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Adding tiotropium to standard combination therapy may help reduce exacerbations in some adults whose asthma is poorly controlled despite the use of inhaled glucocorticoids and long-acting beta-agonists, according to a report of two randomized, controlled trials published online Sept. 3 in the New England Journal of Medicine.
However, tiotropium use did not increase the number of symptom-free days or boost patients’ asthma-related quality of life scores.
Compared with placebo, tiotropium administered once daily via a soft-mist inhaler significantly lengthened the time to a severe exacerbation of asthma, reduced the number of exacerbations, and provided "modest" bronchodilation when added to inhaled glucocorticoids and LABAs, said Dr. Huib A. M. Kerstjens of the University of Groningen (the Netherlands) and the Groningen Research Institute for Asthma and COPD, and his associates (N. Engl. J. Med. 2012 Sept. 3 [doi:10.1056/NEJMoa1208606]).
However, the improvements in forced expiratory volume in 1 second (FEV1) were "relatively small (less than 10%)," and the number of symptom-free days did not differ between patients who received tiotropium and those who received placebo.
Moreover, the use of rescue medications was the same between the two groups, and patient ratings of asthma-related quality of life also were the same on two measures, the researchers noted.
Tiotropium is the most widely used long-acting anticholinergic inhaled bronchodilator in the world for the treatment of chronic obstructive pulmonary disease, but it has only recently been investigated as a potential adjunctive therapy for asthma.
Dr. Kerstjens and his colleagues assessed the drug’s effects in two 48-week randomized, controlled trials conducted in 15 countries, both of which were funded by Boehringer Ingelheim and Pfizer. They presented their findings at the annual meeting of the European Respiratory Society simultaneously with online publication.
The studies included 912 adults aged 18-75 years who had a 5-year or longer history of asthma and persistent airflow limitation despite self-reported daily use of inhaled glucocorticoids and LABAs. They were randomly assigned to self administer puffs of either tiotropium (237 patients in study 1 and 219 patients in study 2) or placebo (222 patients in study 1 and 234 patients in study 2) every morning as add-on therapy.
Patients were allowed to continue the use of stable doses of sustained-release theophylline, leukotriene modifiers, anti-immunoglobulin E antibody, or oral glucocorticoids, and were given open-label inhalers of salbutamol or albuterol for use as rescue medication.
The first two lung-function end points of both studies were the peak FEV1 response and the trough FEV1 response at week 24, expressed as the change from baseline FEV1. Tiotropium topped placebo in peak FEV1 response by an average of 86 mL in trial 1 and 154 mL in trial 2, differences that were significant.
The average difference in trough FEV1 response between tiotropium and placebo groups was 88 mL in trial 1 and 111 mL in trial 2. Those differences were "relatively small" but also statistically significant.
"It should be noted that [these differences occurred] in patients who were already receiving a long-acting bronchodilator and had fixed airflow limitation," the investigators noted. The results also should be considered "in the context of the need for additional treatments for this patient population and the limitations of current alternatives," they added.
A third lung-function end point was the time until at least 25% of patients had their first severe exacerbation of asthma. That interval was 56 days longer with tiotropium (282 days), compared with placebo (226 days).
The number of severe exacerbations was a secondary end point of both trials. That number was 0.53 exacerbations per patient-year with tiotropium, significantly fewer than the 0.66 per patient-year with placebo. In addition, 27% of patients in both tiotropium groups had at least one severe exacerbation, which was significantly less than the 33% rate in both placebo groups.
However, asthma-related quality of life did not differ significantly between tiotropium and placebo groups in either trial. The minimal clinically important difference between the two groups was not achieved when measured by both the Asthma Control Questionnaire 7 and the 32-item Asthma Quality of Life Questionnaire.
Similarly, daily symptom diaries showed "small or nonsignificant" differences between the active drug and the placebo groups in symptom-free days. And the use of rescue medications also was similar.
Adverse events occurred in 73.5% of the tiotropium group and 80.3% of the placebo group, and allergic rhinitis was the only one that occurred more often in the tiotropium group. Adverse events were judged to be treatment related in 5.7% of the tiotropium group and 4.6% of the placebo group.
Serious adverse events occurred in 8.1% of the tiotropium group and 8.8% of the placebo group. Three of those events – two asthma exacerbations and one cerebral infarction – occurred in the tiotropium group and were considered life threatening.
Cardiac events occurred in less than 2% of both study groups; they were considered drug related in 0.4% of patients in the tiotropium group and 0.2% of those in the placebo group. Adverse changes in blood pressure, pulse rate, laboratory measures, and electrocardiograms were balanced between the two study groups.
Less than 2% of all patients experienced dry mouth – a typical adverse event with anticholinergic agents – but it was reported more frequently in the tiotropium group (eight patients vs. three patients), Dr. Kerstjens and his associates said.
Dr. Kerstjens reported additional associations with Almirall, Chiesi, Novartis, and Nycomed, and his associates reported ties to numerous industry sources.
These studies’ findings cannot be generalized to all patients with uncontrolled asthma, because both studies selectively enrolled patients who had persistent airflow limitation – thus skewing the study populations to resemble the COPD patients who are already known to benefit from tiotropium, said Dr. Elisabeth H. Bel.
Both studies also excluded patients with heart disease, which may have masked the fact that soft-mist inhaler delivery of tiotropium "may impose a substantial risk in patients with a history of [cardiovascular] events," Dr. Bel cautioned.
In addition, the researchers failed to verify whether subjects were fully compliant with background asthma therapy at enrollment. Because it is known that more than 80% of patients with poorly controlled asthma have poor treatment adherence, the patients’ relative undertreatment at baseline "might have left room for additional bronchodilation by tiotropium," she noted.
Dr. Bel is in the department of pulmonology at the Academic Medical Center, Amsterdam. She reported ties to Actelion, GlaxoSmithKline, Merck, Novartis, Nycomed, and Schering Plough. These remarks were taken from her editorial accompanying Dr. Kerstjens’ report (N. Engl. J. Med. 2012 Sept. 3 [doi:10.1056/NEJMe1209381]).
These studies’ findings cannot be generalized to all patients with uncontrolled asthma, because both studies selectively enrolled patients who had persistent airflow limitation – thus skewing the study populations to resemble the COPD patients who are already known to benefit from tiotropium, said Dr. Elisabeth H. Bel.
Both studies also excluded patients with heart disease, which may have masked the fact that soft-mist inhaler delivery of tiotropium "may impose a substantial risk in patients with a history of [cardiovascular] events," Dr. Bel cautioned.
In addition, the researchers failed to verify whether subjects were fully compliant with background asthma therapy at enrollment. Because it is known that more than 80% of patients with poorly controlled asthma have poor treatment adherence, the patients’ relative undertreatment at baseline "might have left room for additional bronchodilation by tiotropium," she noted.
Dr. Bel is in the department of pulmonology at the Academic Medical Center, Amsterdam. She reported ties to Actelion, GlaxoSmithKline, Merck, Novartis, Nycomed, and Schering Plough. These remarks were taken from her editorial accompanying Dr. Kerstjens’ report (N. Engl. J. Med. 2012 Sept. 3 [doi:10.1056/NEJMe1209381]).
These studies’ findings cannot be generalized to all patients with uncontrolled asthma, because both studies selectively enrolled patients who had persistent airflow limitation – thus skewing the study populations to resemble the COPD patients who are already known to benefit from tiotropium, said Dr. Elisabeth H. Bel.
Both studies also excluded patients with heart disease, which may have masked the fact that soft-mist inhaler delivery of tiotropium "may impose a substantial risk in patients with a history of [cardiovascular] events," Dr. Bel cautioned.
In addition, the researchers failed to verify whether subjects were fully compliant with background asthma therapy at enrollment. Because it is known that more than 80% of patients with poorly controlled asthma have poor treatment adherence, the patients’ relative undertreatment at baseline "might have left room for additional bronchodilation by tiotropium," she noted.
Dr. Bel is in the department of pulmonology at the Academic Medical Center, Amsterdam. She reported ties to Actelion, GlaxoSmithKline, Merck, Novartis, Nycomed, and Schering Plough. These remarks were taken from her editorial accompanying Dr. Kerstjens’ report (N. Engl. J. Med. 2012 Sept. 3 [doi:10.1056/NEJMe1209381]).
Adding tiotropium to standard combination therapy may help reduce exacerbations in some adults whose asthma is poorly controlled despite the use of inhaled glucocorticoids and long-acting beta-agonists, according to a report of two randomized, controlled trials published online Sept. 3 in the New England Journal of Medicine.
However, tiotropium use did not increase the number of symptom-free days or boost patients’ asthma-related quality of life scores.
Compared with placebo, tiotropium administered once daily via a soft-mist inhaler significantly lengthened the time to a severe exacerbation of asthma, reduced the number of exacerbations, and provided "modest" bronchodilation when added to inhaled glucocorticoids and LABAs, said Dr. Huib A. M. Kerstjens of the University of Groningen (the Netherlands) and the Groningen Research Institute for Asthma and COPD, and his associates (N. Engl. J. Med. 2012 Sept. 3 [doi:10.1056/NEJMoa1208606]).
However, the improvements in forced expiratory volume in 1 second (FEV1) were "relatively small (less than 10%)," and the number of symptom-free days did not differ between patients who received tiotropium and those who received placebo.
Moreover, the use of rescue medications was the same between the two groups, and patient ratings of asthma-related quality of life also were the same on two measures, the researchers noted.
Tiotropium is the most widely used long-acting anticholinergic inhaled bronchodilator in the world for the treatment of chronic obstructive pulmonary disease, but it has only recently been investigated as a potential adjunctive therapy for asthma.
Dr. Kerstjens and his colleagues assessed the drug’s effects in two 48-week randomized, controlled trials conducted in 15 countries, both of which were funded by Boehringer Ingelheim and Pfizer. They presented their findings at the annual meeting of the European Respiratory Society simultaneously with online publication.
The studies included 912 adults aged 18-75 years who had a 5-year or longer history of asthma and persistent airflow limitation despite self-reported daily use of inhaled glucocorticoids and LABAs. They were randomly assigned to self administer puffs of either tiotropium (237 patients in study 1 and 219 patients in study 2) or placebo (222 patients in study 1 and 234 patients in study 2) every morning as add-on therapy.
Patients were allowed to continue the use of stable doses of sustained-release theophylline, leukotriene modifiers, anti-immunoglobulin E antibody, or oral glucocorticoids, and were given open-label inhalers of salbutamol or albuterol for use as rescue medication.
The first two lung-function end points of both studies were the peak FEV1 response and the trough FEV1 response at week 24, expressed as the change from baseline FEV1. Tiotropium topped placebo in peak FEV1 response by an average of 86 mL in trial 1 and 154 mL in trial 2, differences that were significant.
The average difference in trough FEV1 response between tiotropium and placebo groups was 88 mL in trial 1 and 111 mL in trial 2. Those differences were "relatively small" but also statistically significant.
"It should be noted that [these differences occurred] in patients who were already receiving a long-acting bronchodilator and had fixed airflow limitation," the investigators noted. The results also should be considered "in the context of the need for additional treatments for this patient population and the limitations of current alternatives," they added.
A third lung-function end point was the time until at least 25% of patients had their first severe exacerbation of asthma. That interval was 56 days longer with tiotropium (282 days), compared with placebo (226 days).
The number of severe exacerbations was a secondary end point of both trials. That number was 0.53 exacerbations per patient-year with tiotropium, significantly fewer than the 0.66 per patient-year with placebo. In addition, 27% of patients in both tiotropium groups had at least one severe exacerbation, which was significantly less than the 33% rate in both placebo groups.
However, asthma-related quality of life did not differ significantly between tiotropium and placebo groups in either trial. The minimal clinically important difference between the two groups was not achieved when measured by both the Asthma Control Questionnaire 7 and the 32-item Asthma Quality of Life Questionnaire.
Similarly, daily symptom diaries showed "small or nonsignificant" differences between the active drug and the placebo groups in symptom-free days. And the use of rescue medications also was similar.
Adverse events occurred in 73.5% of the tiotropium group and 80.3% of the placebo group, and allergic rhinitis was the only one that occurred more often in the tiotropium group. Adverse events were judged to be treatment related in 5.7% of the tiotropium group and 4.6% of the placebo group.
Serious adverse events occurred in 8.1% of the tiotropium group and 8.8% of the placebo group. Three of those events – two asthma exacerbations and one cerebral infarction – occurred in the tiotropium group and were considered life threatening.
Cardiac events occurred in less than 2% of both study groups; they were considered drug related in 0.4% of patients in the tiotropium group and 0.2% of those in the placebo group. Adverse changes in blood pressure, pulse rate, laboratory measures, and electrocardiograms were balanced between the two study groups.
Less than 2% of all patients experienced dry mouth – a typical adverse event with anticholinergic agents – but it was reported more frequently in the tiotropium group (eight patients vs. three patients), Dr. Kerstjens and his associates said.
Dr. Kerstjens reported additional associations with Almirall, Chiesi, Novartis, and Nycomed, and his associates reported ties to numerous industry sources.
Adding tiotropium to standard combination therapy may help reduce exacerbations in some adults whose asthma is poorly controlled despite the use of inhaled glucocorticoids and long-acting beta-agonists, according to a report of two randomized, controlled trials published online Sept. 3 in the New England Journal of Medicine.
However, tiotropium use did not increase the number of symptom-free days or boost patients’ asthma-related quality of life scores.
Compared with placebo, tiotropium administered once daily via a soft-mist inhaler significantly lengthened the time to a severe exacerbation of asthma, reduced the number of exacerbations, and provided "modest" bronchodilation when added to inhaled glucocorticoids and LABAs, said Dr. Huib A. M. Kerstjens of the University of Groningen (the Netherlands) and the Groningen Research Institute for Asthma and COPD, and his associates (N. Engl. J. Med. 2012 Sept. 3 [doi:10.1056/NEJMoa1208606]).
However, the improvements in forced expiratory volume in 1 second (FEV1) were "relatively small (less than 10%)," and the number of symptom-free days did not differ between patients who received tiotropium and those who received placebo.
Moreover, the use of rescue medications was the same between the two groups, and patient ratings of asthma-related quality of life also were the same on two measures, the researchers noted.
Tiotropium is the most widely used long-acting anticholinergic inhaled bronchodilator in the world for the treatment of chronic obstructive pulmonary disease, but it has only recently been investigated as a potential adjunctive therapy for asthma.
Dr. Kerstjens and his colleagues assessed the drug’s effects in two 48-week randomized, controlled trials conducted in 15 countries, both of which were funded by Boehringer Ingelheim and Pfizer. They presented their findings at the annual meeting of the European Respiratory Society simultaneously with online publication.
The studies included 912 adults aged 18-75 years who had a 5-year or longer history of asthma and persistent airflow limitation despite self-reported daily use of inhaled glucocorticoids and LABAs. They were randomly assigned to self administer puffs of either tiotropium (237 patients in study 1 and 219 patients in study 2) or placebo (222 patients in study 1 and 234 patients in study 2) every morning as add-on therapy.
Patients were allowed to continue the use of stable doses of sustained-release theophylline, leukotriene modifiers, anti-immunoglobulin E antibody, or oral glucocorticoids, and were given open-label inhalers of salbutamol or albuterol for use as rescue medication.
The first two lung-function end points of both studies were the peak FEV1 response and the trough FEV1 response at week 24, expressed as the change from baseline FEV1. Tiotropium topped placebo in peak FEV1 response by an average of 86 mL in trial 1 and 154 mL in trial 2, differences that were significant.
The average difference in trough FEV1 response between tiotropium and placebo groups was 88 mL in trial 1 and 111 mL in trial 2. Those differences were "relatively small" but also statistically significant.
"It should be noted that [these differences occurred] in patients who were already receiving a long-acting bronchodilator and had fixed airflow limitation," the investigators noted. The results also should be considered "in the context of the need for additional treatments for this patient population and the limitations of current alternatives," they added.
A third lung-function end point was the time until at least 25% of patients had their first severe exacerbation of asthma. That interval was 56 days longer with tiotropium (282 days), compared with placebo (226 days).
The number of severe exacerbations was a secondary end point of both trials. That number was 0.53 exacerbations per patient-year with tiotropium, significantly fewer than the 0.66 per patient-year with placebo. In addition, 27% of patients in both tiotropium groups had at least one severe exacerbation, which was significantly less than the 33% rate in both placebo groups.
However, asthma-related quality of life did not differ significantly between tiotropium and placebo groups in either trial. The minimal clinically important difference between the two groups was not achieved when measured by both the Asthma Control Questionnaire 7 and the 32-item Asthma Quality of Life Questionnaire.
Similarly, daily symptom diaries showed "small or nonsignificant" differences between the active drug and the placebo groups in symptom-free days. And the use of rescue medications also was similar.
Adverse events occurred in 73.5% of the tiotropium group and 80.3% of the placebo group, and allergic rhinitis was the only one that occurred more often in the tiotropium group. Adverse events were judged to be treatment related in 5.7% of the tiotropium group and 4.6% of the placebo group.
Serious adverse events occurred in 8.1% of the tiotropium group and 8.8% of the placebo group. Three of those events – two asthma exacerbations and one cerebral infarction – occurred in the tiotropium group and were considered life threatening.
Cardiac events occurred in less than 2% of both study groups; they were considered drug related in 0.4% of patients in the tiotropium group and 0.2% of those in the placebo group. Adverse changes in blood pressure, pulse rate, laboratory measures, and electrocardiograms were balanced between the two study groups.
Less than 2% of all patients experienced dry mouth – a typical adverse event with anticholinergic agents – but it was reported more frequently in the tiotropium group (eight patients vs. three patients), Dr. Kerstjens and his associates said.
Dr. Kerstjens reported additional associations with Almirall, Chiesi, Novartis, and Nycomed, and his associates reported ties to numerous industry sources.
FROM THE NEW ENGLAND JOURNAL OF MEDICINE
Major Finding: Compared with placebo, add-on tiotropium therapy extended the time to a severe asthma exacerbation by 56 days, and reduced the number of exacerbations by 0.13 per patient-year; but it did not improve quality of life, increase symptom-free days, or reduce the use of rescue medication.
Data Source: Two international, replicate, randomized, controlled trials comparing 48 weeks of adjunct therapy with inhaled tiotropium to placebo in 912 adults with asthma that was poorly controlled despite combination treatment with inhaled glucocorticoids and LABAs.
Disclosures: Boehringer Ingelheim and Pfizer funded the studies. Dr. Kerstjens reported additional associations with Almirall, Chiesi, Novartis, and Nycomed, and his associates reported ties to numerous industry sources.