Intervention for Cognitive Reserve Enhancement in Delaying the Onset of Alzheimer's Symptomatic Expression (INCREASE) Study: Results from a Randomized Controlled Study of Medication Therapy Management Targeting a Delay in Prodromal Dementia Symptom Progression.

BACKGROUND: Cognitive reserve has been hypothesized as a mechanism to explain differences in individual risk for symptomatic expression of Alzheimer's Disease (AD). Inappropriate medications may diminish cognitive reserve, precipitating the transition from preclinical AD (pAD) to a symptomatic state. To date, there is limited data on the potential impact of medication optimization as a potential tool for slowing the symptomatic expression of AD. OBJECTIVES: (1) To test the efficacy of a medication therapy management intervention designed to bolster cognitive reserve in community-dwelling older adults without dementia. (2) To evaluate the efficacy of intervention by baseline pAD status. DESIGN: A 1-year randomized controlled trial was conducted in community-dwelling older adults without dementia. Randomization was stratified by amyloid ß positron emission tomography levels. SETTING: Community-based, Lexington, Kentucky. PARTICIPANTS: Adults 65 years or older with no evidence of dementia and reporting at least one potentially inappropriate medication as listed in the Beers 2015 criteria were recruited. The study aimed to enroll 90 participants based on the a priori sample size calculation. INTERVENTION: Medication therapy management versus standard of care. MEASUREMENTS: Primary outcomes were: (1) one-year changes in the Medication Appropriateness Index; (2) one-year changes in Trail Making Test B under scopolamine challenge. RESULTS: The medication therapy management intervention resulted in significant improvement in Medication Appropriateness Index scores. Overall, there was no beneficial effect of the medication therapy management on Trail Making Test B scores, however stratified analysis demonstrated improvement in Trail Making Test B challenged scores associated with the medication therapy management for those with elevated amyloid ß positron emission tomography levels consistent with pAD. CONCLUSIONS: Medication therapy management can reduce inappropriate medication use in older adults at risk for AD. Our study indicated beneficial cognitive effects in those with preclinical Alzheimer's Disease. No statistically significant effects were evident in the study group as a whole, or in those without preclinical cerebral amyloidosis. Further work designed to improve the effectiveness of the medication therapy management approach and defining other preclinical pathologic states that may benefit from medication optimization are readily achievable goals for promoting improved cognitive health and potentially delaying the onset of symptomatic AD.

Comparative effectiveness of budesonide/formoterol combination and tiotropium bromide among COPD patients new to these controller treatments.

BACKGROUND: Inhaled corticosteroid/long-acting ß2-agonist combinations and/or long-acting muscarinic antagonists are recommended first-line therapies for preventing chronic obstructive pulmonary disease (COPD) exacerbation. Comparative effectiveness of budesonide/formoterol combination (BFC, an inhaled corticosteroid/long-acting ß2-agonist combination) vs tiotropium (long-acting muscarinic antagonist) in the US has not yet been studied. METHODS: Using US claims data from the HealthCore Integrated Research Environment, COPD patients (with or without comorbid asthma) ≥40 years old initiating BFC or tiotropium between March 1, 2009 and February 28, 2012 and at risk for exacerbation were identified and followed for 12 months. Patients were propensity score matched on demographics and COPD disease severity indicators. The primary outcome was time to first COPD exacerbation. Secondary outcomes included COPD exacerbation rate, health care resource utilization, and costs. RESULTS: The Cox proportional hazards model for time to first exacerbation yielded a hazard ratio (HR) of 0.78 (95% CI =[0.70, 0.87], P<0.001), indicating a 22% reduction in risk of COPD exacerbation associated with initiation of BFC versus tiotropium. A post hoc sensitivity analysis found similar effects in those who had a prior asthma diagnosis (HR =0.72 [0.61, 0.86]) and those who did not (HR =0.83 [0.72, 0.96]). BFC initiation was associated with lower COPD-related health care resource utilization and costs ($4,084 per patient-year compared with $5,656 for tiotropium patients, P<0.001). CONCLUSION: In COPD patients new to controller therapies, initiating treatment with BFC was associated with improvements in health and economic outcomes compared with tiotropium.

Anticholinergics for treatment of asthma.

Asthma management guidelines emphasize the importance of effective treatment to achieve and maintain control of asthma. However, despite widely available and effective treatments, achieving control of asthma is still an unmet need for many patients. Adding a second bronchodilator with a different mechanism of action for the treatment of uncontrolled asthma can be a suitable therapeutic approach. This review focuses on the role of long-acting muscarinic antagonists, particularly tiotropium, in the treatment of asthma. A number of studies have evaluated the efficacy and safety of tiotropium in asthma patients whose disease is poorly controlled with inhaled corticosteroids (ICSs) with or without long-acting ß2-agonists (LABAs). The effect on several clinical and lung function variables of adding tiotropium to an ICS is greater than doubling the dose of the latter and is not inferior to the addition of a LABA (salmeterol). Studies assessing the role of tiotropium as add-on therapy to ICS combined with a LABA have shown modest but clinically significant and dose-dependent improvements in forced expiratory volume in 1 second, as well as a decrease in the risk of exacerbations. In addition, time to the next episode is longer, particularly in patients who experience severe exacerbations. In conclusion, tiotropium proved noninferior to salmeterol and superior to placebo in patients with moderate-severe asthma who were not adequately controlled using ICSs or ICSs combined with a LABA. The major benefits are the increase in lung function and, in the case of severe asthma, the reduction in the frequency of exacerbations. In patients with asthma, tiotropium is usually well tolerated, and no potential safety signals have been observed.

A US database study characterizing patients initiating a budesonide-formoterol combination versus tiotropium bromide as initial maintenance therapy for chronic obstructive pulmonary disease.

OBJECTIVE: To compare clinical and demographic characteristics, resource utilization and costs of chronic obstructive pulmonary disease (COPD) patients prior to initiating budesonide-formoterol combination (BFC) or tiotropium-maintenance therapy. MATERIALS AND METHODS: This cross-sectional study used claims-based diagnosis to identify COPD patients in the HealthCore Integrated Research Database who initiated BFC or tiotropium therapy between March 1, 2009 and January 31, 2012 (intake period); the index date was defined as the initial prescription fill for either agent. Patients diagnosed with respiratory tract cancer or receiving inhaled corticosteroids/long-acting ß2-adrenergic agonists or tiotropium in 12 months prior to index date were excluded. Categorical variables were evaluated with χ(2) tests; mean cost differences were evaluated using γ-regression. RESULTS: Overall, 6,940 BFC and 10,831 tiotropium patients were identified. The BFC group was younger (mean age 64 versus 67 years), with a greater proportion of females (54% versus 51%). BFC-treated patients had more comorbid respiratory conditions, including asthma (25% versus 13%), but fewer comorbid cardiovascular conditions, including atherosclerosis (7% versus 10%) and myocardial infarction (4% versus 6%). A greater proportion of BFC patients received prior respiratory medication, including oral corticosteroids (46% versus 35%) and short-acting ß2-agonists (44% versus 35%). Tiotropium-treated patients had a greater mean number of COPD-related outpatient visits (4.6 versus 4.1). BFC-treated patients had lower total all-cause ($17,259 versus $17,926) and COPD-related ($1,718 versus $1,930) health care costs, driven by lower all-cause and COPD-related inpatient expenditures. CONCLUSION: Initiators of BFC or tiotropium showed differences in clinical and demographic characteristics and health care utilization and costs prior to starting COPD maintenance therapy.

Cost effectiveness of tiotropium in patients with asthma poorly controlled on inhaled glucocorticosteroids and long-acting ß-agonists.

BACKGROUND: A considerable proportion of patients with asthma remain uncontrolled or symptomatic despite treatment with a high dose of inhaled glucocorticosteroids (ICSs) and long-acting ß2-agonists (LABAs). Tiotropium Respimat(®) added to usual care improves lung function, asthma control, and the frequency of non-severe and severe exacerbations, in a population of adult asthma patients who are uncontrolled despite treatment with ICS/LABA. OBJECTIVE: This study estimated the cost effectiveness of tiotropium therapy as add-on to usual care in asthma patients that are uncontrolled despite treatment with ICS/LABA combination from the perspective of the UK National Health Service (NHS). METHODS: A Markov model was developed which considers levels of asthma control and exacerbations. The model analysed cost and quality-adjusted life-years (QALYs); sensitivity and scenario analyses were also conducted to test the robustness of the base case outcomes. All costs are given at 2012 prices. RESULTS: The model found that in this category of asthma with unmet need, add-on tiotropium therapy generated an incremental 0.24 QALYs and £5,238 costs over a lifetime horizon, resulting in an incremental cost-effectiveness ratio of £21,906 per QALY gained. Sensitivity analysis suggested that findings were most dependent on the costs of managing uncontrolled asthma and the cost of treatment with tiotropium. CONCLUSION: In this modelled analysis of two clinical trials, tiotropium was found to be cost effective when added to usual care in patients who remain uncontrolled despite treatment with high-dose ICS/LABA. Further research should investigate the long-term treatment effectiveness of tiotropium.

Computed tomography assessment of airway dimensions with combined tiotropium and indacaterol therapy in COPD patients.

BACKGROUND AND OBJECTIVE: Combining a long-acting muscarinic antagonist with a long-acting ß2-agonist has been shown to be pharmacologically useful in patients with chronic obstructive pulmonary disease (COPD). The aim of the present study was to evaluate the effectiveness of the dual bronchodilator therapy on airway dimensions in COPD. METHODS: Patients (n = 54) were randomly assigned to receive tiotropium (18 µg once daily), indacaterol (150 µg once daily) or tiotropium plus indacaterol for 16 weeks. Quantitative computed tomography (CT), pulmonary function and health status (St. George's Respiratory Questionnaire) were measured. RESULTS: Compared with tiotropium or indacaterol alone, combination therapy resulted in a significant decrease in percentage wall area (WA%) and wall thickness, corrected for body surface area, and an increase in luminal area (Ai/BSA). Concurrent treatment was superior to monotherapy in physiological indices, including forced vital capacity, forced expiratory volume in 1 s (FEV1) and inspiratory capacity. The changes in WA% and Ai/BSA were significantly correlated with changes in FEV1 (r = -0.44, P < 0.01 and r = 0.37, P < 0.01). There were more significant improvements in SGRQ scores after treatment with combined therapy than with either treatment alone. CONCLUSIONS: Concurrent therapy with tiotropium and indacaterol is effective for COPD patients to promote reduction in airway wall thickness, bronchodilation, and improvements in lung function compared with a single inhaler.

The association between inhaled long-acting bronchodilators and less in-hospital care in newly-diagnosed COPD patients.

BACKGROUND: Although the efficacy of inhaled long-acting bronchodilators has been well documented in randomised controlled studies, whether similar effects are obtained in real-life clinical practice is not clear. In this study, we analysed the effect of inhaled long-acting bronchodilators in newly-diagnosed COPD patients. METHODS: The Korean Health Insurance Review and Assessment Service databases were used. Participants ≥40-years-old who had not been diagnosed with COPD between 2007 and 2008 but were diagnosed and prescribed COPD medication in 2009 were designated as newly-diagnosed COPD patients. Patients were divided into three groups based on the use of bronchodilators, an inhaled long-acting bronchodilator (LA-B), an inhaled short-acting bronchodilator (SA-B) and an oral medication (OM) group. RESULTS: A total of 77,480 newly-diagnosed COPD patients with a mean age of 68.5 years, among which 43,530 (56.2%) were men, were included in the study. ER visits and hospitalisation were associated with SA-B group, male gender, older age, Medicaid coverage, tertiary healthcare centre visits and higher comorbidities. Multivariate analysis showed that the SA-B group was associated with more ER visits, recurrent ER visits, hospitalisation and recurrent hospitalisation (adjusted ORs [95% confidence intervals] = 4.32 [3.93-4.75], 6.19 [5.24-7.30], 5.04 [2.95-3.39], and 8.49 [7.67-9.39], respectively) compared with the LA-B group. Medical utilisation cost was also higher in the SA-B group. CONCLUSION: Inhaled long-acting bronchodilator use was associated with lower rates of hospitalisation, fewer ER visits and lower medical costs in newly-diagnosed COPD patients in real-life clinical practice.

Cost effectiveness of adding budesonide/formoterol to tiotropium in COPD in four Nordic countries.

OBJECTIVE: Assess the cost effectiveness of budesonide/formoterol (BUD/FORM) Turbuhaler(®)+tiotropium (TIO) HandiHaler(®) vs. placebo (PBO)+TIO in patients with chronic obstructive pulmonary disease (COPD) eligible for inhaled corticosteroids/long-acting ß2-agonists (ICS/LABA). METHODS: The cost-effectiveness analysis was based on the 12-week, randomised, double-blind CLIMB trial. The study included 659 patients with pre-bronchodilator forced expiratory volume in 1 s ≤ 50% and ≥1 exacerbation requiring systemic glucocorticosteroids or antibiotics the preceding year. Patients received BUD/FORM 320/9 µg bid + TIO 18 µg qd or PBO bid + TIO 18 µg qd. Effectiveness was defined as the number of severe exacerbations (hospitalisation/emergency room visit/systemic glucocorticosteroids) avoided. A sub-analysis included antibiotics in the definition of an exacerbation. Resource use from CLIMB was combined with Danish (DKK), Finnish (€), Norwegian (NOK) and Swedish (SEK) unit costs (2010). The incremental cost-effectiveness ratios (ICERs) for BUD/FORM + TIO vs. PBO + TIO were estimated using descriptive statistics and uncertainty around estimates using bootstrapping. Analyses were conducted from the societal and healthcare perspectives in Denmark, Finland, Norway and Sweden. RESULTS: From a societal perspective, the ICER was estimated at €174/severe exacerbation avoided in Finland while BUD/FORM + TIO was dominant in the other countries. From the healthcare perspective, ICERs were DKK 1580 (€212), €307 and SEK 1573 (€165) per severe exacerbation avoided for Denmark, Finland and Sweden, respectively, while BUD/FORM + TIO was dominant in Norway. Including antibiotics decreased ICERs by 8-15%. Sensitivity analyses showed that results were overall robust. CONCLUSION: BUD/FORM + TIO represents a clinical and economic benefit to health systems and society for the treatment of COPD in the Nordic countries. (ClinicalTrials.gov Identifier: NCT00496470).

Multidetector-row computed tomography assessment of adding budesonide/formoterol to tiotropium in patients with chronic obstructive pulmonary disease.

BACKGROUND: In patients with chronic obstructive pulmonary disease (COPD), multidetector-row computed tomography (MDCT) showed that tiotropium dilated the inner diameters in airways from the third to the sixth generation of the bronchi. Here we aimed to evaluate the morphological effect by adding a budesonide/formoterol combination to tiotropium in COPD patients using three-dimensional MDCT. METHODS: Pulmonary function tests, St. George's Respiratory Questionnaire (SGRQ) and MDCT imaging studies were performed at the beginning and after budesonide/formoterol combination treatment for 12 weeks in 14 patients with COPD. RESULTS: The median age was 73.5 years and the mean forced expiratory volume in 1 s (FEV1) as a percentage of the predicted value was 57.2 ± 18.3%. The luminal area in the fifth generation bronchi and the emphysema volume/CT-derived total lung volume were significantly correlated with FEV1 at baseline (r = 0.682, p < 0.02 and r = -0.868, p < 0.001, respectively). The average luminal area and wall area percentage in the third, fourth and fifth generations were correlated with the SGRQ total score. Budesonide/formoterol induced insignificant pulmonary function changes and significant symptoms improvement. CT images showed an increased inner luminal area and decreased wall area after budesonide/formoterol treatment. Average luminal area was significantly increased from 24.3 ± 9.7 to 26.0 ± 9.9 mm(2) in the third generation, 13.0 ± 6.5 to 14.7 ± 7.3 mm(2) in the fourth generation, 8.0 ± 4.8 to 9.4 ± 4.9 mm(2) in the fifth generation and 5.6 ± 2.7 to 6.7 ± 3.6 mm(2) in the sixth generation (p < 0.01). The average increase of the third generation luminal area was correlated with the FEV1 increase (r = 0.632, p < 0.03). The wall area percentage significantly decreased from 51.5 ± 9.2 to 49.1 ± 9.7 in the third generation, 56.1 ± 9.7 to 53.0 ± 11.1 in the fourth generation, and 62.3 ± 9.9 to 57.6 ± 9.8 in the fifth generation (p < 0.05). Emphysema volume/CT-derived total lung volume was unchanged with treatment. CONCLUSION: MDCT demonstrated budesonide/formoterol induced bronchodilation in the non-small airway. CT imaging can evaluate drug therapeutic effect and may provide additional insights into pharmacotherapy for COPD.

Cost-effectiveness of tiotropium versus salmeterol: the POET-COPD trial.

The aim of this study was to perform a 1-yr trial-based cost-effectiveness analysis (CEA) of tiotropium versus salmeterol followed by a 5-yr model-based CEA. The within-trial CEA, including 7,250 patients with moderate to very severe chronic obstructive pulmonary disease (COPD), was performed alongside the 1-yr international randomised controlled Prevention of Exacerbations with Tiotropium (POET)-COPD trial comparing tiotropium with salmeterol regarding the effect on exacerbations. Main end-points of the trial-based analysis were costs, number of exacerbations and exacerbation days. The model-based analysis was conducted to extrapolate results to 5 yrs and to calculate quality-adjusted life years (QALYs). 1-yr costs per patient from the German statutory health insurance (SHI) perspective and the societal perspective were €126 (95% uncertainty interval (UI) €55-195) and €170 (95% UI €77-260) higher for tiotropium, respectively. The annual number of exacerbations was 0.064 (95% UI 0.010-0.118) lower for tiotropium, leading to a reduction in exacerbation-related costs of €87 (95% UI €19-157). The incremental cost-effectiveness ratio was €1,961 per exacerbation avoided from the SHI perspective and €2,647 from the societal perspective. In the model-based analyses, the 5-yr costs per QALY were €3,488 from the SHI perspective and €8,141 from the societal perspective. Tiotropium reduced exacerbations and exacerbation-related costs, but increased total costs. Tiotropium can be considered cost-effective as the resulting cost-effectiveness ratios were below commonly accepted willingness-to-pay thresholds.

Cost-utility analysis of tiotropium versus usual care in patients with COPD in the UK and Belgium.

OBJECTIVE: To evaluate the cost-utility of adding tiotropium to usual care versus usual care alone for patients with moderate to very severe chronic obstructive pulmonary disease (COPD) in the UK and Belgium. METHODS: A four-state Markov model was developed with three disease severity states (moderate, severe, very severe) and death. Severity was based on post-bronchodilator FEV1 and transitions were based on outcomes of the Understanding Potential Long Term Impacts on Function with Tiotropium (UPLIFT®) trial. Utilities were derived from EQ-5D scores for a subset of UPLIFT® patients. UK costs were evaluated separately for England (E), and for Scotland, Wales and Northern Ireland (SWNI). Belgian (B) costs were obtained from local sources. Uncertainty was assessed by deterministic and probabilistic sensitivity analysis (PSA). RESULTS: Adding tiotropium to usual care resulted in an incremental cost per patient of €969 (B), £796 (E), and £812 (SWNI), and incremental QALYs of 0.052 (B), and 0.051 (E, SWNI). The four-year incremental cost-effectiveness ratios (ICER) were €18,617 (B), £15,567 (E) and £15,890 (SWNI) per QALY. Probability of tiotropium being cost-effective at £30,000 (€50,000) per QALY gained was greater than 60%. CONCLUSIONS: At willingness to pay thresholds of £(€) 30,000 per QALY gained, adding tiotropium to usual care is cost-effective.

Which long-acting bronchodilator is most cost-effective for the treatment of COPD?

BACKGROUND: The aim of this study was to estimate the cost-effectiveness of tiotropium versus salmeterol to inform decision making within the Dutch healthcare setting. METHODS: A previously published, validated COPD progression model was updated with new exacerbation data and adapted to the Dutch setting by including Dutch estimates of healthcare use for COPD maintenance treatment and Dutch unit costs. Exacerbation data from the POET-COPD trial were combined with evidence from earlier tiotropium studies using Bayesian meta-analysis. The model-based analysis was performed using a one- and five-year time horizon. Main health outcomes were the number of exacerbations and quality-adjusted life years (QALYs). RESULTS: One-year costs per patient from the healthcare perspective were v1370 for tiotropium and v1359 for salmeterol; a difference of v11 (95% uncertainty interval (UI): -198-212). The annual number of exacerbations was 0.068 (-0.005-0.140) lower in the tiotropium group. The number of QALYs in the tiotropium group was 0.011 (-0.019-0.049) higher, resulting in an incremental cost-effectiveness ratio (ICER) of v1015 per QALY. After five years, the difference in exacerbations, QALYs and costs between the tiotropium and salmeterol group were -0.435 (-0.915-0.107), 0.079 (-0.272-0.520) and v-277 (-1586-1074), respectively, indicating that tiotropium was more effective and less costly. Using a societal perspective, tiotropium dominated salmeterol both after one and five years. CONCLUSION: Tiotropium reduced exacerbations and exacerbation-related costs. After one year the cost per QALY of tiotropium compared with salmeterol was very low, while after five years tiotropium was found to dominate salmeterol.

Tiotropium versus long-acting beta-agonists for stable chronic obstructive pulmonary disease.

BACKGROUND: Tiotropium and long-acting beta(2)-agonists (LABAs) are both accepted in the routine management for people with stable chronic obstructive pulmonary disease (COPD). There are new studies which have compared tiotropium with LABAs, including some that have evaluated recently introduced LABAs. OBJECTIVES: To compare the relative clinical effects of tiotropium bromide alone versus LABA alone, upon measures of quality of life, exacerbations, lung function and serious adverse events, in people with stable COPD.To critically appraise and summarise current evidence on the costs and cost-effectiveness associated with tiotropium compared to LABA in people with COPD. SEARCH METHODS: We identified randomised controlled trials (RCTs) from the Cochrane Airways Group Specialised Register of trials and economic evaluations from searching NHS EED and HEED (date of last search February 2012). We found additional trials from web-based clinical trial registers. SELECTION CRITERIA: We included RCTs and full economic evaluations if they compared effects of tiotropium alone with LABAs alone in people with COPD. We allowed co-administration of standard COPD therapy. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed studies for inclusion, then extracted data on study quality and outcomes. We contacted study authors and trial sponsors for additional information. We analysed data using the Cochrane Review Manager(RevMan 5.1) software. MAIN RESULTS: Seven clinical studies totalling 12,223 participants with COPD were included in the review. The studies used similar designs and were generally of good methodological quality. Inclusion criteria for RCTs were similar across the included studies, although studies varied in terms of smoking history and COPD severity of participants. They compared tiotropium (which was delivered by HandiHaler in all studies) with salmeterol (four studies, 8936 participants), formoterol (one study, 431 participants) and indacaterol (two studies, 2856 participants). All participants were instructed to discontinue anticholinergic or long-acting beta(2)-agonist bronchodilators during treatment, but could receive inhaled corticosteroids (ICS) at a stable dose. Study duration ranged from 3 to 12 months. We extracted data for 11,223 participants. In general, the treatment groups were well matched at baseline. Overall, the risk of bias across the included RCTs was low.In the analysis of the primary outcomes in this review, a high level of heterogeneity amongst studies meant that we did not pool data for St George's Respiratory Questionnaire quality of life score. Subgroup analyses based on the type of LABA found statistically significant differences among effects on quality of life depending on whether tiotropium was compared with salmeterol, formoterol or indacaterol. Tiotropium reduced the number of participants experiencing one or more exacerbations compared with LABA (odds ratio (OR) 0.86; 95% confidence interval (CI) 0.79 to 0.93). For this outcome, there was no difference seen among the different types of LABA. There was no statistical difference in mortality observed between the treatment groups.For secondary outcomes, tiotropium was associated with a reduction in the number of COPD exacerbations leading to hospitalisation compared with LABA treatment (OR 0.87; 95% 0.77 to 0.99), but not in the overall rate of all-cause hospitalisations. There was no statistically significant difference in forced expiratory volume in one second (FEV(1)) or symptom score between tiotropium and LABA-treated participants. There was a lower rate of non-fatal serious adverse events recorded with tiotropium compared with LABA (OR 0.88; 95% CI 0.78 to 0.99). The tiotropium group was also associated with a lower rate of study withdrawals (OR 0.89; 95% CI 0.81 to 0.99).We identified six full economic evaluations assessing the cost and cost-effectiveness of tiotropium and salmeterol. The studies were based on an economic model or empirical analysis of clinical data from RCTs. They all looked at maintenance costs and the costs for COPD exacerbations, including respiratory medications and hospitalisations. The setting for the evaluations was primary and secondary care in the UK, Greece, Netherlands, Spain and USA. All the studies estimated tiotropium to be superior to salmeterol based on better clinical outcomes (exacerbations or quality of life) and/or lower total costs. However, the authors of all evaluations reported there was substantial uncertainty around the results. AUTHORS' CONCLUSIONS: In people with COPD, the evidence is equivocal as to whether or not tiotropium offers greater benefit than LABAs in improving quality of life; however, this is complicated by differences in effect among the LABA types. Tiotropium was more effective than LABAs as a group in preventing COPD exacerbations and disease-related hospitalisations, although there were no statistical differences between groups in overall hospitalisation rates or mortality during the study periods. There were fewer serious adverse events and study withdrawals recorded with tiotropium compared with LABAs. Symptom improvement and changes in lung function were similar between the treatment groups. Given the small number of studies to date, with high levels of heterogeneity among them, one approach may be to give a COPD patient a substantial trial of tiotropium, followed by a LABA (or vice versa), then to continue prescribing the long-acting bronchodilator that the patient prefers. Further studies are needed to compare tiotropium with different LABAs, which are currently ongoing. The available economic evidence indicates that tiotropium may be cost-effective compared with salmeterol in several specific settings, but there is considerable uncertainty around this finding.

Computed tomography assessment of pharmacological lung volume reduction induced by bronchodilators in COPD.

Pharmacological lung volume reduction in COPD is an important goal in treatment with long-acting bronchodilators because in addition to airflow limitation, lung hyperinflation considerably affects COPD symptoms. Quantitative computed tomography (CT) simultaneously provides structural information about airway dimensions, emphysematous changes, and lung volumes, some of which are difficult to be evaluated by pulmonary function. Here, we evaluated changes in CT parameters and pulmonary function in 30 patients with COPD who underwent CT scans before and one year after starting tiotropium treatment and in 12 patients with COPD who were not treated with long-acting bronchodilators. Baseline pulmonary function and CT parameters did not differ between the two groups. One-year tiotropium therapy improved physiological-indices including residual volume (RV) and ratio of RV to total lung capacity (RV/TLC) (-235 mL, p = 0.005, and -2.9%, p = 0.0001, respectively), and CT-indices including wall area percent (WA%) and inner luminal area in right upper lobe apical and lower lobe basal segmental bronchi (-1.59%, p = 0.01, 2.27 mm(2), p = 0.0005; and -1.33%, p = 0.0008, 3.42 mm(2), p < 0.0001, respectively), low attenuation volume (LAV) and total lung volume (CT-TLV) (-92 mL, p = 0.0003, and -211 mL, p = 0.002, respectively). Changes in LAV, CT-TLV, RV, and RV/TLC were significantly greater in the tiotropium, than the non-bronchodilator group. The tiotropium-induced reduction in LAV correlated with the decrease in RV (ρ = 0.45, p = 0.01). Our findings not only indicate the value of the comprehensive CT measurements in assessing the effects of bronchodilators, including pharmacological lung volume reduction, but also further understanding of the structural changes underlying physiological improvements induced by bronchodilators.

Clinical and economic outcomes in an observational study of COPD maintenance therapies: multivariable regression versus propensity score matching.

PURPOSE: To investigate equivalency of results from multivariable regression (MR) and propensity score matching (PSM) models, observational research methods used to mitigate bias stemming from non-randomization (and consequently unbalanced groups at baseline), using, as an example, a large study of chronic obstructive pulmonary disease (COPD) initial maintenance therapy. METHODS: Patients were 32,338 health plan members, age ≥40 years, with COPD initially treated with fluticasone propionate/salmeterol combination (FSC), tiotropium (TIO), or ipratropium (IPR) alone or in combination with albuterol. Using MR and PSM methods, the proportion of patients with COPD-related health care utilization, mean costs, odds ratios (ORs), and incidence rate ratios (IRRs) for utilization events were calculated for the 12 months following therapy initiation. RESULTS: Of 12,595 FSC, 9126 TIO, and 10,617 IPR patients meeting MR inclusion criteria, 89.1% (8135) of TIO and 80.2% (8514) of IPR patients were matched to FSC patients for the PSM analysis. Methods produced substantially similar findings for mean cost comparisons, ORs, and IRRs for most utilization events. In contrast to MR, for TIO compared to FSC, PSM did not produce statistically significant ORs for hospitalization or outpatient visit with antibiotic or significant IRRs for hospitalization or outpatient visit with oral corticosteroid. As in the MR analysis, compared to FSC, ORs and IRRs for all other utilization events, as well as mean costs, were less favorable for IPR and TIO. CONCLUSION: In this example of an observational study of maintenance therapy for COPD, more than 80% of the original treatment groups used in the MR analysis were matched to comparison treatment groups for the PSM analysis. While some sample size was lost in the PSM analysis, results from both methods were similar in direction and statistical significance, suggesting that MR and PSM were equivalent methods for mitigating bias.

Rehospitalization risks and outcomes in COPD patients receiving maintenance pharmacotherapy.

OBJECTIVE: To determine clinical and economic outcomes following COPD-related hospitalization/emergency department (ED) care in patients receiving COPD maintenance therapy. METHODS: In this retrospective, observational study using administrative claims data, we identified COPD patients age ≥40 years who received maintenance therapy within 30 days of an initial COPD-related hospitalization or ED visit with: (1) fluticasone propionate/salmeterol combination (FSC 250 mcg/50 mcg) as new therapy, or (2) an anticholinergic (AC; tiotropium or ipratropium with or without albuterol). The FSC and AC patients were matched (1:3 ratio) on various baseline characteristics using propensity scores to mitigate selection bias at baseline. The proportion of patients with COPD-related healthcare events, the mean event rates, and the mean costs in the subsequent 12 months were calculated. RESULTS: The FSC cohort (N = 484) had a significantly lower proportion of rehospitalized patients during follow-up than did the AC cohort (N = 1452), 3.1% versus 4.6% (P = 0.047). The mean number of rehospitalizations was 0.03 in the FSC cohort and 0.07 in the AC cohort (P = 0.001). The proportion of patients with an exacerbation resulting in an ED or physician-outpatient visit and the mean number of such visits did not differ between cohorts. Total annual COPD-related medical costs were lower for FSC than for AC ($2080 versus $2636, P = 0.006), with lower medical and higher pharmacy costs. CONCLUSIONS: Patients receiving FSC as maintenance therapy following an initial COPD-related hospitalization or ED visit experienced better clinical and economic outcomes than patients receiving AC.

Comparative health-care cost advantage of ipratropium over tiotropium in COPD patients.

OBJECTIVE: To compare the total direct health-care costs of patients treated with tiotropium and ipratropium. METHODS: We conducted a cohort study of health-care costs in British Columbia, Canada, by comparing new patients on tiotropium with new patients on ipratropium. Direct health-care costs for study patients were measured in the first 2 years after initiating inhaled anticholinergic treatment. Differences in direct health-care costs between tiotropium and ipratropium patients were estimated by using quantile regression. We analyzed cost differences in the 10th percentile, median, and 90th percentile of patients by cost. High-dimensional propensity score analysis was used as a method of adjustment for potential confounding factors. RESULTS: The study population had 3,140 tiotropium patients and 26,182 ipratropium patients. Higher health system costs in patients who started on tiotropium instead of ipratropium were observed in patients in the median and 10th percentile. The magnitude of these increases was comparable to the price difference between the two drugs. Health system costs in the 90th percentile were not significantly different between tiotropium and ipratropium patients. CONCLUSIONS: The results of this study did not support the preferential use of tiotropium over ipratropium as a basis for savings in direct health-care costs.

Observational study on the impact of initiating tiotropium alone versus tiotropium with fluticasone propionate/salmeterol combination therapy on outcomes and costs in chronic obstructive pulmonary disease.

BACKGROUND: This retrospective cohort study compared the risks of exacerbations and COPD-related healthcare costs between patients with chronic obstructive pulmonary disease (COPD) initiating tiotropium (TIO) alone and patients initiating triple therapy with fluticasone-salmeterol combination (FSC) added to TIO. METHODS: Managed-care enrollees who had an index event of ≥ 1 pharmacy claim for TIO during the study period (January 1, 2003-April 30, 2008) and met other eligibility criteria were categorized into one of two cohorts depending on their medication use. Patients in the TIO+FSC cohort had combination therapy with TIO and FSC, defined as having an FSC claim on the same date as the TIO claim. Patients in the TIO cohort had no such FSC use. The risks of COPD exacerbations and healthcare costs were compared between cohorts during 1 year of follow-up. RESULTS: The sample comprised 3333 patients (n = 852 TIO+FSC cohort, n = 2481 TIO cohort). Triple therapy with FSC added to TIO compared with TIO monotherapy was associated with significant reductions in the adjusted risks of moderate exacerbation (hazard ratio 0.772; 95% confidence interval [CI] 0.641, 0.930) and any exacerbation (hazard ratio 0.763; 95% CI 0.646, 0.949) and a nonsignificant reduction in COPD-related adjusted monthly medical costs. CONCLUSIONS: Triple therapy with FSC added to TIO compared with TIO monotherapy was associated with significant reductions in the adjusted risks of moderate exacerbation and any exacerbation over a follow-up period of up to 1 year. These improvements were gained with triple therapy at roughly equal cost of that of TIO alone.

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

The randomized, double-blind trial UPLIFT(®) demonstrated in 5,993 patients with moderate to very severe COPD that 4 years of tiotropium bromide therapy were associated with improvements in lung function, exacerbations, quality of life, and mortality compared with placebo. The pharmacoeconomic evaluation was performed through a probabilistic, patient-level simulation Markov model. Routine COPD care (RC) was compared with the inclusion of tiotropium bromide on it. The analysis was conducted over a lifetime horizon, with 1 year cycles and a 3.5% annual discount rate. Patients were characterized by gender, age, height, smoking status, and forced expiratory volume in 1 s (FEV1). FEV1 time trend was modeled according to the annual decline recorded in UPLIFT®. Mortality derived from that of the general Italian population was adjusted by smoking status and FEV1. Health utilities derived from published Italian observational studies and were varied in time according to UPLIFT® data. Exacerbation rates were derived from a published Italian observational prospective study. The cost perspective was that of the Italian National Health Service. Healthcare resource consumption for RC and exacerbations derived from Italian observational studies were valued according to current price and tariffs. Simulated patients in the tiotropium arm gained an average (95% CI) 0.50 (-1.63 to 6.27) Life Years (LYs) and 0.42 (-0.25 to 3.05) Quality-Adjusted Life Years (QALYs). The incremental lifetime cost resulted €3,357 (-€10,669 to €29,820). The incremental cost-effectiveness ratio (ICER) was €6,698/LY and €7,916/QALY. In the cost-effectiveness acceptability curve (CEAC), tiotropium had a 90% probability of being cost-effective for a willingness to pay (WTP) threshold of € 10,000/QALY.

Cost-effectiveness analysis of roflumilast/tiotropium therapy versus tiotropium monotherapy for treating severe-to-very severe COPD.

OBJECTIVE: To conduct a cost-effectiveness analysis comparing roflumilast/tiotropium therapy vs tiotropium monotherapy in patients with severe-to-very severe COPD. METHODS: The economic evaluation applied a disease-based Markov cohort model with five health states: (1) severe COPD, (2) severe COPD with a history of severe exacerbation, (3) very severe COPD, (4) very severe COPD with a history of severe exacerbation, and (5) death. Within a given health state, a patient may have a mild/moderate or severe exacerbation or die. Data from roflumilast clinical trials and published literature were used to populate model parameters. The model calculated health outcomes and costs for roflumilast/tiotropium therapy vs tiotropium monotherapy over a 5-year horizon. Incremental cost and benefits were then calculated as cost-effectiveness ratios, including cost per exacerbation avoided and cost per quality adjusted life year ($/QALY). RESULTS: Over a 5-year horizon, the estimated incremental costs per exacerbation and per severe exacerbation avoided were $589 and $5869, respectively, and the incremental cost per QALY was $15,815. One-way sensitivity analyses varying key parameters produced an incremental cost per QALY ranging from $1963-$32,773. LIMITATIONS: A number of key parameters used in the model were obtained from studies in the literature that were conducted under different contexts. Specifically, the relative risk estimate for severe COPD patients originates from a small trial not designed to demonstrate the impact of roflumilast on frequency of exacerbations. In addition, the model extrapolates the relative risk estimates over periods of 5-30 years, even though the estimates were only observed in trials that spanned less than a year. CONCLUSIONS: The addition of roflumilast to tiotropium is cost-effective for the treatment of severe to very severe COPD patients.