Once-daily bronchodilators for chronic obstructive pulmonary disease: indacaterol versus tiotropium. Probabilistic Markov model to assess the cost-effectiveness of bronchodilator therapy in COPD patients in different countries. Tiotropium versus salmeterol for the prevention of exacerbations of COPD. Cost-effectiveness of long-acting bronchodilators for chronic obstructive pulmonary disease. Formoterol mono- and combination therapy with tiotropium in patients with COPD: a 6-month study. Economic analyses comparing tiotropium with ipratropium or salmeterol in UK patients with COPD. Health outcomes following treatment for six months with once daily tiotropium compared with twice daily salmeterol in patients with COPD. Modelling the 5-year cost effectiveness of tiotropium, salmeterol and ipratropium for the treatment of chronic obstructive pulmonary disease in Spain. Blinded 12-week comparison of once-daily indacaterol and tiotropium in COPD. Economic evaluation of tiotropium and salmeterol in the treatment of chronic obstructive pulmonary disease (COPD) in Greece.
Indacaterol is the first once-daily, long-acting inhaled beta(2)-agonist bronchodilator studied in patients with chronic obstructive pulmonary disease (COPD).
                To demonstrate greater efficacy of indacaterol versus placebo on FEV(1) at 24 hours post dose (trough) after 12 weeks, to compare efficacy with placebo and tiotropium, and to evaluate safety and tolerability over 26 weeks.
                Patients with moderate-to-severe COPD were randomized to double-blind indacaterol 150 or 300 microg or placebo, or open-label tiotropium 18 microg, all once daily, for 26 weeks. The primary efficacy outcome was trough FEV(1) at 12 weeks. Additional analyses (not adjusted for multiplicity) included transition dyspnea index (TDI), health status (St George's Respiratory Questionnaire [SGRQ]), and exacerbations. Serum potassium, blood glucose, and QTc interval were measured.
                A total of 1,683 patients (age, 63.3 yr; post-bronchodilator FEV(1), 56% predicted; FEV(1)/FVC, 0.53) were randomized to the four treatment arms. Trough FEV(1) at Week 12 increased versus placebo by 180 ml with both indacaterol doses and by 140 ml with tiotropium (all P < 0.001 vs. placebo). At Week 26, for indacaterol 150/300 microg, respectively, versus placebo, TDI increased (1.00/1.18, P < 0.001) and SGRQ total score decreased (-3.3/-2.4, P < 0.01); corresponding results with tiotropium were 0.87 (P < 0.001) for TDI and (-1.0, P = not significant) for SGRQ total score. The incidence of adverse events, low serum potassium, high blood glucose, and prolonged QTc interval was similar across treatments.
                Indacaterol was an effective once-daily bronchodilator and was at least as effective as tiotropium in improving clinical outcomes for patients with COPD. Clinical trial registered with clinicaltrials.gov (NCT 00463567). The development of a probabilistic Markov model with a time horizon of 1 year to compare the cost-effectiveness of three bronchodilators: 1) the new long-acting anticholinergic tiotropium; 2) the short-acting anticholinergic ipratropium; and 3) the long-acting beta 2-agonist salmeterol, for the treatment of patients with chronic obstructive pulmonary disease (COPD) in different countries. In this article we compare The Netherlands and Canada.
                The Markov model was structured along disease severity states and exacerbations. Transition probabilities between disease states and exacerbation probabilities were derived from patient-level data from six randomized controlled trials assessing the efficacy and safety of tiotropium. Resource utilization during exacerbations and maintenance treatment for The Netherlands were derived from two clinical trials, whereas for Canada these data were obtained from a countrywide observational study that used similar inclusion criteria as the trials. Second-order Monte Carlo simulations were undertaken in which values were randomly drawn from distributions of these parameters. Outcomes of the model are yearly treatment costs, exacerbations, and quality-adjusted life months.
                The mean difference in the number of exacerbations was 0.17 (95% uncertainty interval: -0.02-0.37) in favor of tiotropium when compared with salmeterol and the difference between salmeterol and ipratropium was 0.12 (-0.17-0.44) in favor of salmeterol. The number of quality-adjusted life months did not substantially differ between treatment groups and varied from 8.42 (SE 0.41) in the tiotropium group to 8.17 (0.46) in the salmeterol group and 8.11 (0.50) in the ipratropium group. In The Netherlands, costs in the tiotropium group were 42 Euros (-484-353) lower than in the salmeterol group, whereas costs in the salmeterol group were 128 Euros (-795-457) lower than in the ipratropium group. In Canada, costs were consistently lower than in The Netherlands and nearly the same in all treatment groups. Differences between the two countries were primarily a result of a higher length of hospital stay in case of an exacerbation in The Netherlands. The cost-effectiveness acceptability frontier of exacerbations showed that tiotropium was associated with the maximum expected net benefit for all values of the ceiling ratio above 0 Euros (The Netherlands) and 10 Euros (Canada) in the base case analysis.
                This probabilistic model-based economic evaluation demonstrates how clinical trial data can be combined and integrated with country-specific information about resource utilization and unit cost to assess the cost-effectiveness of bronchodilators in COPD patients. Quality-adjusted life months did not substantially differ between treatment groups. In terms of exacerbations, tiotropium was associated with maximum expected net benefit for plausible values of the ceiling ratio. In sensitivity analyses, this outcome was most sensitive to changes in exacerbation rates. Treatment guidelines recommend the use of inhaled long-acting bronchodilators to alleviate symptoms and reduce the risk of exacerbations in patients with moderate-to-very-severe chronic obstructive pulmonary disease (COPD) but do not specify whether a long-acting anticholinergic drug or a β(2)-agonist is the preferred agent. We investigated whether the anticholinergic drug tiotropium is superior to the β(2)-agonist salmeterol in preventing exacerbations of COPD.
                In a 1-year, randomized, double-blind, double-dummy, parallel-group trial, we compared the effect of treatment with 18 μg of tiotropium once daily with that of 50 μg of salmeterol twice daily on the incidence of moderate or severe exacerbations in patients with moderate-to-very-severe COPD and a history of exacerbations in the preceding year.
                A total of 7376 patients were randomly assigned to and treated with tiotropium (3707 patients) or salmeterol (3669 patients). Tiotropium, as compared with salmeterol, increased the time to the first exacerbation (187 days vs. 145 days), with a 17% reduction in risk (hazard ratio, 0.83; 95% confidence interval [CI], 0.77 to 0.90; P<0.001). Tiotropium also increased the time to the first severe exacerbation (hazard ratio, 0.72; 95% CI, 0.61 to 0.85; P<0.001), reduced the annual number of moderate or severe exacerbations (0.64 vs. 0.72; rate ratio, 0.89; 95% CI, 0.83 to 0.96; P=0.002), and reduced the annual number of severe exacerbations (0.09 vs. 0.13; rate ratio, 0.73; 95% CI, 0.66 to 0.82; P<0.001). Overall, the incidence of serious adverse events and of adverse events leading to the discontinuation of treatment was similar in the two study groups. There were 64 deaths (1.7%) in the tiotropium group and 78 (2.1%) in the salmeterol group.
                These results show that, in patients with moderate-to-very-severe COPD, tiotropium is more effective than salmeterol in preventing exacerbations. (Funded by Boehringer Ingelheim and Pfizer; ClinicalTrials.gov number, NCT00563381.). To evaluate and compare the cost-effectiveness of long-acting bronchodilators by estimating incremental costs per quality-adjusted life-year (QALY) gained in patients with moderate to severe chronic obstructive pulmonary disease.
                This cost-effective analysis was conducted from a third-party payer's perspective. The study was a retrospective pooled analysis, and the effectiveness evidence was derived from a systematic review of literature published from January 1, 1980, to April 14, 2006. Incremental QALYs were estimated by converting the St George's Respiratory Questionnaire scores into EuroQoL-5D scores and using these combined scores as the summary benefit measure.
                The incremental cost per additional QALY was $26,094 (range, $11,780-$77,214) for tiotropium and $41,000 (range, $23,650-$98,750) for salmeterol compared with placebo. The cost per QALY gained was lower with tiotropium compared with salmeterol or ipratropium based on either the pooled data of available trials or a head-to-head trial. Treatment with tiotropium could save $391 per year while gaining 13 quality-adjusted days compared with ipratropium.
                Tiotropium appears to be more cost-effective than the alternatives and may be the preferred agent for maintenance therapy in patients with moderate to severe chronic obstructive pulmonary disease. Compared with ipratropium, tiotropium could be cost saving. Because of the wide ranges of cost-effectiveness ratios for tiotropium and salmeterol and the significant overlap between them, a large prospective head-to-head trial would help address the uncertainty and confirm the results of this analysis. Although guidelines recommend combining long-acting bronchodilators in COPD, data are limited. We examined the clinical efficacy and safety of formoterol, tiotropium and the combination in patients with COPD. Eight hundred and forty-seven patients with COPD (mean FEV(1) 52% predicted; FEV(1)/FVC 53%) were randomized to receive one of the following four treatments for 24 weeks: formoterol 10 microg b.i.d. plus tiotropium 18 microg o.d.; formoterol 10 microg b.i.d.; tiotropium 18 microg o.d., or placebo. The study was partially blinded (formoterol and placebo). For the primary endpoint, FEV(1) 2h post-dose after 24 weeks, there were small differences in favour of the combination therapy versus formoterol (0.07 L, p=0.044) or tiotropium (0.06 L, p=0.066). All three treatments were superior to placebo (p<0.001). The combination was statistically superior to monotherapy for: the primary endpoint (p=0.044 vs. formoterol); FEV(1) 5 min after the first dose (p<0.001) and at 12 weeks (p<0.05 vs. tiotropium); and peak expiratory flow averaged over the first 6 weeks (p<0.001 vs. both). The three active treatments were significantly more effective than placebo for secondary endpoints: COPD-related 'bad days', symptoms, use of rescue medication and peak expiratory flow, and aspects of health-related quality of life. The overall incidence of adverse events was similar with all active treatments, although COPD-related adverse events were more common with tiotropium. Combined bronchodilator therapy may be a valuable treatment option for patients with COPD. This study presents a cost-effectiveness and budget impact analysis comparing cost and outcomes for UK patients with COPD treated with either tiotropium, ipratropium or salmeterol.
                A previously-published COPD cost-effectiveness model was adapted for the UK, then used to estimate the cost-effectiveness of tiotropium compared to salmeterol and ipratropium. Additional epidemiological data were used to estimate the budget impact of switching patients from ipratropium or salmeterol to tiotropium.
                In England, the estimated annual cost per patient on tiotropium was pound1350, on salmeterol was pound1404, and on ipratropium was pound1427; in Scotland/Wales/Northern Ireland (S/W/NI) these costs were pound1439, pound1565, and pound1631, respectively. Tiotropium patients experienced better quality-adjusted life-years (QALYs) across all comparisons, and this option was therefore dominant compared to salmeterol and ipratropium. The probability of tiotropium being dominant ranged from 72% to 87% across comparisons. At a willingness to pay threshold of pound20,000 per QALY, tiotropium had at least a 97% chance of being cost-effective. The estimated annual saving per primary care trust (PCT) of switching patients from salmeterol and ipratropium to tiotropium in England was pound230,000 and in S/W/NI was pound160,000.
                Tiotropium is a cost-effective alternative to ipratropium and salmeterol, and switching COPD patients from ipratropium and salmeterol to tiotropium could result in considerable cost savings for PCTs along with improvements in quality-of-life. A study was undertaken to record exacerbations and health resource use in patients with COPD during 6 months of treatment with tiotropium, salmeterol, or matching placebos.
                Patients with COPD were enrolled in two 6-month randomised, placebo controlled, double blind, double dummy studies of tiotropium 18 micro g once daily via HandiHaler or salmeterol 50 micro g twice daily via a metered dose inhaler. The two trials were combined for analysis of heath outcomes consisting of exacerbations, health resource use, dyspnoea (assessed by the transitional dyspnoea index, TDI), health related quality of life (assessed by St George's Respiratory Questionnaire, SGRQ), and spirometry.
                1207 patients participated in the study (tiotropium 402, salmeterol 405, placebo 400). Compared with placebo, tiotropium but not salmeterol was associated with a significant delay in the time to onset of the first exacerbation. Fewer COPD exacerbations/patient year occurred in the tiotropium group (1.07) than in the placebo group (1.49, p<0.05); the salmeterol group (1.23 events/year) did not differ from placebo. The tiotropium group had 0.10 hospital admissions per patient year for COPD exacerbations compared with 0.17 for salmeterol and 0.15 for placebo (not statistically different). For all causes (respiratory and non-respiratory) tiotropium, but not salmeterol, was associated with fewer hospital admissions while both groups had fewer days in hospital than the placebo group. The number of days during which patients were unable to perform their usual daily activities was lowest in the tiotropium group (tiotropium 8.3 (0.8), salmeterol 11.1 (0.8), placebo 10.9 (0.8), p<0.05). SGRQ total score improved by 4.2 (0.7), 2.8 (0.7) and 1.5 (0.7) units during the 6 month trial for the tiotropium, salmeterol and placebo groups, respectively (p<0.01 tiotropium v placebo). Compared with placebo, TDI focal score improved in both the tiotropium group (1.1 (0.3) units, p<0.001) and the salmeterol group (0.7 (0.3) units, p<0.05). Evaluation of morning pre-dose FEV(1), peak FEV(1) and mean FEV(1) (0-3 hours) showed that tiotropium was superior to salmeterol while both active drugs were more effective than placebo.
                Exacerbations of COPD and health resource usage were positively affected by daily treatment with tiotropium. With the exception of the number of hospital days associated with all causes, salmeterol twice daily resulted in no significant changes compared with placebo. Tiotropium also improved health related quality of life, dyspnoea, and lung function in patients with COPD. Our objective was to assess the 5-year cost effectiveness of bronchodilator therapy with tiotropium, salmeterol or ipratropium for chronic obstructive pulmonary disease (COPD) from the perspective of the Spanish National Health System (NHS). A probabilistic Markov model was designed wherein patients moved between moderate, severe or very severe COPD and had the risk of exacerbation and death. Probabilities were derived from clinical trials. Spanish healthcare utilisation, costs and utilities were estimated for each COPD and exacerbation state. Outcomes were exacerbations, exacerbation-free months, quality-adjusted life years (QALYs), and cost(-effectiveness). The mean (SE) 5-year number of exacerbations was 3.50 (0.14) for tiotropium, 4.16 (0.40) for salmeterol and 4.71 (0.54) for ipratropium. The mean (SE) number of QALYs was 3.15 (0.08), 3.02 (0.15) and 3.00 (0.20), respectively. Mean (SE) 5-year costs were 6,424 euro (305 euro) for tiotropium, 5,869 euro (505 euro) for salmeterol, and 5,181 euro (682 euro) for ipratropium (2005 values). Ipratropium and tiotropium formed the cost-effectiveness frontier, with tiotropium being preferred when willingness to pay (WTP) exceeded 639 euro per exacerbation-free month and 8,157 euro per QALY. In Spain, tiotropium demonstrated the highest expected net benefit for ratios of the willingness to pay per QALY, well within accepted limits. Two, once daily (q.d.) inhaled bronchodilators are available for the treatment of chronic obstructive pulmonary disease (COPD): the β(2)-agonist indacaterol and the anticholinergic tiotropium. This blinded study compared the efficacy of these two agents and assessed their safety and tolerability. Patients with moderate-to-severe COPD were randomised to treatment with indacaterol 150 μg q.d. (n=797) or tiotropium 18 μg q.d. (n=801) for 12 weeks. After 12 weeks, the two treatments had similar overall effects on "trough" (24 h post-dose) forced expiratory volume in 1 s. Indacaterol-treated patients had greater improvements in transition dyspnoea index (TDI) total score (least squares means 2.01 versus 1.43; p<0.001) and St George's Respiratory Questionnaire (SGRQ) total score (least squares means 37.1 versus 39.2; p<0.001; raw mean change from baseline -5.1 versus -3.0), and were significantly more likely to achieve clinically relevant improvements in these end-points (indacaterol versus tiotropium odds ratios of 1.49 for TDI and 1.43 for SGRQ, both p<0.001). Adverse events were recorded for 39.7% and 37.2% of patients in the indacaterol and tiotropium treatment groups, respectively. The most frequent adverse events were COPD worsening, cough and nasopharyngitis. Both bronchodilators demonstrated spirometric efficacy. The two treatments were well tolerated with similar adverse event profiles. Compared with tiotropium, indacaterol provided significantly greater improvements in clinical outcomes. The objective of the study was to assess the cost-effectiveness of two therapeutic alternatives for chronic obstructive pulmonary disease in the Greek National Health Service (NHS) setting.
                A Markov probabilistic model was used to compare tiotropium with salmeterol. A Monte Carlo simulation with 5000 cases was run in the probabilistic analysis. The model was designed to compute the expected time spent in each state, the expected number of exacerbations occurring and the expected treatment cost per patient. Probabilities were extracted from clinical trials, resource utilisation and cost data from a Greek university hospital.
                Quality adjusted life years were 0.70 (95% Uncertainty Interval [UI]: 0.63 to 0.77) in the tiotropium arm and 0.68 (95% UI: 0.60 to 0.75) in the salmeterol arm; a difference of 0.02 (95% UI: -0.08 to 0.13). Exacerbations reached 0.85 (95% UI: 0.80 to 0.91) in the tiotropium arm and 1.02 (95% UI: 0.84 to 1.21) in the salmeterol arm, a difference of -0.17 (95% UI: -0.37 to 0.02). Estimates of the mean annual cost per patient were euro2504 (euro2122 to euro2965) in the tiotropium arm and euro2655 (euro2111 to euro3324) in the salmeterol arm, a difference of -euro151 (-euro926 to euro580). Stochastic analysis showed that tiotropium may have an advantage in reducing exacerbations. The probability that tiotropium is cost-effective was 65% at a ceiling value of euro0 and reached 77% at a ceiling ratio of euro1000. Results stay fairly constant in various sensitivity analyses.
                Even though tiotropium is more expensive to buy than salmeterol in the Greek NHS (using Greek costs there was no statistically significant difference in total costs between tiotropium and salmeterol), overall, during the course of a year, it is actually associated with a lower prevalence of exacerbations and lower treatment costs and thus may represent a viable and cost-effective alternative in the Greek NHS setting.
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.