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MEDICAL FRONTIERS - American Thoracic Society International Conference

San Diego, California / May 15-20, 2009

The newest trial to contribute well controlled evidence to guide therapy choices for the delay of chronic obstructive pulmonary disease (COPD) progression has tested a combination of the inhaled corticosteroid (ICS) budesonide with the long-acting beta-agonist (LABA) formoterol as an add-on to a first-line bronchodilator. The new study, called CLIMB, follows a recent placebo-controlled study that associated an initial maintenance strategy of single-agent bronchodilation with a change in the natural history of disease. Together, these studies provide an evidence-based algorithm for steps 1 and 2 in the effort to delay COPD progression, extending quality of life (QoL) and potentially improving survival.

“To date, no major study has prospectively evaluated the impact of adding the budesonide/formoterol combination to tiotropium,” reported Dr. Tobias Welte, Department of Respiratory Medicine, Hannover Medical School, Germany. “The goal of this study was to evaluate the effect of this addition on clinically important measures, such as lung function and health status.”

CLIMB: Building on First-line Strategies to Extend Benefit

Although there is continuing debate about whether maintenance therapy for COPD is best initiated with a long-acting muscarinic antagonist (LAMA) or a LABA, the LAMA tiotropium was a reasonable choice to test the added benefit of budesonide/formoterol on the basis of the recently published UPLIFT study. In UPLIFT, tiotropium generated some of the best evidence so far that long-acting bronchodilation changes disease course when measured over a period of up to four years. However, the progressive nature of COPD means that additional therapies will be needed to build on any first-line single-agent choice. The new data provide the evidence that the budesonide/formoterol combination is an appropriate next step.

The placebo-controlled CLIMB study randomized 660 patients at 102 centres in nine countries. The study was initiated with a two-week run in of once-daily tiotropium at a dose of 18 µg. Patients were then randomized to receive a combination of 320 µg budesonide/9 µg formoterol administered as a single inhalation twice daily or delivery of a placebo by inhaler on the same schedule. Patients in both arms of the study remained on the LAMA during the course of 12 weeks of follow-up.

Patients were eligible for inclusion in the study if they had sufficiently advanced disease to require combination therapy. This was defined as a pre-bronchodilator forced expiratory volume at 1 second (FEV₁) of <u><</u>50% predicted normal and a FEV₁/vital capacity (VC) <70%. Patients were also required to have had at least one COPD exacerbation that required oral steroids and/or antibiotics during the previous 12 months. At enrolment, about 75% were on a LABA, about 65% were on an ICS and about 52% were on a LAMA, many of who were receiving some combination of these.

Figure 1.

When the 329 patients randomized to the budesonide/formoterol group were compared to the 331 patients randomized to placebo, baseline characteristics were well matched. In both groups, the median FEV₁ of predicted normal was approximately 38%. The average age was approximately 62 years and the median time since COPD diagnosis was 5.7 years. About 40% remained habitual smokers, and the study population overall had a history of more than 35 pack-years of smoking.

Study Findings

Significant benefit was generated for each of the primary outcomes, which included improvement in lung function, control of morning symptoms, and improvement in health status. Specifically, FEV₁ climbed almost immediately in those receiving budesonide/formoterol, including the trough FEV₁ evaluated before the morning dose of budesonide/formoterol. FEV₁ was unchanged in the placebo group. At the last week of treatment, the 6% (P<0.001) improvement in pre-dose FEV₁ from baseline corresponded to a 128 mL pre-dose advantage over placebo. When measured 15 minutes after the dose, the FEV₁ advantage climbed to 186 mL. The rapid onset of effect in the morning response was emphasized (Figure 1).

“Improvements were seen within five minutes of drug administration and was sustained throughout the treatment period,” Dr. Welte reported. “The morning benefit of the combination is of particular relevance given that many patients report breathlessness and cough to be troublesome in the effort to get washed, get dressed and get active. This is a big hurdle for an acceptable QoL.”

In the morning, the Global Chest Symptoms Questionnaire (GCSQ) (scaled 0 to 4) favoured the combination over placebo for breathlessness (-0.148; P=0.001) even before the first dose. Its advantage in chest tightness approached significance (-0.90, P=0.051). Fifteen minutes after the morning dose, the relative advantage for both breathlessness (- 0.185; P<0.001) and chest tightness (-0.121; P=0.014) increased. On the Capacity of Daily Living during the Morning (CDLM) scale, total scores for getting washed and dressed, eating breakfast, and mobility were more than twice as high on budesonide/formoterol vs. placebo at week 1 (0.13 vs. 0.05; P=0.027), climbing gradually to about a fivefold difference (0.26 vs. 0.06; P<0.001) by week 12.

When symptoms were measured overall with the Saint George’s Respiratory Questionnaire for COPD patients (SGRQ-C), the same types of advantages were documented. About half of the combination patients achieved a 4.0-point increase, which was a 25% gain (P=0.016) over that observed for the LAMA alone.

On COPD symptom scores at 12 weeks, the advantage for budesonide/formoterol was highly significant for breathlessness, chest tightness, cough and nighttime awakenings (all P<0.001 vs. tiotropium alone). There was also a reduction in rescue medication use in the morning, daytime and nighttime periods (all P<0.001 for the combination vs. tiotropium alone).

Fewer Severe Exacerbations

In COPD, outcomes generally track together so that improvements in lung function correlate with improvements in symptoms and QoL. In the CLIMB study, the rate of severe exacerbations was reduced by 62% (P<0.001) relative to those who received tiotropium alone. When graphed, the curves had clearly separated within 15 days of the randomization and then widened consistently over the course of the study (Figure 2). When a hazard ratio (HR) was calculated for a first severe exacerbation, there was a 61% reduction (HR 0.39; 95% CI, 0.17-0.89; P=0.026) for budesonide/formoterol relative to tiotropium alone. The percentage of patients requiring exacerbation-related antibiotics was reduced by almost exact
12%).

Figure 2.

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“The advantage of budesonide/formoterol on this measure of worsening COPD provides additional support for adding this combination to maintenance when patients require more than tiotropium alone for disease control,” Dr. Welte stated. Again, the data provide an evidence basis for selecting the next step in disease control over a single-agent bronchodilator.

A Question of Sequence

The data from the CLIMB study build on the recent results of UPLIFT, which associated the LAMA tiotropium with sustained benefits over four years even though patients were allowed to use any respiratory medication other than another LAMA over this period. Although the CLIMB study was not designed to address the debate of whether a LAMA or a LABA should be used first-line, it does provide guidance for the next step in therapy when a single agent is not enough.

“My own view is that it is probably not a question of one long-acting bronchodilator being better than another for first-line treatment. I suspect that we may eventually find that some patients respond better to a LAMA and some respond better to a LABA,” suggested Dr. Welte, when asked if a LAMA should be defined as first-line. However, the CLIMB study demonstrates that “further improvement in lung function, symptoms, and health-related QoL when the combination of budesonide/formoterol is added.”

Findings in Exercise Tolerance

It is specifically the additive effects of an ICS and a LABA together that appear to be important. A separate double-blind study was conducted at 13 centres in Germany and Switzerland that randomized 111 patients to the same dose of budesonide/formoterol used in the CLIMB study, 9 µg of formoterol alone or placebo. Findings indicate the exercise endurance time (EET) improved in a stepwise fashion for formoterol relative to placebo and for the combination relative to formoterol wheth
hour or six hours after the morning dose (Figure 3).

Figure 3.

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“The superiority of budesonide/formoterol on exercise tolerance compared with formoterol demonstrates the contribution to the clinical effect of the ICS component of the combination,” reported the senior author, Dr. Heinrich Worth, Klinikum Fürth, Universität Erlangen-Nürnberg, Germany. “The improvement in EET anticipates an ability to participate in more strenuous activities for at least six hours after a dose of budesonide/formoterol.”

One of the key issues of improving exercise tolerance with any therapy, including a LABA, a LAMA, an ICS or some combination, is an interruption of the vicious cycle that links declining respiratory function to progressive comorbidities such as cardiovascular disease. In a retrospective review of 664 consecutive cases presented by Dr. Irena Sarc, University Clinic of Respiratory and Allergic Diseases, Golnik, Slovenia, 69% of COPD patients had some form of cardiovascular disease. Although it has been appreciated previously that cardiovascular disease and COPD are closely correlated, there is growing understanding that poor control of COPD may be a major contributor to progressive cardiovascular impairment.

“Exercise is an important defence against cardiovascular disease. As patients lose mobility due to advancing COPD, this defence is lost,” Dr. Sarc explained. She indicated that better control of respiratory symptoms should be specifically evaluated for their ability to alter cardiovascular outcomes in COPD patients. It is notable that in the UPLIFT study, there was a 16% reduction (HR 0.84; 95% CI, 0.73-0.98; P<0.05) in cardiovascular events, including a 29% reduction (HR 0.71; 95% CI, 0.52-0.99; P<0.05) in myocardial infarction. These results were seen at the end of four years for those randomized to an effective long-acting bronchodilator as first-line therapy when compared to those initiated on placebo.

“It is appropriate to begin thinking more intently about the interrelationship of COPD and cardiovascular disease and how treatment in one may affect outcome in the other,” Dr. Sarc concluded.

Summary

There is an expanding body of data to provide objective guidance for organizing therapies in the long-term control of COPD. While COPD remains a progressive disorder, the new evidence suggests that the natural history of the disease, including the slope of the decline in lung function and QoL, can be altered with effective maintenance therapies. The correlation between improved lung function and greater exercise tolerance with long-acting bronchodilators alone or in combination has important implications for long-term outcome, including protection from the relative risk of developing comorbidities such as cardiovascular disease.