Comorbidities of patients in tiotropium clinical trials: comparison with observational studies of patients with chronic obstructive pulmonary disease

Introduction

Randomized controlled trials (RCTs) provide the best evidence to support the efficacy and safety of therapies and form the basis for regulatory approval of treatment for all diseases, including chronic obstructive pulmonary disease (COPD). A well-designed RCT has a high degree of internal validity and allows for data-driven determination of whether a cause–effect relationship exists between a study drug and its outcome. Patient populations in RCTs are subject to stringent inclusion and exclusion criteria, and thus could be perceived as having an inherent lack of external validity.^1–4 Furthermore, because patients entering RCTs are selected, their characteristics and concomitant treatment regimens may not reflect daily clinical practice.⁵ Randomization and stringency in inclusion and exclusion criteria are nevertheless important for determining the comparative efficacy and safety of the study drug, limiting the potential for confounding and excluding patients at specific risks.

To bridge the gap between RCTs and how medications are used by clinicians in daily practice, noninterventional, or observational, studies or analyses of existing databases are conducted. Unlike RCTs, observational studies normally have less stringent inclusion and exclusion criteria and thus may provide a broader perspective on disease background, comorbid conditions, treatment patterns, and outcomes. Observational studies are also more representative of normal patterns of care.⁴ Because they are more representative of daily clinical practice, observational studies have high external validity and can be generalized,⁴ but can also be more prone to assessment bias¹ and outcomes may be confounded, in contrast to RCTs.⁶

According to published epidemiological and observational studies, some comorbid conditions with a high prevalence in patients with COPD include hypertension, ischemic heart disease, hypercholesterolemia, diabetes, arrhythmias, interstitial lung disease, lung cancer, anxiety, and depression.^7–12

Based on the ongoing scientific discussion around the external validation of RCTs,^13–15 we sought to understand how representative the patients included in RCTs are to patients in a real-life clinical setting, and how the inclusion and exclusion criteria implemented for these trials may have influenced the recruited patient population. In particular, it is important to know whether patients with comorbidities are adequately represented in clinical trials of COPD, or whether they are deselected by exclusion criteria – or simply not recruited in sufficient numbers. To achieve this goal, we surveyed a database of patients recruited into tiotropium RCTs and also conducted a systematic literature review of large-scale observational studies in order to compare the demography and baseline characteristics of the RCT population with “real-life” patient populations.

Methods

Analysis of tiotropium RCTs

Data on patient baseline characteristics were taken from a database (Boehringer Ingelheim GmbH, Ingelheim am Rhein, Germany) of 28 placebo-controlled clinical trials conducted with a tiotropium HandiHaler^® (SPIRIVA^®, Boehringer Ingelheim GmbH) and seven placebo-controlled trials using the tiotropium Respimat^® Soft Mist™ Inhaler (SPIRIVA^®, Boehringer Ingelheim GmbH). The 4-year Understanding the Potential Long-term Impacts on Function with Tiotropium (UPLIFT^®) trial (trial number 205.235) contributed the largest portion of patients to the placebo-controlled HandiHaler^® database population (Table S1).

Statistical analysis was based on descriptive characterization of the pooled trials.

Design of the RCTs in the analysis

Studies were randomized, placebo-controlled, double-blind, parallel-group trials of ≥4 weeks’ duration, assessing either tiotropium HandiHaler^® 18 μg (once daily) or tiotropium Respimat^® 5 μg (two puffs of 2.5 μg once daily) for the indication of COPD. Written informed consent was obtained from all patients and ethics committee approval was obtained for all protocols. As all trials were part of the tiotropium COPD development program, inclusion and exclusion criteria were similar across all trials. However, later trials were modified to have somewhat broader selection criteria (see inclusion and exclusion criteria). Principal patient characteristics like age, sex, anthropometrics, and ethnicity were recorded for all patients at baseline. Lung function (as measured by forced expiratory volume in 1 second [FEV₁]) and smoking history were also captured for the entire population.

Inclusion criteria of the RCTs in the analysis

The key inclusion criteria common to all tiotropium trials were: diagnosis of COPD, FEV₁/forced vital capacity ratio ≤70%, age ≥40 years, and ≥10 pack-years’ smoking history. Other inclusion criteria such as FEV₁ cutoffs and requirement for exacerbation history varied between studies.

Exclusion criteria of the RCTs in the analysis

The key exclusion criteria were: diagnosis of asthma, symptomatic prostatic hypertrophy or bladder neck obstruction, narrow-angle glaucoma, and known hypersensitivity to the study medication or components. For practical reasons, significant disease other than COPD that could significantly confound the study results or preclude study completion was also an exclusion criterion. Other exclusion criteria in earlier trial protocols were: heart failure resulting in hospitalization in the previous 3 years, cardiac arrhythmia requiring drug treatment, or myocardial infarction (MI) within the past year. Nevertheless, heart failure and ischemic heart disease were not necessarily exclusion criteria. Cardiac exclusion criteria were more liberal in more recent trials such as UPLIFT^® with HandiHaler^® and trial number 205.372 with Respimat^® (Table S1). Drug therapy for arrhythmias was permitted, provided the therapy was stable and the patient had no history of a life-threatening arrhythmia or pacemaker insertion. In addition, the criterion for recent MI was decreased to 6 months.

Use of theophylline, inhaled corticosteroids, ≤10 μg daily doses of oral corticosteroids (provided the dosing was stable), and short-acting β₂-agonists was permitted in all trials. The 4-year UPLIFT^® trial (5,992 patients),¹⁶ as well as trial numbers 205.259,¹⁷ 205.266 (1,829 patients),¹⁸ 205.270,¹⁹ 205.282,²⁰ 205.284,²¹ 205.368,²² and 205.372²³ also permitted use of long-acting β₂-agonists (LABAs) as prescribed. Nonstudy inhaled anticholinergics had to be withdrawn during the conduct of all studies.

Definitions of comorbidities

The Medical Dictionary for Regulatory Activities (MedDRA) version 14.0 was used to code relevant medical history/concomitant diagnoses (within the past 5 years) as reported by the investigator at baseline; preferred terms (PTs) were categorized under system organ classes (SOCs) within MedDRA. For conditions that are known to have a high prevalence in patients with COPD, MedDRA PTs denoting similar conditions were pooled as pharmcovigilance (PV) endpoints and Standardised MedDRA Queries (SMQs).

Systematic literature review of observational studies

To identify suitable studies, a systematic literature search of studies reporting comorbidities among patients with COPD was conducted in the following databases: (1) MEDLINE^® 1990, May 14, 2013; (2) BIOSIS Previews^® 1993–2008, May 2013; (3) EMBASE Alert, May 14, 2013; (4) EMBASE 1993, May 15, 2013; and (5) SciSearch^® 1990, May 2013.

The inclusion and exclusion criteria for the literature review are detailed in Figure 1. The inclusion criteria for the literature search did not specify how patient demography and comorbidity data were presented. It was only important that this information be reported. For this reason, the number of studies used for the individual analyses will vary.

Figure 1 Systematic literature review of observational studies. Abbreviations: COPD, chronic obstructive pulmonary disease; RCTs, randomized controlled trials.

Results

In total, 17,990 and 6,565 patients were included in the HandiHaler^® and Respimat^® trials, respectively. For the systematic literature search, using the search parameters detailed in the “Methods” section, 806 study publications were returned. Following a secondary screen to exclude all studies reporting RCTs, hospitalized patient populations, age-restricted populations, or reported study populations of fewer than 900 patients, 793 studies were excluded and 13 epidemiological and observational studies^12,24–38 (n=61,361 patients) were included for comparison with the anthropometrics of patients with COPD recruited in tiotropium RCTs (Table S2).

Baseline demographics and clinical characteristics

The baseline demographics (Table 1) of the placebo and tiotropium groups were balanced between patient populations in the pooled HandiHaler^® and Respimat^® trials, with 34.1%–37.6% of patients enrolled in the tiotropium RCTs identified as current smokers, compared with 36.2%–43.0% in the observational studies. Patients enrolled in the tiotropium RCTs had a mean baseline post-bronchodilator FEV₁ of 1.18±0.47 L standard deviation (SD) and 1.11±0.41 L SD, for HandiHaler^® and Respimat^® trials, respectively, that were 41.5% and 40.2% of postbronchodilator FEV₁ predicted, for HandiHaler^® and Respimat^® trials, respectively. In the observational studies, the mean baseline post-bronchodilator FEV₁ ranged from 47.0%–56.7% of predicted. The distribution of patients with COPD enrolled in the tiotropium RCTs by Global Initiative for Chronic Obstructive Lung Disease (GOLD) stage was 51.5% and 40.0% (GOLD stages I–II), 39.8% and 45.8% (GOLD stage III), and 7.2% and 13.6% (GOLD stage IV) for HandiHaler^® and Respimat^® trials, respectively. In the comparison observational studies, there were more patients enrolled with mild to moderate disease (GOLD stage I+II; 24.5%–44.1%), compared with GOLD disease stages III or IV (13.7%–42.1%; Table 2).

Table 1 Baseline characteristics of patients in the 28 pooled tiotropium HandiHaler® and seven pooled tiotropium Respimat® trials Notes: aGOLD stage I, ≥80% predicted; stage II, <80% to ≥50% predicted; stage III, <50% to ≥30% predicted; stage IV, <30% predicted. Only eight HandiHaler® trials where post-bronchodilator values have been collected contribute to the denominator of the percentages. Abbreviations: FEV1, forced expiratory volume in 1 second; FVC, forced vital capacity; GOLD, Global initiative for chronic Obstructive Lung Disease; L, liters; SD, standard deviation.

Table 2 Baseline demographics and clinical characteristics of patients with COPD in the pooled tiotropium HandiHaler®, pooled tiotropium Respimat® trials, and comparison observational studies Notes: a95% confidence intervals presented; bGOLD stage I, ≥80% predicted; stage II, <80% to ≥50% predicted; stage III, <50% to ≥30% predicted; stage IV, <30% predicted; cFEV1/FVC ratio <0.7 was an inclusion criterion. *n=9,814 for the pooled tiotropium HandiHaler® RCTs. †The number of patients in GOLD stages I–IV only makes up 27.1% of patients that either had lung function of FEV1/FVC <0.70 and FEV1≥80% predicted; presence of respiratory symptoms in the absence of any lung function abnormality; or FEV1/FVC ≥0.70 and FVC <80% predicted. Abbreviations: FEV1, forced expiratory volume in 1 second; FVC, forced vital capacity; GOLD, Global initiative for chronic Obstructive Lung Disease; SD, standard deviation; COPD, chronic obstructive pulmonary disease.

Although all of the observational studies reported baseline comorbidities in the patient population, they differed in how this was reported. In some instances, these were reported either by SOC or PT. The observational studies also differed in the level of additional information reported, relating to patient baseline characteristics and baseline concomitant medications. For this reason, the numbers of studies included in the comparisons of these parameters differ in Tables 2–4.

Baseline comorbidities

The majority of patients in the HandiHaler^® and Respimat^® trials were diagnosed with comorbidities at baseline (79.4% and 74.2%, respectively), with vascular and cardiac disorders being the most frequent (39.3% and 24.6% in the HandiHaler^® trials, respectively, and 40.1% and 24.3% in the Respimat^® trials, respectively) (Table 3). The incidence of comorbidities was similar between the placebo and tiotropium treatment groups in both sets of trials. In four observational studies that enrolled a total of 17,048 patients with COPD, associated comorbidities grouped by SOC included cardiac (9.4%–32.3%), vascular (11.4%–45.0%), metabolic and nutritional (9.9%–22.2%), and psychiatric (11.9%) disorders (Table 3).

Table 3 Prevalence of comorbidities of interest by Medical Dictionary for Regulatory Activities (MedDRA) system organ class at baseline in patients with COPD Notes: aA total of 1,627 patients eligible for this analysis; b1,924 eligible patients for this analysis. Concomitant diagnoses of comorbidities were not collected in HandiHaler® trial number 205.257; comorbidities of interest include those most frequently reported in COPD trials. MedDRA v 14.0 was used for analysis of the 28 SPIRIVA® HandiHaler® trials and the seven Respimat® trials. Abbreviation: COPD, chronic obstructive pulmonary disease.

For comorbidities that are known to have a high prevalence in patients with COPD (hypertension, ischemic heart disease, dyslipidemia, diabetes, anxiety, and depression), SMQs or PV endpoints were used for the RCTs and applicable PTs were grouped to combine endpoints for observational studies in order to evaluate their prevalence in study populations at baseline (Table 4 and Table S3). Hypertension was diagnosed in 39.4% of patients in the HandiHaler® and 40.0% of patients in the Respimat^® trials. Diagnoses of ischemic heart disease (14.2% and 12.3%) cardiac arrhythmias (7.8% vs 11.4%), depression (9.5% vs 8.5%), and diabetes (10.3% vs 10.9%) were similar in the pooled HandiHaler^® and Respimat^® trials, respectively (Table 4).

Table 4 Prevalence of comorbidities of interest by pharmacovigilance (PV) endpoint/Standardized MedDRA Query (SMQ) at baseline in subjects with COPD Notes: †Data are SMQs. MedDRA v 14.0 was used for analysis of the 28 SPIRIVA® HandiHaler® trials and the seven Respimat® trials; however concomitant diagnoses of comorbidities were not collected in HandiHaler® trial number 205.257. Comorbidities of interest include those most frequently reported in COPD trials. Abbreviations: MedDRA, Medical Dictionary for Regulatory Activities; MI, myocardial infarction; COPD, chronic obstructive pulmonary disease.

When reported by applicable PTs, the comorbidities with the highest prevalence in epidemiological and observational studies were hypertension (40.1%–60.6%), cardiac arrhythmia (11.3%–15.8%), depressed mood (17.0%–20.6%), cardiac failure (7.0%–49.0%), and ischemic heart disease (12.5%–41.0%, Table 4). In UPLIFT^®, increases in comorbid conditions from baseline to year 4 were observed (Table S4).

Discussion

We have analyzed the demographic data of patients in randomized, placebo-controlled clinical studies with tiotropium HandiHaler^® and Respimat^® of at least 4 weeks’ duration and compared these with data from epidemiological and observational studies. The background for this comparison was that, recently, several authors questioned the validity of RCTs for the evaluation of the safety of drugs in the treatment of COPD in clinical practice.^13,14 The pivotal argument for these concerns was that the inclusion and exclusion criteria of RCTs prevent patients at greater risk (notably of cardiovascular [CV] risk) from participating in these studies. This could then potentially lead to a more positive safety evaluation of the drugs in question compared with clinical practice in a real-life setting.

This study of the characteristics of the 24,555 patients included in the randomized trials of tiotropium showed that the clinical profile, including age, sex, smoking history, and anthropometrics of these patients, is similar to that observed in large epidemiological and observational studies of patients with COPD. However, the proportions of patients with mild to moderate disease (GOLD stages I+II) ranged from 24.5% to 44.1% in the observational studies but from 40.0% to 51.5% in the tiotropium trials, while patients with severe disease (GOLD stage III or IV) were represented in similar numbers in the tiotropium RCTs (7.2%–45.8%) as in the observational studies (13.7%–42.1%).

Comorbidities

The most prevalent comorbidities reported by SOC observed in the COPD patient population at baseline in the pooled tiotropium trials were: cardiac, vascular, respiratory, gastrointestinal, psychiatric, and metabolic disorders. These were represented in the observational studies in similar proportions (Table 3). In particular, the prevalence of cardiac disorders in the 22,916 evaluable patients in the tiotropium RCT population was 24.3%–24.6%. Of the 17,048 patients with COPD in the epidemiologic/observational studies,^21,25,26,30 the prevalence of cardiac disorders was in the range of 9.4%–32.3%. In a recent letter to the editor,³⁹ the authors conducted an audit of patients discharged from hospital in New Zealand after an exacerbation of COPD and found that 38% patients prescribed tiotropium had comorbidities that would have made them ineligible for participation in UPLIFT^®. Based on this observation, the authors concluded that the findings from UPLIFT^® had limited generalizability to clinical practice in New Zealand. However, this New Zealand patient population is a very severe population of patients that required hospital admission, whereas patients included in UPLIFT^®, as in all major clinical trials of COPD, consisted of ambulatory patients. The pattern of comorbidities of very severe admitted patients may differ, but this New Zealand patient population represents a minority of patients with COPD of special severity with increased risks of side effects secondary to all drugs and that require a personalized approach with careful evaluation of the expected benefits and risks of any given treatment.

Although it was excluded from our systematic literature review because it is a pooled analysis of epidemiological studies, validation of the current analysis is provided by a study conducted by Patel and Hurst.⁴⁰ Using data from two large, population-based epidemiological studies (the Atherosclerosis Risk in Communities [ARIC] Study and the Cardiovascular Health Study [CHS], 20,296 adults aged >44 years),⁴⁰ they reported that the prevalence of CV disease (defined as a composite of ischemic heart disease, heart failure, stroke, and/or transient ischemic attack) in patients with COPD was 20.0%–22.0%. This is similar to the 24.6% and 24.3% prevalence of cardiac disorders that we determined in the tiotropium trials. This contradicts the concerns that the inclusion and exclusion criteria of tiotropium RCTs prevent patients at greater risk (notably of CV risk) from participating in these studies.

Comorbidities of interest were selected on the basis of being the most frequently reported in COPD trials and also to maximize the degree of comparisons with the observational studies identified in our systematic literature review. For eight selected comorbidities of interest (Table 4), our analysis revealed that hypertension had the highest prevalence in patients enrolled in tiotropium RCTs (39.4%–40.0%). This was lower than the range (51.4%–60.6%) reported in four out of nine observational studies^{26,28,32,35,36} (total: 6,884 patients) used in our comparison. However, in a population-based National Institutes of Health cohort of 20,296 patients with COPD aged ≥45 years, the prevalence of hypertension was 40.1%,³² similar to that reported for patients in tiotropium RCTs.

Although not included in our current analysis because it is not among the most frequently reported comorbidities among patients with COPD, two reports, by Verhamme et al⁴¹ and Mathioudakis et al,⁴² have suggested an association between mortality and renal impairment in patients with COPD treated with tiotropium via HandiHaler^® or Respimat^®. A pooled safety analysis of tiotropium delivered via the HandiHaler^® or the Respimat^® Soft Mist™ Inhaler that encompasses 22 Phase III and IV tiotropium clinical trials and evaluated 10,805 patients showed that that there was no trend for increased incidence rate ratios of adverse events with worsening renal function for either tiotropium HandiHaler^® or Respimat^®. (Table S5).⁴³

Limitations of the study

A major limitation of this study is the difference in the reporting of baseline characteristics and comorbidities in the observational studies identified in our systematic literature review. Only six of the observational studies reported the GOLD staging of patients. Although included in this comparison, Mannino et al’s study³² reports GOLD staging for only 27.1% of the patients enrolled, which complicates interpretation of these results. Furthermore, four studies reported baseline comorbidities by SOC, and none of these allowed for a full comparison with the tiotropium RCTs. This means that for comorbidities such as respiratory, thoracic and mediastinal disorders, gastrointestinal disorders, psychiatric disorders, and neoplasms, the patient population against which the tiotropium RCT population is compared is limited (only 2,846 from two of the four observational studies as compared with 22,916 in the tiotropium RCTs combined). This variability complicates interpretation of these results due to the limited sample size. Although this situation is repeated for comparison of baseline comorbidities in Table 4, it is mitigated to some extent by the inclusion of 51,050 patients from nine out of 13 observational studies for comparison to the 22,916 patients identified in the included tiotropium RCTs.

Another limitation of this study is that it does not take into account the various factors that add to the complexity of studying comorbidities in patients with COPD. These include: smoking status, which has been shown to be a risk factor for diabetes mellitus and dyslipidemia; age; polypharmacy; lack of treatment of comorbidities; and lack of specific case definitions for comorbidities.⁷ However, with regard to smoking status, the percentage of current smokers enrolled in the tiotropium RCTs is similar to the percentage identified as current smokers in the observational studies included in our analysis.

Lastly, patients with recent unstable cardiac diseases (MI within 6 months and new unstable arrhythmia or severe heart failure within 1 year) were excluded from the tiotropium RCTs. Therefore, the findings in the tiotropium studies cannot be extended to these patients.

Conclusion

The clinical profile (defined by SOC) of patients with COPD treated in the tiotropium trial program appears to be largely in the range of clinical characteristics, including CV comorbidities reported for “real-life patients.” Overall, patients in the tiotropium studies were comparable to those patients enrolled in the observational studies with regard to the severity of disease (GOLD stages III and IV).

Acknowledgments

The authors are fully responsible for all content and editorial decisions made, were involved at all stages of manuscript development, and have approved the final version for publication. Editorial assistance, supported financially by Boehringer Ingelheim and Pfizer, was provided by Godfrey Lisk of PAREXEL International during the preparation of this manuscript.

Disclosure

Marc Miravitlles has received speaker fees from Almirall, Boehringer Ingelheim, Pfizer, AstraZeneca, Chiesi, Esteve, GlaxoSmithKline, Menarini, Novartis, Talecris-Grifols, Takeda-Nycomed, and Novartis, and consulting fees from Almirall, Boehringer Ingelheim, Pfizer, GlaxoSmithKline, Gebro Pharma, MediImmune, Novartis, Talecris-Grifols, and Takeda-Nycomed.

David Price is a board member of Almirall, AstraZeneca, Boehringer Ingelheim, Chiesi, GlaxoSmithKline, Merck, Mundipharma, Medapharma, Novartis, Napp, Nycomed, Pfizer, Sandoz, and Teva. He or his research team has received grants and support for research in respiratory disease from the following organizations in the last 5 years: UK National Health Service, Aerocrine, AstraZeneca, Boehringer Ingelheim, Chiesi, GlaxoSmithKline, Merck, Mundipharma, Novartis, Nycomed, Orion, Pfizer, and Teva. In addition, he has consulted for Almirall, AstraZeneca, Boehringer Ingelheim, Chiesi, GlaxoSmithKline, Merck, Mundipharma, Medapharma, Novartis, Napp, Nycomed, Pfizer, Sandoz, and Teva; has received or has grants pending from the UK National Health Service, Aerocrine, AstraZeneca, Boehringer Ingelheim, Chiesi, GlaxoSmithKline, Merck, Mundipharma, Novartis, Nycomed, Orion, Pfizer, Takeda, and Teva; has received payments for lectures/speaking from Almirall, AstraZeneca, Activaero, Boehringer Ingelheim, Chiesi, Cipla, GlaxoSmithKline, Kyorin, Novartis, Merck, Mundipharma, Pfizer, Takeda, and Teva; received payment for manuscript preparation from Merck, Mundipharma, and Teva; has had patents planned, pending or issued from AKL Ltd; received payment for the development of educational materials from GlaxoSmithKline; has shares in AKL Ltd, which produces phytopharmaceuticals and owns 80% of Research in Real Life Ltd and its subsidiary social enterprise, Optimum Patient Care; and has received payment for travel/accommodations/meeting expenses from Aerocrine, Boehringer Ingelheim, Napp, Novartis, Mundipharma, and Teva.

Klaus Rabe has provided legal consultation services or expert witness testimony to AstraZeneca, Boehringer Ingelheim, Chiesi Pharmaceutical, Novartis, MSD and GlaxoSmithKline. He has also received research funding from Altana Pharma, Novartis, AstraZeneca, MSD and Nycomed/Takeda. Ha has served on FDA and EMA panels for registration of drugs for COPD. Bartolome Celli has received grants from Boehringer Ingelheim, Almirall, GlaxoSmithKline, Novartis, Forrest, Aeris, and AstraZeneca. He has also received consultancy fees from GlaxoSmithKline, Boehringer Ingelheim, Dey, Altana, AstraZeneca, Almirall, Sepracor, Pfizer, Novartis, Rox, and Medimmune.

Norbert Metzdorf and Hendrik Schmidt are full-time employees of Boehringer Ingelheim Pharma GmbH & Co KG.

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Supplementary materials

Table S1 Clinical trials included in the pooled tiotropium HandiHaler® and Respimat® analysis Note: Trial numbers refer to the Boehringer Ingelheim trials database. Abbreviations: ECLIPSE, Evaluation of COPD Longitudinally to Identify Predictive Surrogate Endpoints; EXACTT, Exercise Endurance and COPD Treated With Tiotropium; MISTRAL, Mesure de l’Influence de SPIRIVA® sur les Troubles Respiratoires Aigus à Long terme [measuring the influence SPIRIVA® on acute respiratory disorders for the long term]; SAFE, SPIRIVA® Assessment of FEV1; SPRUCE, SPIRIVA® Usual CarE; TIPHON, Tiotropium: Influence sur la Perception de l’amelioration des activités Habituelles Objectivée par une echelle Numerique; UPLIFT®, Understanding the Potential Long-term Impacts on Function with Tiotropium; COPD, chronic obstructive pulmonary disease.

Table S2 Observational studies meeting the inclusion criteria for the systematic literature review Abbreviations: BODE, Body mass index, airflow Obstruction, Dyspnea and Exercise capacity; COPD, chronic obstructive pulmonary disease; ECLIPSE, Evaluation of COPD Longitudinally to Identify Predictive Surrogate Endpoints; GPRD, General Practice Research Database; MI, myocardial infarction; NHANES, National Health and Nutrition Examination Survey.

Table S3 Reference listing – definition of pharmacovigilance endpoints Note: MedDRA v 14.0 used for reporting. Abbreviations: MedDRA, Medical Dictionary for Regulatory Activities; PT, preferred term; PV, pharmacovigilance; SMQ, Standardised MedDRA Query.

Table S4 Distribution of patient comorbidities by pharmacovigilance endpoint/Standardised MedDRA Query (SMQ) in the UPLIFT® trial Note: MedDRA version 13.1 used for reporting. Abbreviations: MedDRA, Medical Dictionary for Regulatory Activities; PT, preferred term; UPLIFT®, Understanding Potential Long-term Impacts on Function with Tiotropium; PV, pharmacovigilance.

Table S5 Incidence rate ratios (IRRs) (95% confidence interval) of on-treatment adverse events (AEs) categorized by renal function at baseline (NICE cutoff) Notes: Renal function classification: normal ≥90 mL/min, mild ≥60 to <90 mL/min, moderate ≥30 to <60 mL/min, severe <30 mL/min creatinine. The IRR could not be calculated for severe renal impairment due to low patient numbers. #The same patients may fulfill criteria for inclusion in different AE categories. Hence, numbers are not additive. *If there are no events in the placebo or tiotropium group, IRRs cannot be calculated (division by zero) or are equal to zero, respectively; the incident rates for tiotropium/placebo are presented instead. Abbreviations: FAE, fatal adverse event; MACE, major adverse cardiovascular event; NICE, National Institute for Health and Care Excellence; SAE, serious adverse event; SOC, system organ class.

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