International Differences in the Frequency of Chronic Obstructive Pulmonary Disease Exacerbations Reported in Three Clinical Trials

Abstract

Rationale: Exacerbations of chronic obstructive pulmonary disease (COPD) are an important endpoint in multinational clinical treatment trials, but the observed event rate is often lower than anticipated and appears to vary between countries. Objectives: We investigated whether systematic differences in national exacerbation rates might explain this observed variation. Methods: We reviewed data from three large multicenter international randomized trials conducted over an 18-year period with different designs and clinical severities of COPD, comparing bronchodilator and/or inhaled corticosteroids with bronchodilators alone and/or placebo. Exacerbations were defined by antibiotic and/or oral corticosteroid use (moderate) or need for hospitalization (severe). We calculated crude exacerbation rates in the 30 countries contributing 30 or more patients to at least two trials. We grouped data by exacerbation rate based on their first study contribution. Measurements and Main Results: For the 29,756 patients in 41 countries analyzed, the mean exacerbation rate was two- to threefold different between the highest and lowest tertiles of the recruiting nations. These differences were not explained by demographic features, study protocol, or reported exacerbation history at enrollment. Of the 18 countries contributing to all trials, half of those in the highest and half in the lowest tertiles of exacerbation history remained in these groups across trials. Severe exacerbations showed a different rank order internationally. Conclusions: Countries contributing to COPD trials differ consistently in their reporting of healthcare-defined exacerbations. These differences help explain why large studies have been needed to show differences between treatments that decrease exacerbation risk.

Keywords: bronchodilators; chronic obstructive pulmonary disease; exacerbations; inhaled corticosteroids.

Figure 1.

Ranking of countries according to the observed rate of moderate and severe exacerbations (countries with fewer than 30 patients or only participating in one of the three trials are excluded). For each country, the figure shows the within-trial exacerbation rate ranking (first and highest rate to last and lowest rate), the within-trial exacerbation rate (exacerbations/years of exposure), and, in square brackets, the percentage contribution of patients to this analysis from that trial and country. Colors represent within-trial exacerbation tertile grouping (red: high; yellow: middle; green: low); however, the overall high, middle, and low exacerbating groups in this table, based mostly on TORCH, are used for this analysis. The number (n) of patients in each subgroup participating in each tertile of the exacerbation rate distribution is shown within a box above each trial group. COPD = chronic obstructive pulmonary disease; IMPACT = Informing the Pathway of COPD Treatment; ITT = intent-to-treat; Pop = population; SUMMIT = Study to Understand Mortality and Morbidity in COPD; TORCH = Towards a Revolution in COPD Health.

Figure 2.

Ranking of countries according to the observed rate of severe exacerbations (n, %). Color coding and other data are as described in Figure 1. For definition of abbreviations, see Figure 1.

Figure 3.

Power curves for different exacerbation rates to detect a difference assuming a 20% reduction in the rate from the comparator. The statistical power of the trial is shown on the y-axis and the number of participants per arm on the x-axis. Representative power curves are shown for trials with a mean exacerbation in the placebo arm of the rates seen in the highest and lowest thirds of participating countries in the TORCH (Towards a Revolution in COPD Health) trial (see Table 2). COPD = chronic obstructive pulmonary disease.