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IntroductionChronic obstructive pulmonary disease (COPD) exacerbations are associated with systemic consequences. Data from a 4-year trial (Understanding Potential Long-term Impacts on Function with Tiotropium [UPLIFT®], n = 5,992) were used to determine risk for nonlower respiratory serious adverse events (NRSAEs) following an exacerbation.MethodsPatients with ≥1 exacerbation were analyzed. NRSAE incidence rates (incidence rate [IR], per 100 patient-years) were calculated for the 30 and 180 days before and after the first exacerbation. NRSAEs were classified by diagnostic terms and organ classes. Maentel-Haenszel rate ratios (RR) (pre- and postexacerbation onset) along with 95% confidence intervals (CI) were computed.ResultsA total of 3,960 patients had an exacerbation. The mean age was 65 years, forced expiratory volume in 1 s (FEV1) was 38% predicted, and 74% were men. For all NRSAEs, the IRs 30 days before and after an exacerbation were 20.2 and 65.2 with RR (95% CI) = 3.22 (2.40–4.33). The IRs for the 180-day periods were 13.2 and 31.0 with RR (95% CI) = 2.36 (1.93–2.87). The most common NRSAEs by organ class for both time periods were cardiac, respiratory system (other), and gastrointestinal. All NRSAEs as well as cardiac events were more common after the first exacerbation, irrespective of whether the patient had cardiac disease at baseline.ConclusionsThe findings confirm that, after exacerbations, serious adverse events in other organ systems are more frequent, particularly those that are cardiac in nature.

BackgroundThe 2013 GOLD classification system for COPD distinguishes four stages: A (low symptoms, low exacerbation risk), B (high symptoms, low risk), C (low symptoms, high risk) and D (high symptoms, high risk). Assessment of risk is based on exacerbation history and airflow obstruction, whatever results in a higher risk grouping. The previous system was solely based on airflow obstruction. Earlier studies compared the predictive performance of new and old classification systems with regards to mortality and exacerbations. The objective of this study was to compare the ability of both classifications to predict the number of future (total and severe) exacerbations and mortality in a different patient population, and to add an outcome measure to the comparison: lung function decline.MethodsPatient-level data from the UPLIFT trial were used to analyze 4-year survival in a Weibull model, with GOLD stages at baseline as covariates. A generalized linear model was used to compare the numbers of exacerbations (total and severe) per stage. Analyses were repeated with stages C and D divided into substages depending on lung function and exacerbation history. Lung function decline was analysed in a repeated measures model.ResultsMortality increased from A to D, but there was no difference between B and C. For the previous GOLD stages 2–4, survival curves were clearly separated. Yearly exacerbation rates were: 0.53, 0.72 and 0.80 for stages 2–4; and 0.35, 0.45, 0.58 and 0.74 for A-D. Annual rates of lung function decline were: 47, 38 and 26 ml for stages 2–4 and 44, 48, 38 and 39 for stages A-D. With regards to model fit, the new system performed worse at predicting mortality and lung function decline, and better at predicting exacerbations. Distinguishing between the sub-stages of high-risk led to substantial improvements.ConclusionsThe new classification system is a modest step towards a phenotype approach. It is probably an improvement for the prediction of exacerbations, but a deterioration for predicting mortality and lung function decline.Trial registrationClinicalTrials.gov NCT00144339 (September 2, 2005).Electronic supplementary materialThe online version of this article (doi:10.1186/1471-2466-14-163) contains supplementary material, which is available to authorized users.

BackgroundTiotropium is an anticholinergic bronchodilator for symptom relief and reducing exacerbations with an established safety profile in patients with chronic obstructive pulmonary disease (COPD). Using data from the 4-year Understanding Potential Long-term Impacts on Function with Tiotropium (UPLIFT®) study, we re-evaluated the safety of tiotropium HandiHaler® in patients who experienced recent myocardial infarction (MI), heart failure or unstable rhythm disorder during the study.MethodsA post-hoc analysis of all-cause mortality and serious cardiac adverse events (cardiac SAEs), including cardiac deaths and death unknown, was conducted in patients who had experienced cardiac arrhythmia, MI or cardiac failure during UPLIFT® and who completed the study. Descriptive analyses were performed.ResultsMost patients experiencing cardiac events, for which they would have been excluded at baseline, remained in the trial. Kaplan-Meier analyses revealed a trend to later occurrence of cardiac SAEs with tiotropium HandiHaler® versus placebo. Patients who experienced a cardiac event and continued in UPLIFT® were not found to be at subsequently increased risk of all-cause mortality or cardiac SAEs with tiotropium treatment. Evaluation of deaths by major adverse cardiac events composite endpoints also showed that patients treated with tiotropium were not at increased risk of mortality or cardiac SAEs compared with placebo.ConclusionsRisk of cardiac events, mortality or SAEs was not increased by tiotropium in patients experiencing cardiac events for which they would have been excluded at study baseline. The findings support the cardiac safety of tiotropium HandiHaler® in patients with COPD.Electronic supplementary materialThe online version of this article (doi:10.1186/s12931-015-0216-4) contains supplementary material, which is available to authorized users.

Background: COPD exacerbations are responsible for the morbidity and mortality of this disease. The relationship between exacerbations and patient-related clinical outcomes is not clearly understood. Methods: A retrospective analysis of two 1-year, placebo-controlled clinical trials with tiotropium 18 µg daily was conducted to examine relationships between exacerbations and other clinical outcomes. The relationship between FEV 1 , St. George's Respiratory Questionnaire (SGRQ), and the transition dyspnea index (TDI) were examined based on the frequency of exacerbations (0, 1, 2, 2). Results: 921 patients participated in the trials (mean age 65 years, mean FEV 1 = 1.02 L (39% predicted). The percent change from baseline in FEV 1 in the tiotropium group was +12.6%, +12.0%, +2.1% and +8.9%; and in the placebo group was-3.4%,-3.4%,-5.7% and-6.7% for exacerbation frequencies of 0, 1, 2, 2, respectively. Compared with baseline, the largest improvement in SGRQ occurred in patients with no exacerbations. In the placebo group, there was a significant association between an increased frequency of exacerbations and worsening SGRQ scores. A reduction in exacerbation rates of 4.4% to 42.0% such as that shown in this study cohort was associated with meaningful changes in questionnaire based instruments. Conclusions: In the placebo-treated patients increased frequency of exacerbations was associated with larger decrements in FEV 1 , TDI, and SGRQ. A reduction in the frequency of exacerbations is associated with changes that are considered meaningful in these clinical outcomes.