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This report is based on medical evidence presented at sanctioned medical congress, from peer reviewed literature or opinion provided by a qualified healthcare practitioner. The consumption of the information contained within this report is intended for qualified Canadian healthcare practitioners only.

ABSTRACTS IN PERSPECTIVE based on presentations from the International Conference of the American Thoracic Society

San Diego, California / May 15-20, 2009

EDITORIAL OVERVIEW:

Meyer Balter, MD, FRCPC, Director, Asthma and COPD Education Clinic, UHN-Mount Sinai Hospital, Professor of Medicine, Division of Respiratory Medicine, University of Toronto, Toronto, Ontario

Conducted over four years, the UPLIFT (Understanding Potential Long-term Impacts on Function with Tiotropium) Trial validated the hypothesis that treatment of chronic obstructive pulmonary disease (COPD) anchored with effective bronchodilation can modify important clinical measures of disease severity over the long term (Tashkin et al. N Engl J Med 2008;359:1543-54). Although most COPD patients require combination therapy over time commensurate with disease progression, new data from the UPLIFT trial, presented at the American Thoracic Society (ATS) Conference, provide a framework for creating a hierarchy of therapies starting with a long-acting muscarinic antagonist (LAMA).

In the multinational, double-blind UPLIFT trial, 5993 COPD patients were randomized to the once-daily LAMA tiotropium (18 µg inhalation) or placebo. Over the course of four years, a mean absolute improvement in forced expiratory volume in one second (FEV₁) was maintained among those randomized to active treatment relative to placebo (P<0.001) despite a design that permitted patients in either arm to receive additional treatment as needed (with the exception of an inhaled anticholinergic). In addition to the improvement in lung function, those randomized to the active treatment had significant reductions in exacerbations, related hospitalizations and respiratory failure than those randomized to placebo over the course of the four-year study. As predicted by these advantages, tiotropium offered improved quality of life (QOL) as measured by the St. George’s Respiratory Questionnaire (SGRQ) throughout the study period (P<0.001) (Figure 1).

Figure 1.

First-line Maintenance Therapy

A substudy of the UPLIFT trial presented at the ATS tested the hypothesis that tiotropium is effective as first-line maintenance therapy in COPD by evaluating efficacy in those patients who entered the study without having received any previous therapy. In this group of 810 patients (13.5% of the total study population), 403 were randomized to active therapy and 407 were randomized to placebo. The baseline characteristics of the two groups were comparable with a mean FEV₁ of approximately 52% +/-12%. In this substudy, the relative benefits of tiotropium over placebo were even greater than those observed in the study overall, reinforcing the primary results and encouraging early initiation of effective bronchodilation.

In particular, tiotropium provided protection against the rate of decline of FEV₁ over the period of follow-up (42 mL/year vs. 53 mL/year; P=0.026), an advantage that did not reach statistical significance in the study population as a whole. The change in the rate of decline is important because it provides evidence that treatment is altering the natural history of COPD by slowing its progression. In the published results, tiotropium was associated with a consistent improvement in lung function when measured by FEV₁ or forced vital capacity (FVC) over the course of the study, but a physiologic difference in rate of lung function decline could not be documented in the full study population. By this measure, there was a slight but insignificant advantage for tiotropium (40 mL/year vs. 42 mL/year; P=0.21) after bronchodilation but not before. The treatment-naïve substudy indicated protection against disease progression.

The only other strategy to show significant protection against the rate of lung function decline prior to this substudy analysis was smoking cessation. This relative protection in the treatment-naïve population was reinforced by other benefits. In particular, the relative risk of starting a second COPD therapy, such as a long-acting beta agonist (LABA) bronchodilator or inhaled corticosteroid (ICS), was reduced by 28% (HR 0.72; 95% CI,59-0.89) in those randomized to tiotropium as first-line therapy when compared to placebo. At the end of four years, the median advantage in the SGRQ score was 4.6 points (P<0.001), which was greater than that observed in the study as a whole (Table 1).

The 26% reduction in mortality (HR 0.74; 95% CI, 0.50-1.10) in the treatment-naïve subgroup did not reach statistical significance, but a similar trend for a mortality advantage was observed in the study population as a whole (HR 0.89; 95% CI, 0.79-1.02) when evaluated 30 days after study agents were discontinued. During the four years that patients remained on their assigned therapy, the mortality advantage did reach statistical significance (HR 0.87; 95% CI, 0.76-0.99), suggesting, but not proving, a relative survival advantage because this was not a primary or even a prespecified end point.

In newly reported data from the UPLIFT substudy of persistent smokers, the 846 patients who admitted that they were continuing to smoke were compared to the 3534 participants who reported sustained abstinence. Patients who reported intermittent smoking were excluded from the analysis. Although tiotropium, as compared to placebo, did not alter the rate of post-bronchodilation decline in FEV₁ among either smokers (59 mL/year) or non-smokers (36 mL/year), smokers achieved an even greater average improvement in SGRQ total score at 48 months on tiotropium than nonsmokers (4.6 vs. 2.8) as well as a slightly greater reduction in the risk of exacerbation (19% vs. 14%).

The four-year follow-up data from the UPLIFT trial also reconfirm the safety of tiotropium vs. placebo even when administered long-term. The rate of any adverse event over the course of the study was nearly identical in both groups. Serious adverse events occurring in more than 1% of patients involved either cardiac or respiratory events such as congestive heart failure, COPD exacerbations, dyspnea or respiratory failure, and these were all lower on tiotropium. Systematic reviews and meta-analysis of previous papers studying the effects of inhaled anticholinergics in COPD had suggested an increased risk for all-cause and cardiovascular deaths, myocardial infarction, and stroke in treated patients. The UPLIFT results were extremely reassuring, not only by demonstrating none of these associations in a prospective four-year trial with tiotropium but actually demonstrating reduced cardiac events, including myocardial infarction, and fewer episodes of respiratory failure in the treated group. The agent proved to be very well tolerated over the course of the long-term study, confirming utility and safety in a maintenance regimen.

If UPLIFT establishes tiotropium as an appropriate firstline therapy for COPD maintenance, then the clinical goal is to identify a rational choice for adjunctive treatment as symptoms progress. Several candidates were set forth in studies presented at the ATS that employed tiotropium as the first-line anchor. In a multicentre European trial, the study adjunctive agent was a combination inhaler of budesonide 320 µg and formoterol 9 µg. In the double-blind, parallel-group trial, 660 patients taking a standard once-daily 18-µg dose of tiotropium were randomized to receive budesonide/formoterol or placebo. The entry criterion was a pre-bronchodilator FEV₁ of =50%. The mean FEV₁ at entry was 37.9%. The primary end point, assessed at the end of 12 weeks, was rate of severe exacerbations defined as need for oral steroid use or an emergency room visit
r COPD.

Table 1.

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Adjunctive Therapy

Relative to placebo, the addition of budesonide/formoterol reduced the number of severe exacerbations by 62% (HR 0.38; 95% CI, 0.25-0.57; P<0.001). As an isolated outcome, hospitalizations or emergency room visits were reduced by 65% (P=0.01). Both outcomes were achieved without evidence of an increased risk of severe adverse events, including those related to impaired immune function. Notably, the absolute rates of nasopharyngitis (2% vs. 4%), bronchitis (1% both groups) and upper respiratory tract infections (1% both groups) were lower or the same when the ICS budesonide and the LABA formoterol were compared to placebo in combination with tiotropium.

In pooled data from two studies, the addition of nebulized formoterol (20 µg in twice-daily administration) was tested as an adjunctive therapy to maintenance tiotropium in COPD patients with a FEV₁ =25% but <65% of predicted. The pooled analysis included 284 patients randomized to the active therapy or placebo. Efficacy measurements included serial spirometry, the Transitional Dyspnea Index (TDI), rescue salbutamol use and SGRQ. By the end of the six-week study, there was a 192-mL advantage (P<0.0001) for FEV₁ among those who received formoterol relative to placebo even though they experienced a significant end-of-study decline in salbutamol use (approximately 1 puff/day; P<0.0001). The SGRQ score for symptoms but not for other domains was significantly reduced. No exacerbations were observed in the active treatment arm vs. 2% in the placebo arm. This study supports the Canadian Thoracic Society COPD Guidelines’ suggestion that a second long-acting bronchodilator should be added to a long-acting bronchodilator in another class as the next step in treatment.

In a third study evaluating a next step in therapy with tiotropium as the anchor maintenance regimen, 83 patients were randomized to a tulobuterol patch or placebo. Although conducted over only eight weeks, the total SGRQ score was significantly improved in correlation with reduced rates of dyspnea and peak expiratory flow (PEF) improvements. While the study is consistent with the others in demonstrating an incremental benefit from adding another active therapy to tiotropium, the study is noteworthy for its method of drug delivery. In combination with once-daily tiotropium, patch delivery raises the potential for a very simple regimen even in patients who require combination therapy for adequate symptom control.

Summary

In the absence of therapies capable of reversing COPD, the ultimate test of an optimal regimen is the ability to slow progression. UPLIFT demonstrated that COPD patients randomized to maintenance inhaled tiotropium have sustained improvements in lung function for a period of at least four years. The substudy evidence of a reduction in the slope of decline in FEV₁ among patients initiated on active treatment reinforces the evidence that tiotropium is an evidence-based choice as an anchor or first-line therapy in this disease. As most or all COPD patients will require combination treatments as the disease progresses, selection of an optimal secondline treatment to sustain benefits is an important focus of current trials.

ABSTRACT 201 Long-Term Efficacy of Tiotropium in Continuing Smokers vs. Sustained Ex-Smokers in the UPLIFT Trial

D.P. Tashkin, B. Celli, D. Burkhart, S. Kesten, D. Liu, S. Mehra, M. Decramer, Los Angeles, CA, Ridgefield, CT, Boston, MA, New York City, NY, Leuven, Belgium

Background: The influence of smoking behavior on long-term airway medication responses has not been fully evaluated. Long-term trial data from UPLIFT provides information regarding the interaction of smoking and airway treatment.

Methods: Analysis of outcome data from UPLIFT (randomized double-blind, parallel-group, placebo-controlled [PBO] 4-yr trial of tiotropium [TIO] in COPD patients). All respiratory drugs except inhaled anticholinergics were allowed during the trial. Spirometry, SGRQ, exacerbations & adverse events were collected during the trial. Treatment effects were examined in the subgroup of patients reporting smoking at each clinic visit (S) and those reporting sustained abstinence (XS) based on self-reports at clinic visits q. 3 months. Intermittent smokers are excluded in the present analysis.

Results: A total of 5,993 patients were randomized. Baseline characteristics of S (n=846) vs. XS group (n=3534): 67% vs. 71% men, 61 vs. 66 years old, post-bronchodilator(BD) FEV1 49 vs. 47% predicted, SGRQ total score 49 vs. 45 units. Differences (TIO-PBO) in A.M. pre-dose FEV1 (48 mths) were 125 (S) & 97 (XS) ml. Rate of decline in post-BD FEV1 (mL/yr) was 59 (S) vs. 36 (XS) and not affected by treatment assignment. SGRQ total score improved (TIO-PBO) at 48 mths by 4.6 (S) & 2.8 units (XS). Risk of exacerbation was reduced in both groups (19% [S], 14% [XS]). Hazard ratios for mortality during treatment (TIO/PBO) were 0.79 [XS] & 1.16 [S].

Conclusions: Long-term treatment with tiotropium provides sustained improvements in lung function & healthrelated quality of life, while reducing the risk of an exacerbation in both continued smokers & sustained ex-smokers.

Commentary on abstract 201

The placebo-controlled UPLIFT study with tiotropium was the first trial to associate any therapy for COPD other than smoking cessation with long-term improvements in lung function (Tashkin et al. N Engl J Med2008;359:1543-54). In this new UPLIFT analysis, outcomes were stratified by smoking status. Typical of COPD populations, almost 15% of the UPLIFT population continued to smoke over the course of the study. Compared to those who reported abstinence from smoking, persistent smokers achieved even greater benefit against all of the major end points relative to placebo. These included greater relative improvement in quality of life, a greater relative reduction in the rate of exacerbations and a greater relative protection from a decline in lung function. Even though the absolute values for measures of lung function, such as FEV₁, remained lower in smokers than in abstainers, this analysis demonstrates that this agent’s relative benefits are at least as great among those who continue to smoke as in those who no longer smoke. As in the study as a whole, the benefits in smokers were achieved on top of other respiratory medications, all of which (except for inhaled anticholinergics) were permitted to patients in either study arm.

Questions and Answers with Dr. Donald P. Tashkin, Emeritus Professor of Medicine, University of California, Los Angeles

Q: What was the significance of this substudy?

A: Unfortunately, a sizeable minority of COPD patients continue to smoke despite all the evidence we can give them that it accelerates disease progression. It was important to evaluate whether the benefits of tiotropium were still present despite smoking. So far, we really have not identified a subgroup of COPD patients who do not benefit from long-term treatment with tiotropium.

Q: Is there a risk that these results will encourage patients to keep smoking?

A: The benefits of tiotropium in smokers are relative to placebo, not to non-smokers on tiotropium. Smokers lost lung function over the course of the study at a much greater rate than those who abstained from smoking whether or not they were taking tiotropium, which is what we would expect. Relative to placebo, tiotropium reduces the rate of lung function whether patients continue to smoke or abstain, but all outcomes are better for those who stop smoking. This study is consistent with previous studies in that regard.

Q: Were these results expected?

A: We would expect a short-term relative benefit from effective bronchodilation, but we needed these results to prove that effective bronchodilation still provides relative protection against lung deterioration over a period of years even when patients continue to smoke. I think it was also important to show the reduction in the risk of exacerbations in smokers over a long-term follow-up.

Q: Is it important that these findings were based on self reports of smoking status?

A: From a clinical perspective, this may be an advantage because it would be reasonable to expect that more patients report abstinence when they continue to smoke than the other way around. These data suggest that tiotropium provides a benefit whether or not patients are providing an accurate smoking history.

ABSTRACT 2467 Effectiveness of Tiotropium as First Maintenance Drug in Patients with COPD. Secondary Analysis of the UPLIFT Trial

T. Troosters, S. Kesten, D. Burkhart, B. Celli, D. Liu, S. Mehra, D. Tashkin, M. Decramer, Ridgefield, New York, Los Angeles, Boston, Leuven, Belgium, Ingelheim, Germany

Data on the long-term effect of tiotropium (TIO) in COPD patients not on maintenance (MN) drugs would assist determining initial choice of therapy. The effect of TIO in COPD was evaluated in a randomized doubleblind, parallel-group, placebo (PBO)-controlled 4-yr trial (UPLIFT). We focused on the effect of TIO in 13.5% of patients not on other maintenance drugs (MN-naïve: no inhaled LABA, ICS, theophyllines, anticholinergics) at randomization. 403 (TIO, age 63 yrs, post-bronch. (PB)-FEV1 53±12% pred) and 407 (PBO, age 64 yrs, PB-FEV₁ 51±12%pred) patients were randomized. Rate of FEV₁ decline from 1-48 months was 42±4mL/yr in TIO vs. 53±4mL/yr in PBO (P=0.026). At 4 years, improvement (TIO-PBO) in morning pre-dose FEV₁=134 mL (P<0.001). SGRQ total score declined more slowly in TIO compared to PBO (difference 1.05±0.34 units/yr, P=0.002), particularly for the domains ‘impact’ (difference 1.08±0.37 units/yr, P=0.004) and ‘activity’ (1.44±0.40 units/yr, P<0.001), but not for symptoms (0.26±0.50 units/yr, P=0.6). At 48 months, improvement in SGRQ total score (TIO-PBO)=4.6 units (P<0.001). The hazard ratio [HR, (TIO/PBO)] to start of LABA or ICS was 0.72 (95%CI 0.59-0.89). HR to experience a hospitalized exacerbation (TIO/PBO) was 0.77 (95%CI 0.62-0.94, P=0.012). Risk for an exacerbation was similar. Mortality did not differ significantly (HR 0.74, 95%CI 0.50-1.10).

Conclusion: Tiotropium is an effective first maintenance therapy in COPD. It reduces decline in lung function and HRQoL, improves lung function, reduces the risk for subsequent additional respiratory therapy and reduces the risk for exacerbation hospitalizations over 4 years.

Commentary on abstract 2467

In the UPLIFT trial, which validated tiotropium as an effective long-term maintenance agent in patients with COPD (Tashkent et al. N Engl J Med 2008;359:1543-54), 810 (13.5%) of the 5993 patients randomized were treatment-naive at entry (no prior maintenance therapy and no current treatment with other long-acting bronchodilators or anti-inflammatory drugs). In this analysis, relative benefit of tiotropium was evaluated as a first-line agent in the subgroup of UPLIFT patients who were treatmentnaive. When the 403 patients receiving tiotropium were compared to the 407 randomized to placebo, those on active therapy had less decline in FEV₁, greater improvement in morning pre-dose FEV₁, and a better quality of life. In addition, the tiotropium patients were almost 30% less likely to have initiated a LABA or an ICS over the course of the follow-up. The 26% reduction in the risk of mortality (HR 0.74; 95% CI, 0.5-1.10) did not reach statistical significance, but there was a reduction in the risk of hospitalization for an exacerbation. The results extend the findings of UPIFT by indicating that tiotropium is an effective maintenance therapy but can be used first-line to delay the requirement for additional drugs.

Questions and Answers with Dr. Thierry Troosters, Associate Professor, Catholic University, Leuven, Belgium

Q: Do these data suggest that tiotropium is the first-line agent for COPD?

A: UPLIFT overall demonstrated that tiotropium can change important outcomes of COPD over a period of up to four years. We have no comparable evidence with any alternative except for smoking cessation. Although UPLIFT was not a study of first-line maintenance, this substudy in those who received therapy first-line showed benefits that paralleled those observed in the total study population, and in that way provides some validation that this is very effective as the initial therapy in the treatment of COPD.

Q: Should tiotropium be initiated immediately on diagnosis of COPD?

A: In symptomatic patients, the UPLIFT data demonstrate that tiotropium improves lung function and quality of life and reduces exacerbations. In patients with sufficient symptoms to warrant therapy, starting with tiotropium reduced their need to move on to other medications over the course of the study, which is an important finding. The data suggest that if you start with tiotropium you can stick with a fairly simple maintenance regimen before you need to add additional maintenance therapies.

Q: Would you expect to see the same results with another long-acting bronchodilator?

A: We really do not have a comparable long-term study and so we cannot answer the question. In the TORCH study, COPD patients were randomized to receive the LABA salmeterol, the corticosteroid fluticasone, both components, or placebo, and did not show benefits with comparable statistical certainty. But there are many problems with comparing strategies across studies that may have had different design elements, such as patient selection, that influence results. The only thing we can say is we do have evidence that tiotropium improves outcomes.

Q: Do you think these results will influence guidelines?

A: This was a very large, well-controlled, multinational study providing the kind of level 1 evidence important to evidence-based guidelines, so that would be a reasonable expectation.

ABSTRACT 215 Budesonide/Formoterol Added to Tiotropium Is Well Tolerated and Reduces Risk of Severe Exacerbations in COPD Patients

T. Welte, L. Hartman, T. Polanowski, P. Hernandez, Canada, Germany, Lund, Sweden

Rationale: This study assessed whether budesonide/formoterol (BUD/FORM, Symbicort®) added to tiotropium (TIO) is well tolerated and reduces exacerbations in patients with COPD.

Methods: In a 12-week, double-blind, parallel-group, multicenter study, 660 patients with COPD (pre-bronchodilator FEV₁ =50% predicted normal [pn] [mean FEV₁ 1.1, 37.9% pn], mean age 62 yrs [range 40-85 yrs]) were randomized to TIO 18 µg 1 inhalation (inh) once daily (qd) + BUD/FORM 320/9 µg 1 inh twice daily (bid) (n=329) or TIO 18 µg 1 inh qd + placebo 1 inh bid (n=331) following a 2-week run-in with TIO 18 µg 1 inh qd. Severe exacerbations were defined as deterioration in COPD leading to oral steroid use, an emergency room (ER) visit and/or hospitalization.

Results: The frequency of adverse events (AEs) was similar with TIO + BUD/FORM vs TIO alone (124 vs 113 events [COPD-related AEs 4% vs 6% of patients; nasopharyngitis 2% vs 4%; bronchitis 1% vs 1%; hypertension 2% vs 1%; upper respiratory tract infection 1% vs 1%]), as were serious AEs (10 vs 16) and discontinuations due to AEs (9 vs 12). TIO + BUD/FORM decreased the number of severe exacerbations by 62% vs TI
and ER visits and/or hospitalizations (65%, P=0.01).

Figure:

<img3346|center>

Conclusion: Treatment with BUD/FORM added to TIO is well tolerated and reduces the risk of severe exacerbations compared with TIO alone in COPD patients.

Commentary on abstract 215

In a study designed to evaluate the next logical step in control of COPD after maintenance with a long-acting anticholinergic bronchodilator, 660 patients on tiotropium were randomized to receive ICS budesonide combined with the LABA or placebo. In this double-blind, multicentre and multinational study of 660 patients, the major outcome was the mean number of severe exacerbations. Importantly, one of the entry criteria was a pre-bronchodilator FEV₁ of 50% or less. All therapies were delivered in commonly used dosages. Over the course of 90 days of follow-up, the risk of a severe exacerbation, defined as the need for oral steroids or a visit to an emergency room (ER) or a hospitalization, was reduced by 62% (HR 0.38; 95% CI, 0.25–0.57; P<0.001). There were also significant reductions in ER visits and in hospitalizations when these were assessed separately. Yet the addition of two additional agents did not appear to produce any significant increase in the rate of drug-related adverse events. The study provides evidence for a next step in therapy when patients maintained on first-line tiotropium reach a level of lung function impairment that indicates a need for more aggressive management.

Questions and Answers with Prof. Tobias Welte, Medizinische Hochschule, Hanover, Germany

Q: Were the entry criteria for this study a reasonable threshold at which to consider adding therapies in patients on some kind of baseline maintenance regimen?

A: This is not a guideline-recommended milestone. We considered it a reasonable level at which to test the added contribution of budesonide/formoterol in this study. I think there is some room for debate about when you might step up therapy in COPD.

Q: Do you feel tiotropium is established as the first-line therapy in COPD to which additional therapies should be added when the disease progresses?

A: I think it is one of the bronchodilators that is a reasonable first-line choice. We do not really have controlled evidence comparing a LAMA with a LABA so this question is not fully answered. The UPLIFT study does provide good support for tiotropium as a first line therapy, so it was a reasonable choice for testing the added value of budesonide/formoterol in this study.

Q: Were you surprised at the marked reduction in severe exacerbations with the addition of an ICS/ LABA combination?

A: We have seen combination therapies reduce the risk of exacerbations compared to a single agent before. In this study, I think it is very reassuring to look at the graph and see the curves separate within a couple of days in favour of budesonide/formoterol. The curves continue to widen in favour of the combination over the entire course of the study.

Q: So in a stepped therapy approach, is budesonide/formoterol a reasonable next step in control of COPD?

A: Yes, that’s basically what the study shows.

ABSTRACT 2465 Decreased Risk of Cardiovascular Events with Tiotropium: An Analysis of a Pooled Clinical Trial Database

M. Decramer, S. Kesten, I. Leimer, D. Tashkin, B.R. Celli, Los Angeles, Boston, Leuven, Belgium, Ingelheim, Germany

Background: The accumulating safety database for tiotropium (TIO) has been augmented with information from the 4-yr UPLIFT trial in COPD. This database provides an opportunity to further the understanding of the cardiovascular (CV) adverse event profile of tiotropium.

Methods: We conducted an evaluation of adverse event reporting from 30 TIO trials meeting the following criteria: =4 weeks duration, randomized, parallel group, placebo (PBO) controlled, double-blind. The inclusion/exclusion criteria were similar including a spirometric diagnosis of COPD, =10 pk-yr smoking, age =40 yrs. Adverse events incidence rates were determined from the total number of patients with an event divided by total time at risk. Rate ratios (RR) and 95% CI for TIO/PBO were calculated. A composite CV endpoint was defined to include CV deaths + non-fatal myocardial infarction (MI) + non-fatal stroke + sudden death + sudden cardiac death + cardiac death.

Results: 19,545 patients were treated (TIO=10,846, PBO=8,699), 76% men, FEV₁= 1.15±0.46 L (41±14% predicted). Cumulative drug exposure was 13,146 (TIO) and 11,095 (PBO) pt-yrs. The incidence rate (IR) for a CV event was 2.15 (TIO) and 2.67 (PBO) per 100 pt-yrs [RR (95%CI)=0.83 (0.71, 0.98)]. The IR for fatal CV events (excluding non-fatal MI and stroke) was 0.91 (TIO) and 1.24 (PBO) per 100 pt-yrs [RR (95% CI)=0.77 (0.60, 0.98)]. For total MI and stroke the RR (95% CI) were 0.78 (0.59, 1.02) and 1.03 (0.79, 1.35) respectively.

Conclusions: In a comprehensive safety database of randomized, controlled, double-blind clinical trials, tiotropium reduced the risk of composite CV adverse events and mortality due to CV events. There is no increased risk for stroke and a possible decreased risk for MI with tiotropium.

Commentary on abstract 2465

COPD is strongly associated with cardiovascular (CV) disease and events. It is therefore important to verify that treatments for COPD do not exacerbate CV risk. In this analysis, data from 30 studies with tiotropium that included almost 11,000 patients treated with tiotropium. The study included the large amount of data generated by UPLIFT, which had four years of placebo-controlled follow-up. When compared to almost 9,000 controls, the incidence rate of a CV event was 17% lower on tiotropium relative to placebo (RR 0.83; 95% CI, 0.71–0.98). When further stratified by fatal CV events including stroke, there was a 23% relative reduction per 100 patient-years for tiotropium (RR 0.77; 95% CI, 0.6–0.99). When specific events were evaluated, the relative differences no longer reached statistical significance, but treatment with tiotropium trended for protection against myocardial infarction but appeared to have a neutral effect on stroke risk. It is likely that the reduction in CV events, including fatal events, stems from relative protection against COPD progression, which is a variable for increased cardiac stress, rather than a direct beneficial effect on CV pathology, although such a direct effect is possible.

Questions and answers for Dr. Bartolome R. Celli, Professor of Medicine, Tufts University School of Medicine, Boston, Massachusetts

Q: What was the purpose of this study?

A: There was at least a theoretical risk that a LAMA antagonist might actually have a negative effect on CV risk. This potential risk has been discussed for years, but we now have the evidence to put this to rest. The results tell us that there is no signal at all for increased risk of events. Rather, treatment with tiotropium reduced events.

Q: Do you think blocking muscarinic receptors might improve CV function?

A: It might, but the more important point is that tiotropium does not increase CV risk. The reduction in events on tiotropium relative to placebo is probably due to its activity against COPD. We would expect better control of COPD to reduce the risk of CV events because these are so closely associated. Many COPD patients actually die of their heart disease.

Q: Does the large database evaluated make results conclusive?

A: Is anything conclusive? This is a post-hoc analysis, but what you would expect from a database this large is some kind of signal. These retrospective data are hypothesis-generating, so you can look at it the other way. There is nothing from this data to support a hypothesis of an increased CV risk. Rather, the data predict a protective effect from tiotropium against CV events. This might be a testable hypothesis.

Q: When evaluated alone, UPLIFT also associated tiotropium with good safety and tolerability. Is this consistent with other data?

A: We really have a very large database from controlled trials and, of course, large numbers of patients are now taking tiotropium. This is a well-tolerated drug even in COPD patients, who often have a number of medical problems. Safety is not a significant issue with this agent.

ABSTRACT J51 In COPD, Adding Nebulized Formoterol to Tiotropium Treatment Provides Added Benefits in Pulmonary Function, Dyspnea, and Rescue Medication Use: A Pooled Analysis

J. New, N. Hanania, E. Matovinovic, D. Tashkin, Los Angeles, Napa, CA, Houston, TX

Rationale: In COPD patients, adding long-acting ß2-agonist, nebulized formoterol fumarate inhalation solution (FFIS, Perforomist™ Inhalation Solution, Dey, LP, Napa, CA), to tiotropium (TIO, Spiriva® HandiHaler® Boehringer Ingelheim Pharmaceuticals, Inc, Ridgefield, CT/Pfizer Inc, NY) treatment improved pulmonary function over treatment with tiotropium alone. We pooled results from 2 similar studies to provide a more complete analysis of the potential effects of adding FFIS to TIO treatment.

Methods: COPD subjects (=25% to <65% predicted FEV1) entered a 7-14 day run-in treatment with 1x-daily TIO 18 µg followed by randomization to 2x-daily FFIS (Perforomist Inhalation Solution 20 µg, n=144) or nebulized placebo (PLC, n=140) while continuing maintenance TIO treatment for 6 weeks. Efficacy was measured by serial spirometry, transitional dyspnea index (TDI), rescue albuterol use, and St. George’s Respiratory Questionnaire (SGRQ).

Results: Mean FEV1AUC0-3 was higher in FFIS/TIO than PLC/TIO on Day 1 (140 mL difference, P<0.0001) and Week 6 (192 mL difference, P<0.0001). Mean TDI scores were 1.97 FFIS/TIO and 0.67 PLC/TIO (P=0.0001). By the final 3 weeks, mean albuterol use declined in FFIS/TIO from 2.65 to 1.56 puffs/day compared with PLC/TIO, which continued to use 2.79 puffs/day (P<0.0001). SGRQ scores were similar both between treatments and to baseline, except the symptom domain score, which fell in the FFIS/TIO (-5.8) compared with PLC/TIO (-1.0). No FFIS/TIO subjects and 5 (2%) PLC/TIO subjects experienced COPD exacerbations.

Conclusions: Adding nebulized formoterol to maintenance tiotropium provided significant improvement in pulmonary function, dyspnea, and rescue medication use over tiotropium alone and reduced the occurrence of COPD exacerbations.

Commentary on abstract J51

Employing tiotropium as a first-line therapy, two studies attempted to evaluate whether the nebulized form of the LABA formoterol could improve pulmonary function in patients with advancing COPD. The results of the two studies which had nearly identical designs were pooled. In both, patients were initiated on 18 µg tiotropium once daily for a one- to two-week run-in before being randomized to a nebulized formoterol solution in a dose of 20 µg or a nebulized placebo. When lung function was compared at the end of 6 weeks of treatment, mean FEV₁ area under the curve measurements were greater on both day 1 and on week six (P<0.0001 for both time points) in the 144 patients receiving the nebulized LABA vs. the 140 receiving placebo. The transitional dyspnea index also recorded a highly significant advantage for tiotropium and formoterol vs. tiotropium plus placebo (P=0.0001). Over the final three weeks of the study, albuterol use was more than 40% lower in the group receiving two active therapies (2.79 puffs 1.56 puffs/day; P<0.0001). The difference in exacerbations did not reach statistical significance in this short study, but the results identify both an immediate and a sustained benefit from adding a nebulized LABA to tiotropium.

Questions and Answers with Dr. Donald P. Tashkin, Emeritus Professor of Medicine, University of California, Los Angeles

Q: Does this study suggest formoterol is a reasonable next step in COPD patients who are progressing on maintenance tiotropium?

A: This is a study of relatively modest size, so we have to be cautious in relying too heavily on the conclusions, but the study did demonstrate a very rapid response that was sustained over the course of the study. It indicates that this approach may be effective for quickly regaining control in patients with deteriorating lung function.

Q: Would you anticipate similar benefits regardless of first-line therapy?

A: We can only speculate about what results we might see with different agents, although the activity of nebulized formoterol is likely to be additive to other active therapies. We selected tiotropium for this study because the results of UPLIFT have demonstrated that tiotropium is effective long-term as a maintenance drug.

Q: Are nebulized formulations well accepted by patients?

A: They are well accepted by some patients, not all. It is useful to have several different types of delivery methods because patient preferences and circumstances do differ. This study provides evidence that nebulized formoterol is active and can improve lung function substantially in patients no longer adequately controlled on tiotropium.

ABSTRACT J60 Effects of Combined Treatment with Inhaled Tiotropium and Tulobuterol Patch in Patients with COPD

M. Ichinose, K. Seyama, M. Nishimura, A. Nagai, Y. Fukuchi, Tokyo, Japan

Background: The GOLD guidelines recommend use of more than one bronchodilator in the management of chronic obstructive pulmonary disease (COPD). Tulobuterol patch is a transdermal long-acting ß2-agonist, however the data for COPD is still sparse.

Objective: To examine the effects of tulobuterol patch added to tiotropium.

Design: A multicenter, randomized, parallel-group comparison study. Patients were allocated by an independent central registration center. Subjects and Methods: Clinically stable COPD patients with FEV₁ 30 to 80% of the predicted value after inhalation of a short-acting inhaled ß2-agonist were enrolled. After a 2-week run-in period, patients were administered either tiotropium monotherapy (18 µg/day QD) (Group T) or combination therapy with tiotropium 18 µg/day and tulobuterol patch QD (Group COM) for 8 weeks, and spirometry, peak expiratory flows (PEFs), MRC dyspnea scale, and St. George’s Respiratory Questionnaire (SGRQ) were evaluated.

Results: 83 patients (39 in Group T and 44 in Group COM) were analyzed. FVC, FEV₁, and PEFs were significantly improved during the treatment period in both groups compared with the run-in period. Significant improvement in PEF was observed in Group COM compared with Group T. MRC dyspnea scale score was also improved during treatment in both groups. Further, in severe COPD, significant improvement was observed in Group COM compared with Group T. Total SGRQ score was significantly improved in Group COM at Week 8 (-6.48 ±1.72) with a clinically significant change (=4 U) in total SGRQ score. Significant improvement of SGRQ was observed in Group COM compared with Group T. In SGRQ domain, Group COM exhibited significant improvement in activity (-6.12±2.68) and impact (-6.63±1.66) compared with the values of Group T.

Conclusions: These results suggest that the benefits of tiotropium are enhanced with concomitant use of tulobuterol patch.

Commentary on abstract J60

Employing tiotropium as a first-line therapy, Japanese investigators evaluated whether the LABA tulobuterol delivered through a transdermal patch would yield clinical improvements in patients with progressive COPD. COPD patients were eligible with a FEV₁ that was 80% of less than predicted (but 30% or greater). All patients received 18 µg tiotropium q.d. over a two-week run-in before being randomized to receive the tulobuterol patch or no additional therapy. Although all measures of respiratory function, including FEV₁ and peak expiratory flow (PEF) improved significantly in both groups at the end of eight weeks relative to baseline, the addition of the patch was associated with a significantly greater improvement than tiotropium alone for PEF. Those with greater lung function impairment at baseline benefited most for symptom control as measured with the SGRQ scores. In patients with severe disease, the SGRQ improvements included greater level of activity. The results of the study suggest that a patch delivery system is another viable approach to control of COPD when patients are no longer adequately controlled on first-line therapy.

Questions and Answers with Dr. Masakazu Ichinose, Professor of Internal Medicine, Wakayama Medical University, Japan

Q: Why did you permit patients into the study with 80% of predicted FEV₁, which is fairly mild COPD?

A: The GOLD guidelines now recommend use of more than one bronchodilator in the management of all COPD patients. The study was designed to evaluate whether a patch could be used in addition with an inhaled bronchodilator.

Q: Why did you evaluate the patch specifically with tiotropium?

A: Tiotropium is now used in many centres as first-line therapy, and this may become even more common with the results of UPLIFT. This seemed to be a reasonable standard on which to test the addition of the patch.

Q: Do you think a patch could be widely used?

A: The patch has many advantages, including the potential for better compliance. Many patients may want to reduce their inhaler use. Patches are easy to use and well tolerated, and they may be a very attractive option for maintenance therapy for some individuals. Is patch delivery of a LABA as effective as an inhaler? We need to look at this specifically, but it may be better when patients are not taking their medicine as prescribed.

ABSTRACT J70 Improvement in Physical Functioning in COPD Patients with Tiotropium

T. Glaab, H. Rau-Berger, Ingelheim, Germany

The long-acting anticholinergic tiotropium (Spiriva®) has demonstrated its efficacy and safety in several randomized controlled clinical trials: it improves lung function, reduces breathlessness and hyperinflation, improves exercise tolerance, prevents exacerbations, and improves health-related quality of life in patients with chronic obstructive pulmonary disease (COPD). Here, we evaluated the effect of tiotropium on physical function in a real-life setting. Patients with symptomatic COPD received tiotropium 18 µg once daily via HandiHaler® for 6 weeks in a prospective, open-label observational study in 250 office-based pulmonology practices in Germany. At baseline and week 6, physical function as determined by the standardized PF-10 score, and Physician’s Global Evaluation (PGE) were assessed. Of 1296 patients screened (813 men and 483 women; mean age: 65.1 ±10.3 years), 754 were evaluated for efficacy. After 6 weeks the mean PF-10 score increased from 42.4 ± 20.7 points to 58.1 ± 21.2 points, i.e., the patients’ physical function had on average improved by 15.8 ± 14.9 points (P<0.001). The therapeutic success rate (improvement by =10 points in PF-10 score) after 6 weeks of treatment was 68.3% (95% CI: 64.8% to 71.6%). The mean PGE value increased from 3.5 ± 1.1 at baseline to 4.5 ± 1.1 at final visit, i.e., the patients’ general condition on average improved by 1.0 ± 1.1 points. All safety data obtained in this study were in accordance with the known safety profile of tiotropium. In conclusion, the significant improvement in physical functioning in COPD patients receiving inhaled tiotropium in daily practice supports previous findings of randomized, controlled trials.

Commentary on abstract J70

Numerous well controlled studies have associated tiotropium with improvements in clinically important end points in COPD, including improved lung function, a reduction in exacerbations and an improvement in quality of life. This study was designed to determine whether tiotropium produced an improvement in physical functioning, perhaps the most important outcome for patients, outside of a controlled clinical trial. In the study, 754 COPD patients were evaluated at 250 office-based pulmonology practices before and after six weeks after being placed on tiotropium 18 µg q.d. Success in improving physical function was pre-defined as an improvement of 10 points or more on the 10-item standardized the Physical Function Evaluation (PF-10) as well as on Physician’s Global Evaluation (PGE). At the end of six weeks, 68.3% achieved the end point. The average improvement in PF-10 score was 15.8 points. The improvements in the PF-10 were reinforced by the PGE, which documented an almost 20% improvement in physical functioning. According to the authors, these “real-life” results provide support for similar findings from the controlled trials.

Questions and Answers with Dr. Thomas Glaab, Ingelheim, Germany

Q: Why conduct an open-label study when large, multicentre studies have already been conducted?

A: Post-marketing data are very important to demonstrate that drug use in the community is producing the types of results that were predicted in the formal trials. Real-life practice can be different from the trial setting.

Q: Were the results expected?

A: Yes. The question posed by the study is whether patients are doing better in their daily activities on therapy. The data show they improve physical function, which is an important outcome from the perspective of quality of life but may also have other health benefits that result from more mobility and exercise.

Q: Is the improvement in physical functioning an important outcome?

A: It is for patients. Severe COPD can be a very confining disease, preventing patients from doing even normal household tasks. The average 20% improvement we saw in this study is meaningful from a clinical perspective. Patients are very aware of an improvement of this size.