Peripheral Artery Disease and Its Clinical Relevance in Patients with Chronic Obstructive Pulmonary Disease in the COPD and Systemic Consequences-Comorbidities Network Study.

RATIONALE: Knowledge about the prevalence of objectively assessed peripheral artery disease (PAD) and its clinical relevance in patients with chronic obstructive pulmonary disease (COPD) is scarce. OBJECTIVES: We aimed to: (1) assess the prevalence of PAD in COPD compared with distinct control groups; and (2) study the association between PAD and functional capacity as well as health status. METHODS: The ankle-brachial index was used to diagnose PAD (ankle-brachial index ≤ 0.9). The 6-minute-walk distance, health status (St. George's Respiratory Questionnaire), COPD Assessment Test, and EuroQol-5-Dimensions were assessed in patients enrolled in the German COPD and Systemic Consequences-Comorbidities Network cohort study. Control groups were derived from the Study of Health in Pomerania. MEASUREMENTS AND MAIN RESULTS: A total of 2,088 patients with COPD (61.1% male; mean [SD] age, 65.3 [8.2] years, GOLD (Global Initiative for Chronic Obstructive Lung Disease) stages I-IV: 9.4, 42.5, 37.5, and 10.5%, respectively) were included, of which 184 patients (8.8%; GOLD stage I-IV: 5.1, 7.4, 11.1, and 9.5%, respectively, vs. 5.9% in patients with GOLD stage 0 in the COPD and Systemic Consequences-Comorbidities Network) had PAD. In the Study of Health in Pomerania, PAD ranged from 1.8 to 4.2%. Patients with COPD with PAD had a significantly shorter 6-minute-walk distance (356 [108] vs. 422 [103] m, P < 0.001) and worse health status (St. George's Respiratory Questionnaire: 49.7 [20.1] vs. 42.7 [20.0] points, P < 0.001; COPD Assessment Test: 19.6 [7.4] vs. 17.9 [7.4] points, P = 0.004; EuroQol-5-Dimensions visual analog scale: 51.2 [19.0] vs. 57.2 [19.6], P < 0.001). Differences remained significant after correction for several confounders. CONCLUSIONS: In a large cohort of patients with COPD, 8.8% were diagnosed with PAD, which is higher than the prevalence in control subjects without COPD. PAD was associated with a clinically relevant reduction in functional capacity and health status.

Costs and health-related quality of life in Alpha-1-Antitrypsin Deficient COPD patients.

BACKGROUND: Alpha-1-Antitrypsin Deficiency (AATD) is an economically unexplored genetic disease. METHODS: Direct and indirect costs (based on self-reported information on healthcare utilization) and health-related quality of life (HRQL, as assessed by SGRQ, CAT, and EQ-5D-3 L) were compared between 131 AATD patients (106 with, 25 without augmentation therapy (AT)) and 2,049 COPD patients without AATD participating in the COSYCONET COPD cohort. The medication costs of AT were excluded from all analyses to reveal differences associated with morbidity profiles. The association of AATD (with/without AT) with costs or HRQL was examined using generalized linear regression modelling (GLM) adjusting for age, sex, GOLD grade, BMI, smoking status, education and comorbidities. RESULTS: Adjusted mean direct annual costs were €6,099 in AATD patients without AT, €7,117 in AATD patients with AT (excluding costs for AT), and €7,460 in COPD patients without AATD. AATD with AT was significantly associated with higher outpatient (+273%) but lower inpatient (-35%) and medication costs (-10%, disregarding AT) compared with COPD patients without AATD. There were no significant differences between groups regarding indirect costs and HRQL. CONCLUSION: Apart from AT costs, AATD patients tended to have lower, though not significant, overall costs and similar HRQL compared to COPD patients without AATD. AT was not associated with lower costs or higher HRQL. TRIAL REGISTRATION: NCT01245933.

Relative impact of COPD and comorbidities on generic health-related quality of life: a pooled analysis of the COSYCONET patient cohort and control subjects from the KORA and SHIP studies.

BACKGROUND: Health-related quality of life (HRQL) is an important patient-reported outcome measure used to describe the burden of chronic obstructive pulmonary disease (COPD) which is often accompanied by comorbid conditions. METHODS: Data from 2275 participants in the COPD cohort COSYCONET and from 4505 lung-healthy control subjects from the population-based KORA and SHIP studies were pooled. Main outcomes were the five dimensions of the generic EQ-5D-3 L questionnaire and two EQ-5D index scores using a tariff based on valuations from the general population and an experience-based tariff. The association of COPD in GOLD grades 1-4 and of several comorbid conditions with the EQ-5D index scores was quantified by multiple linear regression models while adjusting for age, sex, education, body mass index (BMI), and smoking status. RESULTS: For all dimensions of the EQ-5D, the proportion of participants reporting problems was higher in the COPD group than in control subjects. COPD was associated with significant reductions in the EQ-5D index scores (-0.05 points for COPD grades 1/2, -0.09 for COPD grade 3, -0.18 for COPD grade 4 according to the preference-based utility tariff, all p < 0.0001). Adjusted mean index scores were 0.89 in control subjects and 0.85, 0.84, 0.81, and 0.72 in COPD grades 1-4 according to the preference-based utility tariff and 0.76, 0.71, 0.68, 0.64, and 0.58 for control subjects and COPD grades 1-4 for the experience-based tariff respectively. Comorbidities had additive negative effects on the index scores; the effect sizes for comorbidities were comparable to or smaller than the effects of COPD grade 3. No statistically significant interactions between COPD and comorbidities were observed. Score differences between COPD patients and control subjects were most pronounced in younger age groups. CONCLUSIONS: Compared with control subjects, the considerable reduction of HRQL in patients with COPD was mainly due to respiratory limitations, but observed comorbidities added linearly to this effect. Younger COPD patients showed a greater loss of HRQL and may therefore be in specific need of comprehensive disease management. TRIAL REGISTRATION: NCT01245933.

Patient Heterogeneity in Health Economic Decision Models for Chronic Obstructive Pulmonary Disease: Are Current Models Suitable to Evaluate Personalized Medicine?

OBJECTIVES: To assess how suitable current chronic obstructive pulmonary disease (COPD) cost-effectiveness models are to evaluate personalized treatment options for COPD by exploring the type of heterogeneity included in current models and by validating outcomes for subgroups of patients. METHODS: A consortium of COPD modeling groups completed three tasks. First, they reported all patient characteristics included in the model and provided the level of detail in which the input parameters were specified. Second, groups simulated disease progression, mortality, quality-adjusted life-years (QALYs), and costs for hypothetical subgroups of patients that differed in terms of sex, age, smoking status, and lung function (forced expiratory volume in 1 second [FEV1] % predicted). Finally, model outcomes for exacerbations and mortality for subgroups of patients were validated against published subgroup results of two large COPD trials. RESULTS: Nine COPD modeling groups participated. Most models included sex (seven), age (nine), smoking status (six), and FEV1% predicted (nine), mainly to specify disease progression and mortality. Trial results showed higher exacerbation rates for women (found in one model), higher mortality rates for men (two models), lower mortality for younger patients (four models), and higher exacerbation and mortality rates in patients with severe COPD (four models). CONCLUSIONS: Most currently available COPD cost-effectiveness models are able to evaluate the cost-effectiveness of personalized treatment on the basis of sex, age, smoking, and FEV1% predicted. Treatment in COPD is, however, more likely to be personalized on the basis of clinical parameters. Two models include several clinical patient characteristics and are therefore most suitable to evaluate personalized treatment, although some important clinical parameters are still missing.

Assessing health-related quality of life in COPD: comparing generic and disease-specific instruments with focus on comorbidities.

BACKGROUND: Chronic Obstructive Pulmonary Disease (COPD) influences different aspects of patient's health-related quality of life (HRQL). While disease-specific HRQL instruments focus on symptoms and functional impairments, generic instruments cover a broader view on health. This study compares the generic EQ-5D-3 L and two disease-specific questionnaires (St.-George's Respiratory Questionnaire (SGRQ-C), COPD Assessment Test (CAT)) in a comprehensive spectrum of COPD disease grades with particular attention on comorbidities and assesses the discriminative abilities of these instruments. METHODS: Using data from the baseline visit of the German COPD cohort COSYCONET, mean HRQL scores in different COPD grades were compared by linear regression models adjusting for age, sex, education, smoking status, BMI, and low vs. high number of comorbidities or a list of several self-reported comorbid conditions. Discriminative abilities of HRQL instruments to differentiate between COPD grades were assessed by standardized mean differences. RESULTS: In 2,291 subjects in COPD GOLD grades 1-4 EQ-5D-3 L utility, EQ-5D VAS, SGRQ, and CAT were found able to discriminate between COPD grades, with some limitations for the EQ-5D utility in mild disease. Both generic and disease-specific HRQL instruments reflected the burden of comorbid conditions. The SGRQ showed the best discrimination between COPD grades and was less influenced by comorbidities, while EQ-5D utility put a higher weight on comorbid conditions. For all instruments, psychiatric disorders and peripheral artery disease showed the strongest negative associations with HRQL. CONCLUSION: All HRQL instruments considered reflect considerable impairment of HRQL in COPD patients, worsening with increasing COPD grade and number of comorbidities. Findings may support clinical assessment, choice of HRQL instrument in future studies, and parameterization of decision-analytic models.

Health-related quality of life and chronic obstructive pulmonary disease in early stages - longitudinal results from the population-based KORA cohort in a working age population.

BACKGROUND: It is widely recognized that health-related quality of life (HRQL) is impaired in patients with Chronic Obstructive Pulmonary Disease (COPD), but there is a lack of research on longitudinal associations of COPD and HRQL. This study examined the effects of COPD in early stages of disease on HRQL over ten years in a working-age general population setting in Southern Germany while considering the influence of common comorbidities. METHODS: In the population-based KORA F4 study (2006-08) 1,321 participants aged 41-61 years performed spirometry and reported information on HRQL (measured by the generic SF-12) and comorbidities. For the same participants, HRQL information was available seven years before and three years after the lung function test from the previous S4 (1999-2001) and the F4L follow-up study (2010). Using linear mixed models, the physical and mental component summary scores (PCS-12 / MCS-12) of the SF-12 were compared over time between COPD groups. RESULTS: 7.8% of participants were classified as having COPD (according to the LLN definition and the Global Lungs Initiative), 59.4% of them in grade 1. Regression models showed a negative cross-sectional association of COPD grade 2+ with PCS-12 which persisted when comorbidities were considered. Adjusted mean PCS-12 scores for the COPD grade 2+ group were reduced (-3.5 (p=0.008) in F4, -3.3 (p=0.014) in S4 and -4.7 (p=0.003) in F4L) compared to the group without airflow limitation. The size of the COPD effect in grade 2+ was similar to the effect of myocardial infarction and cancer. Over ten years, a small decline in PCS-12 was observed in all groups. This decline was larger in participants with COPD grade 2+, but insignificant. Regarding MCS-12, no significant cross-sectional or longitudinal associations with COPD were found. CONCLUSION: Despite small HRQL differences between COPD patients in early disease stages and controls and small changes over ten years, our results indicate that it is important to prevent subjects with airflow limitation from progression to higher grades. Awareness of HRQL impairments in early stages is important for offering early interventions in order to maintain high HRQL in COPD patients.

Are health risk attitude and general risk attitude associated with healthcare utilization, costs and working ability? Results from the German KORA FF4 cohort study.

BACKGROUND: Risk attitudes influence decisions made under uncertainty. This paper investigates the association of risk attitudes with the utilization of preventive and general healthcare services, work absence and resulting costs to explore their contribution to the heterogeneity in utilization. METHODS: Data of 1823 individuals (56.5 ± 9.5 years), participating in the German KORA FF4 population-based cohort study (2013/2014) were analyzed. Individuals' general and health risk attitude were measured as willingness to take risk (WTTR) on 11-point scales. Utilization of preventive and medical services and work absence was assessed and annual costs were calculated from a societal perspective. Generalized linear models with log-link function (logistic, negative-binomial and gamma regression) adjusted for age, sex, and height were used to analyze the association of WTTR with the utilizations and costs. RESULTS: Higher WTTR was significantly associated with lower healthcare utilization (physician visits, physical therapy, and medication intake), work absence days and indirect costs. Regarding preventive services, an overall negative correlation between WTTR and utilization was examined but this observation remained non-significant except for the outcome medical check-up. Here, higher WTTR was significantly associated with a lower probability of participation. For all associations mentioned, Odds Ratios ranged between 0.90 and 0.79, with p < 0.05. Comparing the two risk attitudes (general and regarding health) we obtained similar results regarding the directions of associations. CONCLUSIONS: We conclude that variations in risk attitudes contribute to the heterogeneity of healthcare utilization. Thus, knowledge of their associations with utilization might help to better understand individual decision-making - especially in case of participation in preventive services.

Determinants of healthcare utilization and costs in COPD patients: first longitudinal results from the German COPD cohort COSYCONET.

Background: In light of overall increasing healthcare expenditures, it is mandatory to study determinants of future costs in chronic diseases. This study reports the first longitudinal results on healthcare utilization and associated costs from the German chronic obstructive pulmonary disease (COPD) cohort COSYCONET. Material and methods: Based on self-reported data of 1904 patients with COPD who attended the baseline and 18-month follow-up visits, direct costs were calculated for the 12 months preceding both examinations. Direct costs at follow-up were regressed on baseline disease severity and other co-variables to identify determinants of future costs. Change score models were developed to identify predictors of cost increases over 18 months. As possible predictors, models included GOLD grade, age, sex, education, smoking status, body mass index, comorbidity, years since COPD diagnosis, presence of symptoms, and exacerbation history. Results: Inflation-adjusted mean annual direct costs increased by 5% (n.s., €6,739 to €7,091) between the two visits. Annual future costs were significantly higher in baseline GOLD grades 2, 3, and 4 (factors 1.24, 95%-confidence interval [1.07-1.43], 1.27 [1.09-1.48], 1.57 [1.27-1.93]). A history of moderate or severe exacerbations within 12 months, a comorbidity count >3, and the presence of dyspnea and underweight were significant predictors of cost increase (estimates ranging between + €887 and + €3,679, all p<0.05). Conclusions: Higher GOLD grade, comorbidity burden, dyspnea and moderate or severe exacerbations were determinants of elevated future costs and cost increases in COPD. In addition we identified underweight as independent risk factor for an increase in direct healthcare costs over time.

The contribution of symptoms and comorbidities to the economic impact of COPD: an analysis of the German COSYCONET cohort.

Background: Although patients with COPD often have various comorbidities and symptoms, limited data are available on the contribution of these aspects to health care costs. This study analyzes the association of frequent comorbidities and common symptoms with the annual direct and indirect costs of patients with COPD. Methods: Self-reported information on 33 potential comorbidities and symptoms (dyspnea, cough, and sputum) of 2,139 participants from the baseline examination of the German COPD cohort COSYCONET was used. Direct and indirect costs were calculated based on self-reported health care utilization, work absence, and retirement. The association of comorbidities, symptoms, and COPD stage with annual direct/indirect costs was assessed by generalized linear regression models. Additional models analyzed possible interactions between COPD stage, the number of comorbidities, and dyspnea. Results: Unadjusted mean annual direct costs were €7,263 per patient. Other than COPD stage, a high level of dyspnea showed the strongest driving effect on direct costs (+33%). Among the comorbidities, osteoporosis (+38%), psychiatric disorders (+36%), heart disease (+25%), cancer (+24%), and sleep apnea (+21%) were associated with the largest increase in direct costs (p<0.01). A sub-additive interaction between advanced COPD stage and a high number of comorbidities reduced the independent cost-driving effects of these factors. For indirect costs, besides dyspnea (+34%), only psychiatric disorders (+32%) and age (+62% per 10 years) were identified as significant drivers of costs (p<0.04). In the subsequent interaction analysis, a high number of comorbidities was found to be a more crucial factor for increased indirect costs than single comorbidities. Conclusion: Detailed knowledge about comorbidities in COPD is useful not only for clinical purposes but also to identify relevant cost factors and their interactions and to establish a ranking of major cost drivers. This could help in focusing therapeutic efforts on both clinically and economically important comorbidities in COPD.

Comorbid Influences on Generic Health-Related Quality of Life in COPD: A Systematic Review.

BACKGROUND: Chronic obstructive pulmonary disease (COPD) is a leading cause of mortality and of loss of disability-adjusted life years worldwide. It often is accompanied by the presence of comorbidity. OBJECTIVES: To systematically review the influence of COPD comorbidity on generic health-related quality of life (HRQoL). METHODS: A systematic review approach was used to search the databases Pubmed, Embase and Cochrane Library for studies evaluating the influence of comorbidity on HRQoL in COPD. Identified studies were analyzed according to study characteristics, generic HRQoL measurement instrument, COPD severity and comorbid HRQoL impact. Studies using only non-generic instruments were excluded. RESULTS: 25 studies met the selection criteria. Seven studies utilized the EQ-5D, six studies each used the SF-36 or SF-12. The remaining studies used one of six other instruments each. Utilities were calculated by four EQ-5D studies and one 15D study. Patient populations covered both early and advanced stages of COPD and ranged from populations with mostly stage 1 and 2 to studies with patients classified mainly stage 3 and 4. Evidence was mainly created for cardiovascular disease, depression and anxiety as well as diabetes but also for quantitative comorbid associations. Strong evidence is pointing towards the significant negative association of depression and anxiety on reduced HRQoL in COPD patients. While all studies found the occurrence of specific comorbidities to decrease HRQoL in COPD patients, the orders of magnitude diverged. Due to different patient populations, different measurement tools and different concomitant diseases the study heterogeneity was high. CONCLUSIONS: Facilitating multimorbid intervention guidance, instead of applying a parsimony based single disease paradigm, should constitute an important goal for improving HRQoL of COPD patients in research and in clinical practice.

Excess costs of comorbidities in chronic obstructive pulmonary disease: a systematic review.

BACKGROUND: Chronic obstructive pulmonary disease (COPD) is a leading cause of morbidity and mortality worldwide. Comorbidities are often reported in patients with COPD and may influence the cost of care. Yet, the extent by which comorbidities affect costs remains to be determined. OBJECTIVES: To review, quantify and evaluate excess costs of comorbidities in COPD. METHODS: Using a systematic review approach, Pubmed and Embase were searched for studies analyzing excess costs of comorbidities in COPD. Resulting studies were evaluated according to study characteristics, comorbidity measurement and cost indicators. Mark-up factors were calculated for respective excess costs. Furthermore, a checklist of quality criteria was applied. RESULTS: Twelve studies were included. Nine evaluated comorbidity specific costs; three examined index-based results. Pneumonia, cardiovascular disease and diabetes were associated with the highest excess costs. The mark-up factors for respective excess costs ranged between 1.5 and 2.5 in the majority of cases. On average the factors constituted a doubling of respective costs in the comorbid case. The main cost driver, among all studies, was inpatient cost. Indirect costs were not accounted for by the majority of studies. Study heterogeneity was high. CONCLUSIONS: The reviewed studies clearly show that comorbidities are associated with significant excess costs in COPD. The inclusion of comorbid costs and effects in future health economic evaluations of preventive or therapeutic COPD interventions seems highly advisable.