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.

ACCEPT 2·0: Recalibrating and externally validating the Acute COPD exacerbation prediction tool (ACCEPT)

“…Moreover, a recent study has documented international differences in the frequency of COPD exacerbations even among patients with the same exacerbation history. 38 It is not clear to what extent the presence of multiple other predictors could explain away such variability. In general, it is likely that prediction models of exacerbations need to be recalibrated to their specific settings (e.g., country, type of care [primary, secondary, or tertiary], and socioeconomic status), as has been demonstrated recently for cardiovascular risk prediction models.…”

Contemporary Concise Review 2022: Chronic obstructive pulmonary disease

“…As ever, the devil is in the detail. Another understudied form of noise in study data was reported by Calverley et al who looked at the effect of country of origin on the observed exacerbation rates of participant in three large clinical trials with different entry criteria 39 . Observed rate was almost always lower than the number of events reported before the study, often substantially so, and some countries included patients with substantially lower exacerbation rates than required to adequately test the effectiveness of the intervention studied (Figure 3).…”

“…The figure shows the within trial exacerbation rate ranking, the within trial exacerbation rate and the percentage contribution of patients to this analysis from that trial and country. Reproduced with permission from Calverley et al [39]…”

“…The figure shows the within trial exacerbation rate ranking, the within trial exacerbation rate and the percentage contribution of patients to this analysis from that trial and country. Reproduced with permission from Calverley et al [39] diastolic volume (RVEDVI) on dynamic CT scanning was elevated in half 37 and predicted future hospitalization When combined with predictive indices like BODE, RVEDVI improved their ability to predict mortality.…”

Letter to the Editor Regarding “Fluticasone Furoate/Umeclidinium/Vilanterol (FF/UMEC/VI) Triple Therapy Compared with Other Therapies for the Treatment of COPD: A Network Meta-Analysis”

“…Furthermore, FULFIL was conducted primarily in Eastern Europe, whereas KRONOS was conducted primarily in the US, Japan, and China [ 14 , 15 ]. The countries in which studies are conducted are known to affect exacerbation results [ 17 ]. Additionally, prior exacerbations are well-recognized as a strong predictor of future exacerbation risk [ 18 ].…”