PaO2 and an increase in the alveolar-arterial PO2 gradient than salmeterol, consistent with previous studies3132 comparing ipratropium with ß-adrenergic agents.

Symptom Outcomes
Dyspnea:
The effect of tiotropium on this cardinal symptom of COPD has been measured by the transition dyspnea index (TDI) of Mahler et al.33 This questionnaire-based index measures changes in perceived breathlessness from one time to another. Its scale is from – 9 (worse) to + 9 (better); a change of 1 U is considered to be clinically significant.3435 TDI has been systematically measured in all the long-term studies19202122 already mentioned. The improvement in TDI of tiotropium subjects was statistically significant as compared to placebo,192122 tending to increase with duration of use, and sometimes exceeding the 1-U threshold of clinical significance.19 In the studies where salmeterol was included, the improvement in TDI with tiotropium was statistically greater than that with salmeterol in one study21 (p < 0.05, Fig 4 ), but did not reach statistical significance in the other study.22



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  		Figure 4. TDI focal scores at days 57, 113, and 169 for the tiotropium, salmeterol, and placebo groups. *p < 0.05 for tiotropium vs placebo. +p < 0.05 for tiotropium vs salmeterol. From Donohue et al.21

 
Other Symptoms:
In the placebo-controlled study,19 COPD symptoms (wheezing, shortness of breath, coughing, and chest tightness) were evaluated using a severity score (from 0 to 3) at baseline and at each visit. Wheezing and shortness of breath were significantly improved in the tiotropium group compared with the placebo group (p < 0.05), but not cough or chest tightness.

Health Status (Quality of Life)
The effects of tiotropium on health status have been measured in each of the long-term studies19202122 using the St. George’s Respiratory Questionnaire (SGRQ).3637 The total score range is 0 to 100, with lower scores signifying better health status. A difference of 4 U is considered to be clinically significant. It has been validated in patients with COPD.3738

The mean total SGRQ score of subjects who received tiotropium improved significantly compared to baseline in each of these studies, as well as in comparison to placebo192122 or ipratropium,20 but not compared to salmeterol2122 (Fig 5 ). The proportion of patients who obtained a clinically significant improvement in SGRQ score was likewise greater with tiotropium than with placebo or active control. The improvement with tiotropium occurred at the earliest observation point, and tended either to improve further or to remain constant throughout the trials (p < 0.05).



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  		Figure 5. SGRQ total score at baseline and days 57, 113, and 169 for tiotropium, salmeterol and placebo groups. *p < 0.05 for tiotropium vs placebo; other comparisons were not statistically significant. From Donohue et al.21

 
The Medical Outcomes Study Short Form-36 is a generic health status instrument39 with a number of domains not specific for respiratory disease that has also been used in the 1-year tiotropium trials.1920 In both trials,1920 the domains of role physical and physical health summary scores were significantly improved in the tiotropium group in comparison to the control groups (p < 0.05).

Acute Exacerbations of COPD
Acute exacerbations occur one to three times per year in patients with moderate-to-severe COPD. Each exacerbation is associated with significant mortality and deterioration in lung function and quality of life.404142 Exacerbations also account for the major portion of the annual cost of the disease.43 A reduction in the frequency and severity of acute exacerbations is thus an important goal in the management of COPD.3

The effect of tiotropium treatment on the incidence of acute exacerbations has been determined (as a secondary outcome) in each of the long-term studies.192022 The number of COPD exacerbations and hospitalizations due to exacerbations during the treatment period are shown in Table 1 . Patients receiving tiotropium consistently experienced 20 to 30% fewer exacerbations and hospitalizations than patients in the placebo or ipratropium study arms (p < 0.05). The differences between tiotropium and salmeterol were not statistically significant.


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  		Table 1. COPD Exacerbations and Hospitalizations Due to Exacerbations per Patient Year

 
A preliminary report of a recent multicenter study44 in which the time to first exacerbation was the primary outcome showed a statistically significant benefit for patients receiving tiotropium vs the placebo group (p < 0.05). Acute exacerbations of COPD were also less frequent, less likely to require hospitalization, and there was less utilization of health care in patients who were assigned to regular tiotropium, each outcome being less by approximately 20% (p < 0.01).

Other Outcomes
Other outcomes of major importance include mortality and the long-term rate of decline in lung function. Data on these outcomes are lacking at present, but may be provided by ongoing trials.


   Safety and Side Effects
TOP
 Abstract
 Introduction
 Pharmacology and Actions
 Clinical Efficacy
 Safety and Side Effects
Clinical Recommendations
 References
 
Tiotropium, like ipratropium, is poorly absorbed from the GI tract and has very low systemic bioavailability. It therefore has a wide therapeutic margin. The most common adverse effect in trials19202122 has been dryness of the mouth, a typical anticholinergic effect. This was significantly more frequent than in the placebo study arms, and occurred in approximately 10 to 16% of study patients overall, a frequency that may be slightly greater than that observed with ipratropium.19202122 This effect was reported to be mild and rarely led to cessation of the drug. Other adverse events, including serious adverse events, had about the same frequency as in the control groups. Withdrawals from the trials for any reason tended to be less common in the tiotropium groups than the control groups. Adverse effects and warnings are similar to those for ipratropium. To my knowledge, no unfavorable interactions between tiotropium and other drugs have been reported.


   Clinical Recommendations
TOP
 Abstract
 Introduction
 Pharmacology and Actions
 Clinical Efficacy
 Safety and Side Effects
 Clinical Recommendations
References
 
Bronchodilators are the mainstay of therapy in COPD; the latest version of the Global Initiative for Chronic Obstructive Lung Disease guidelines3 states that "regular treatment with long-acting bronchodilators is more effective and convenient than treatment with short-acting bronchodilators... " Due to its prolonged action, tiotropium appears well suited for once-daily therapy of stable COPD. A bronchodilator reversibility test prior to its institution does not predict the long-term benefits of tiotropium,23 and is unnecessary. Because bronchodilation tends to increase over the first week of daily administration, tiotropium is best used on a regular daily basis. For the same reason, and also because its peak effect may take some hours to be achieved, tiotropium is not recommended (or approved) for the rapid relief of dyspnea. The approved dose of tiotropium, 18 µg qd, preferably administered in the morning,15 is optimal and should not be exceeded. Ipratropium is unlikely to augment bronchodilation in this situation,45 nor has ipratropium been approved for as-needed use in United States. It is recommended, rather, that when patients receiving tiotropium experience "breakthrough" dyspnea, they should take a rapidly acting ß2-agonist.

Tiotropium is not recommended for the initial management of acute exacerbations of COPD. Current guidelines3 recommend the use of short-acting agents for these events. Patients already receiving regular tiotropium can continue to receive it if they are able to use the delivery device. Tiotropium in its present dry-powder formulation is not intended or suitable for use with mechanical ventilation.

Data about the co-administration of tiotropium with either inhaled corticosteroids, long-acting ß-adrenergic agents, or methylxanthines are incomplete. Preliminary data suggest that the addition of formoterol twice daily or even once daily significantly increases the bronchodilation obtained with once-daily tiotropium.4647 The benefit of co-administration of other agents requires further study. Tiotropium has consistently shown benefits in lung function, dyspnea, health status, and acute exacerbations, and can therefore be considered as appropriate for first-line maintenance therapy of COPD, including mild (Global Initiative for Chronic Obstructive Lung Disease stage I) disease.48


   Acknowledgements
 
Nicole Pushlar is thanked for editorial support.


   Footnotes
 
Abbreviations: IC = inspiratory capacity; SGRQ = St. George’s Respiratory Questionnaire; TDI = transition dyspnea index

Dr. Gross has received speaking honoraria from the manufacturer of tiotropium, Boehringer-Ingelheim Pharmaceuticals Inc., as well as from Pfizer, GlaxoSmithKline, and Sepracor. Dr. Gross has received payment for consultative services to GlaxoSmithKline, Astra-Zeneca, Dey Labs, Aventis, Sepracor, and Boehringer-Ingelheim. His institution has received research grants from Boehringer-Ingelheim, GlaxoSmithKline, and Dey Labs, and an educational grant from Boehringer-Ingelheim Pharmaceuticals Inc. for invited speakers.

Editorial assistance was provided by personnel employed by Boehringer-Ingelheim Pharmaceuticals, Inc.

Received for publication March 23, 2004. Accepted for publication July 21, 2004.


   References
TOP
 Abstract
 Introduction
 Pharmacology and Actions
 Clinical Efficacy
 Safety and Side Effects
 Clinical Recommendations
 References
 

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