Chronic obstructive pulmonary disease (COPD) represents an enormous health burden worldwide. Its prevalence is relatively high in Latin America, affecting an estimated 14.3%1 of the population versus 9.2%2 in the rest of the world (RoW). A substantial proportion of Latin American patients had experienced an exacerbation (18.2%),3 and respiratory causes, including COPD, are amongst the leading cause of mortality in this region.4 Smoking is a behaviour that is seemingly ingrained in Latin American culture,5 with smokers from Latin America constituting 8%–10% of tobacco smokers globally.6 Solid fuels are used by 30%–75% of households7 (traditionally in rural areas8) and contribute to mortality rates similar to those observed in tobacco smokers.9 Management guidelines for COPD recognize that curbing the smoking epidemic10,11 and reducing exposure to pollutants10 are necessary to lower COPD risk in developing countries, but do not detail regional differences in risk, outcomes, or treatment options.

The TIOtropium Safety and Performance In Respimat® (TIOSPIR®) study demonstrated similar efficacy and safety profiles between tiotropium Respimat® (2.5 or 5μg) and tiotropium HandiHaler® 18μg, with respect to risk of mortality and risk of exacerbation.12 A recent TIOSPIR® subanalysis demonstrated similar mortality rates in Asian patients versus RoW. Although exacerbation rates were lower in Asia, a higher proportion of patients had severe exacerbations than in RoW.13

The purpose of this post-hoc analysis was to determine whether there are differences in the baseline characteristics, mortality, exacerbations, cardiac adverse event, and serious adverse event (SAE) outcomes of patients from Latin American geographical region versus RoW in the TIOSPIR® trial.

Latin America is undergoing demographic changes characterized by increased ageing of the population, and the higher proportion of patients aged ≥60 years in Latin American countries is a reflection of this statistic.7,15 As expected, Latin American patients also had higher pack-years of smoking history versus RoW, although current smokers were less frequent in Latin America, indicating that more patients had stopped smoking prior to study start.

Compared with RoW, more patients in Latin America had very severe COPD (GOLD Stage IV) at baseline, possibly indicating that these patients remained undiagnosed during the early stages of COPD, and reflecting suboptimal disease management in this region.15,16 The PLATINO study, identified underdiagnosis as an issue across Latin America,17 while more than half of patients included in the PUMA study were not using bronchodilators.18 Our findings support this earlier research, with few patients using bronchodilators at baseline, suggesting a significant gap between guideline recommendations and prescribing patterns in this region.18 A scarcity of respiratory specialists and training programmes in many Latin American countries7 is likely to increase the risk of poor clinical outcomes.10 These factors could also have contributed to the observed higher proportion of patients with exacerbations in the year prior to our study. Thorough assessment, accurate diagnosis, and prompt initiation of management strategies (such as smoking cessation and maintenance respiratory therapy) in COPD are known to be essential for mitigating future risks.7,10,15 Evidence-based literature recommends smoking cessation at early stages of COPD.19

Latin American patients had increased risk of death compared with RoW, even when adjusted for age, gender, FEV1% predicted, exacerbation history, smoking history (pack-years), BMI, and history of cardiac disorders, MI, CAD/IHD, cardiac arrhythmia, heart failure (class I–IV), and stroke/TIA. These factors are proposed drivers of mortality and morbidity in COPD10,20,21 and are likely to be relevant regardless of geographical location. Findings from the PLATINO study also support an association between COPD and increased mortality when adjusted by age, smoking status, pack-years smoking, quality of life, BMI, and comorbidities.4 Comparable with previous findings,4 the incidence rate of death due to respiratory, thoracic, and mediastinal disorders, including COPD, was higher in Latin America versus RoW in our study.

Latin American patients also had a higher risk of moderate-to-severe exacerbation than patients in RoW. The risk was consistently higher in most subgroups, except for patients receiving LABA (but not ICS) at baseline. Nevertheless, although Latin American patients presented with more severe disease at baseline, and higher mortality or moderate-to-severe exacerbation risks, our analysis demonstrated that they were less likely to have severe exacerbation than RoW. This was true even when the analysis was adjusted for covariates, except for patients receiving ICS at baseline and patients with cardiac arrhythmia; underweight patients had an increased risk in Latin America versus RoW. Fewer severe exacerbations were recorded as a result of the scarcity of admission beds22 in Latin American hospitals, or related healthcare challenges such as inadequate facilities for critical care units.7 Our findings were contrary to those of several Latin American epidemiology studies, which found that hospitalization due to exacerbation was commonplace, reflecting undertreatment.15,16,18 In the PUMA study, frequent overtreatment with corticosteroids was observed in patients without an exacerbation in the past year, while a lower hospitalization rate was not deemed to support the extensive use of corticosteroids.16 Our results showed that corticosteroid overuse was prevalent in Latin America, as more patients were likely to receive ICS at baseline versus RoW.

Unlike the regional differences we identified for Latin American patients, the TIOSPIR® subanalysis of an Asian cohort observed similar mortality rates in Asian patients versus RoW patients.13 Further, Asian patients reported fewer exacerbations than those in RoW, whereas the proportion with a severe exacerbation was higher.13 This may be attributed to differences in the healthcare system in different regions; for example, in Asia, patients are frequently hospitalized for an exacerbation due to non-availability of corticosteroids or antibiotics in a primary healthcare unit.13 The observed discrepancies between the results for the Asian and the Latin American cohort illustrate how racial and/or geographical differences can impact hospitalization rates and treatment outcomes in COPD trials.

Patients enrolled in TIOSPIR® in Latin America were less likely to have a history of cardiac disorders or to be receiving cardiovascular medications at baseline compared with RoW. Assuming that their initial cardiovascular comorbidity was indeed lower, it is therefore rational that Latin American patients were less likely to experience a cardiac disorder SAE than those in RoW during the trial. The composite outcome of MACE was actually similar for both regions, though the risk of fatal MACE was numerically increased in Latin American patients. Further research is needed to clarify relative cardiac risks in this cohort, and the predisposing factors.

It was beyond the scope of our analysis to assess differences in baseline characteristics and outcomes between individual countries in the Latin American region, as the sample sizes may be too small to enable meaningful assessment. Environmental factors not assessed here also influence COPD-related risks, such as access to healthcare and alternative disease management strategies,7,23–25 the extent of solid fuel use,10 or living at high altitude. Hypoxia can have unwanted extra pulmonary systemic effects in patients with COPD, and might be associated with high altitude and mortality from COPD.26 Temperature inversions can also result in a buildup of air pollution that is detrimental to those with respiratory conditions.27 In addition, patients with COPD in tropical countries (such as Brazil, Columbia, and Peru) may be particularly prone to exacerbations, as infections are more prevalent throughout the year, and not just in the winter months (owing to the high humidity and lack of seasonal variation in temperature).28

The large population size and 2- to 3-year duration of the TIOSPIR® trial, along with the wide range of nationalities included (50 countries across different regions of the world14), constitute strengths of this analysis. Patients in TIOSPIR® constituted a convenience sample from 7 Latin American countries (rather than a sample representative of the whole population) and should therefore be interpreted with caution if generalized to Latin America overall. However, the patient characteristics are representative of the patients seen in specialist practice globally, and the continuation of regular maintenance respiratory medication and inclusion of patients with cardiac disease ensured that the population reflects real-world patients.12,14 Thus, we feel that the results are likely to be valid in a clinical setting. However, as this was a post-hoc rather than a predefined subgroup analysis, it is not possible to confirm the reasons why outcome risks differed between Latin America and RoW.

Latin American patients with COPD in TIOSPIR® had a higher risk of death and COPD exacerbations versus RoW patients, but were less likely to be hospitalized for an exacerbation. The prevalence of tobacco smoking, exposure to environmental contaminants, or healthcare challenges might impact treatment outcomes and lead to different results for patients enrolled from various regions in international trials of COPD. This should be considered when designing trials and evaluating the global clinical relevance of the results. Further studies should explore factors influencing the increased risk of mortality in Latin America compared with RoW.

The TIOSPIR® trial and this post-hoc study were funded by Boehringer Ingelheim.

All authors confirm involvement in the conception, hypotheses delineation, and design of the study; acquisition, analysis, or interpretation of the data; writing or substantial involvement in the article's revision prior to submission.

AA reports receiving consulting fees, lecture fees, or travel support from AstraZeneca, Boehringer Ingelheim, Forest Laboratories, GlaxoSmithKline, and Novartis. PMAC has received research grants from GlaxoSmithKline and Takeda; personal fees from AstraZeneca, Boehringer Ingelheim, GlaxoSmithKline, Novartis, and Takeda; and non-financial support from Boehringer Ingelheim. AM, NM, and MH are employees of Boehringer Ingelheim. JRJ reports receiving consulting fees, lecture fees, or travel support from AstraZeneca, Boehringer Ingelheim, Novartis, Grifols, CSL, Zambon, EMS, and Chiesi in the past 12 months. EP reports receiving consulting fees, lecture fees, or travel support from Ache, AstraZeneca, Boehringer Ingelheim, GlaxoSmithKline, Novartis, and Chiesi in the past 12 months; EP is currently a Global Medical Expert for GlaxoSmithKline. HG is an advisory member of Boehringer Ingelheim, Novartis, GSK, AstraZeneca, and Mundipharma; and has received lecture fees from Novartis, and travel support from MSD and AstraZeneca. ARV reports travel support from AstraZeneca and Novartis in the past 12 months. ERG reports receiving travel support, consulting fees and lecture fees from GlaxoSmithKline, AstraZeneca, Boehringer Ingelheim and Mundipharma.