Multisystemic Effects of Elexacaftor-Tezacaftor-Ivacaftor in Adults with Cystic Fibrosis and Advanced Lung Disease.

Rationale: Limited data exist on the safety and effectiveness of elexacaftor-tezacaftor-ivacaftor (ETI) in people with cystic fibrosis (pwCF) and advanced lung disease. Objectives: To evaluate the effects of ETI in an unselected population of pwCF and advanced lung disease. Methods: A prospective observational study, including all adults aged 18 years and older with percentage predicted forced expiratory volume in 1 second (ppFEV1) ⩽ 40 who initiated ETI from December 2019 to June 2021 in France, was conducted. PwCF were followed until August 8, 2022. Results: ETI was initiated in 434 pwCF with a median ppFEV1 of 30 (interquartile range, 25-35), including 27 with severe cystic fibrosis liver disease and 183 with diabetes. PwCF were followed for a median of 587 (interquartile range, 396-728) days after ETI initiation. Discontinuation of ETI occurred in 12 (2.8%) pwCF and was due mostly to lung transplantation (n = 5) or death (n = 4). Absolute increase in ppFEV1 by a mean of +14.2% (95% confidence interval, 13.1-15.4%) occurred at 1 month and persisted throughout the study. Increase in ppFEV1 in the youngest age quartile was almost twice that of the oldest quartile (P < 0.001); body mass index < 18.5 kg/m2 was found in 38.6% at initiation versus 11.3% at 12 months (P = 0.0001). Increases in serum concentrations of vitamins A and E, but not 25-hydroxy vitamin D3, were observed. Significant reductions in the percentages of pwCF using oxygen therapy, noninvasive ventilation, nutritional support, and inhaled and systemic therapies (including antibiotics) were observed; insulin was discontinued in 12% of patients with diabetes. Conclusions: ETI is safe in pwCF and advanced lung disease, with multisystem pulmonary and extrapulmonary benefits.

Sustained effectiveness of elexacaftor-tezacaftor-ivacaftor in lung transplant candidates with cystic fibrosis.

BACKGROUND: Elexacaftor-tezacaftor-ivacaftor induces rapid clinical improvement in patients with cystic fibrosis (CF) and advanced pulmonary disease, often leading to suspend the indication for lung transplantation. Yet no long-term data is available in lung transplant candidates. METHODS: Lung transplant candidates (defined as being waitlisted for lung transplantation or considered for listing within 3 months) who have initiated elexacaftor-tezacaftor-ivacaftor were identified in the French cohort of patients with CF and advanced pulmonary disease. Patients were prospectively followed to evaluate treatment safety and effectiveness from initiation to July 20th, 2021. RESULTS: Among the 331 patients with advanced CF pulmonary disease who initiated elexacaftor-tezacaftor-ivacaftor, 65 were lung transplant candidates (17 listed for transplantation, 48 considered for listing within 3 months). Median [IQR] follow-up time was 363 [329; 377] days. At the end of the follow-up period, two patients were transplanted five and 11 days following treatment initiation, two were listed for transplantation, and 61 no longer met transplantation criteria. Improvement in percent predicted forced expiratory volume in 1 s (ppFEV1) at one month was +13.4% (95% confidence interval, 10.3%-16.5%; P < 0.0001) and remained stable thereafter. Treatment burden decreased substantially, with an 86% decrease in the need for intravenous antibiotics, 59% for oxygen therapy and 62% for non-invasive ventilation. CONCLUSION: In lung transplant candidates eligible for elexacaftor-tezacaftor-ivacaftor, the rapid improvement following initiation of treatment persisted over one year with a reduction in treatment burden and lung transplantation could be safely deferred in most patients.

Real-world assessment of LCI following lumacaftor-ivacaftor initiation in adolescents and adults with cystic fibrosis.

Lung clearance index (LCI) is a biomarker of ventilation inhomogeneity. Data are scarce on its usefulness in daily practice for monitoring the effects of treatments in older children and adults with CF. In this French observational study of lumacaftor-ivacaftor, 63 of 845 patients (7.5%) had available LCI performed at baseline and at six (M6; n=34) or 12 months (M12; n=46) after lumacaftor-ivacaftor initiation. At inclusion, median [IQR] age was 16 years [13-17], ppFEV1 was 72.8 [59.6-80.7], and LCI was 12.3 [10.3-15.0]. At both M6 and M12, no statistically significant LCI increases of 0.13 units or 1.34% (95% CI: -4.85-7.53) and 0.6 units or 6.66% (95% CI: -0.03-13.5) were observed. Discordant results between LCI and ppFEV1 were observed in one-third of the patients. In daily practice, LCI monitoring in adolescents and young adults with moderate lung disease gives results that are more heterogenous than those reported in children with milder disease.

Burden and Characteristics of Severe Chronic Hypoxemia in a Real-World Cohort of Subjects with COPD.

BACKGROUND: Chronic respiratory failure may occur as a consequence of chronic obstructive pulmonary disease (COPD) and is associated with significant morbidity and mortality. Hypoxemia is determined by underlying disease characteristics and comorbidities. Severe hypoxemia is typically only found in subjects with severe airflow obstruction (FEV1<50% predicted). However, how hypoxemia relates to disease characteristics is not fully understood. METHODS: In the French Initiatives BPCO real-life cohort, arterial blood gases were routinely collected in most patients. Relationships between severe hypoxemia, defined by a Pa02<60 mmHg (8 kPa) and clinical/lung function features, comorbidities and mortality were assessed. In subjects with severe hypoxemia, clinical characteristics and comorbidities were compared between those with non-severe versus severe airflow limitation. Classification and regression trees (CART) were used to define clinically relevant subgroups (phenotypes). RESULTS: Arterial blood gases were available from 887 subjects, of which 146 (16%) exhibited severe hypoxemia. Compared to subjects with a PaO2≥60 mmHg, the severe hypoxemia group exhibited higher mMRC dyspnea score, lower FEV1, higher RV and RV/TLC, more impaired quality of life, lower 6-minute walking distance, less frequent history of asthma, more frequent diabetes and higher 3-year mortality rate (14% versus 8%, p=0.026). Compared to subjects with Pa02<60 mmHg and FEV1<50% (n=115, 13%), those with severe hypoxemia but FEV1≥50% predicted (n=31) were older, had higher BMI, less hyperinflation, better quality of life and a higher rate of diabetes (29% versus 13%, p=0.02). Severe hypoxemia was better related to CART-defined phenotypes than to GOLD ABCD classification. CONCLUSION: In this cohort of stable COPD subjects, severe hypoxemia was associated with worse prognosis and more severe symptoms, airflow limitation and hyperinflation. Compared to subjects with severe hypoxemia and severe airflow limitation, subjects with severe hypoxemia despite non-severe airflow limitation were older, had higher BMI and more diagnosed diabetes. TRIAL REGISTRATION: 04-479.

Rapid Improvement after Starting Elexacaftor-Tezacaftor-Ivacaftor in Patients with Cystic Fibrosis and Advanced Pulmonary Disease.

Rationale: Elexacaftor-tezacaftor-ivacaftor is a CFTR (cystic fibrosis [CF] transmembrane conductance regulator) modulator combination, developed for patients with CF with at least one Phe508del mutation. Objectives: To evaluate the effects of elexacaftor-tezacaftor- ivacaftor in patients with CF and advanced respiratory disease. Methods: A prospective observational study, including all patients aged ⩾12 years and with a percent-predicted FEV1 (ppFEV1) <40 who initiated elexacaftor-tezacaftor-ivacaftor from December 2019 to August 2020 in France was conducted. Clinical characteristics were collected at initiation and at 1 and 3 months. Safety and effectiveness were evaluated by September 2020. National-level transplantation and mortality figures for 2020 were obtained from the French CF and transplant centers and registries. Measurements and Main Results: Elexacaftor-tezacaftor- ivacaftor was initiated in 245 patients with a median (interquartile range) ppFEV1 = 29 (24-34). The mean (95% confidence interval) absolute increase in the ppFEV1 was +15.1 (+13.8 to +16.4; P < 0.0001), and the mean (95% confidence interval) in weight was +4.2 kg (+3.9 to +4.6; P < 0.0001). The number of patients requiring long-term oxygen, noninvasive ventilation, and/or enteral tube feeding decreased by 50%, 30%, and 50%, respectively (P < 0.01). Although 16 patients were on the transplant waiting list and 37 were undergoing transplantation evaluation at treatment initiation, only 2 received a transplant, and 1 died. By September 2020, only five patients were still on the transplantation path. Compared with the previous 2 years, a twofold decrease in the number of lung transplantations in patients with CF was observed in 2020, whereas the number of deaths without transplantation remained stable. Conclusions: In patients with advanced disease, elexacaftor-tezacaftor-ivacaftor is associated with rapid clinical improvement, often leading to the indication for lung transplantation being suspended.

Clinical response to lumacaftor-ivacaftor in patients with cystic fibrosis according to baseline lung function.

BACKGROUND: Phase 3 trials have demonstrated the safety and efficacy of lumacaftor-ivacaftor (LUMA-IVA) in patients with cystic fibrosis (CF) homozygous for the Phe508del CFTR mutation and percent predicted forced expiratory volume in 1 s (ppFEV1) between 40 and 90. Marketing authorizations have been granted for patients at all levels of ppFEV1. METHODS: To evaluate the safety and effectiveness of LUMA-IVA over the first year of treatment in patients with ppFEV1<40 or ppFEV1≥90 in comparison with those with ppFEV1 [40-90[. Analysis of data collected during a real world study, which included all patients aged ≥12 years who started LUMA-IVA in 2016 across all 47 French CF centers. RESULTS: 827 patients were classified into 3 subgroups according to ppFEV1 at treatment initiation (ppFEV1<40, n = 121; ppFEV1 [40-90[, n = 609; ppFEV1≥90, n = 97). Treatment discontinuation rate was higher in ppFEV1<40 patients (28.9%) than in those with ppFEV1 [40-90[(16.4%) or ppFEV1≥90 (17.5%). In patients with uninterrupted treatment, significant increase in ppFEV1 occurred in the ppFEV1 [40-90[subgroup (+2.9%, P<0.001), and in those ppFEV1<40 (+0.5%, P = 0.03) but not in those with ppFEV1≥90 (P = 0.46). Compared with the year prior to initiation, the number of days of intravenous antibiotics were reduced in all subgroups, although 72% of patients with ppFEV1<40 still experienced at least one exacerbation/year under LUMA-IVA. Comparable increase in body mass index was seen in the three subgroups. CONCLUSION: Phe508del homozygous CF patients benefit from LUMA-IVA at all levels of baseline lung function, but the characteristics and magnitude of the response vary depending on ppFEV1 at baseline.

Real-Life Safety and Effectiveness of Lumacaftor-Ivacaftor in Patients with Cystic Fibrosis.

Rationale: Lumacaftor-ivacaftor is a CFTR (cystic fibrosis transmembrane conductance regulator) modulator combination recently approved for patients with cystic fibrosis (CF) homozygous for the Phe508del mutation.Objectives: To evaluate the safety and effectiveness of lumacaftor-ivacaftor in adolescents (≥12 yr) and adults (≥18 yr) in a real-life postapproval setting.Methods: The study was conducted in the 47 CF reference centers in France. All patients who initiated lumacaftor-ivacaftor from January 1 to December 31, 2016, were eligible. Patients were evaluated for lumacaftor-ivacaftor safety and effectiveness over the first year of treatment following the French CF Learning Society's recommendations.Measurements and Main Results: Among the 845 patients (292 adolescents and 553 adults) who initiated lumacaftor-ivacaftor, 18.2% (154 patients) discontinued treatment, often owing to respiratory (48.1%, 74 patients) or nonrespiratory (27.9%, 43 patients) adverse events. In multivariable logistic regression, factors associated with increased rates of discontinuation included adult age group, percent predicted FEV1 (ppFEV1) less than 40%, and numbers of intravenous antibiotic courses during the year before lumacaftor-ivacaftor initiation. Patients with continuous exposure to lumacaftor-ivacaftor showed an absolute increase in ppFEV1 (+3.67%), an increase in body mass index (+0.73 kg/m2), and a decrease in intravenous antibiotic courses by 35%. Patients who discontinued treatment had significant decrease in ppFEV1, without improvement in body mass index or decrease in intravenous antibiotic courses.Conclusions: Lumacaftor-ivacaftor was associated with improvement in lung disease and nutritional status in patients who tolerated treatment. Adults who discontinued lumacaftor-ivacaftor, often owing to adverse events, were found at high risk of clinical deterioration.

Relationship between gender and survival in a real-life cohort of patients with COPD.

BACKGROUND: Although COPD affects both men and women, its prevalence is increasing more rapidly in women. Disease outcomes appear different among women with more frequent dyspnea and anxiety or depression but whether this translates into a different prognosis remains to be determined. Our aim was to assess whether the greater clinical impact of COPD in women was associated with differences in 3-year mortality rates. METHODS: In the French Initiatives BPCO real-world cohort, 177 women were matched up to 458 menon age (within 5-year intervals) and FEV1 (within 5% predicted intervals). 3-year mortality rate and survival were analyzed. Univariate and multivariate logistic regression analyses were performed. RESULTS: For a given age and level of airflow obstruction, women with COPD had more severe dyspnea, lower BMI, and were more likely to exhibit anxiety. Nevertheless, three-year mortality rate was comparable among men and women, respectively 11.2 and 10.8%. In a multivariate model, the only factors significantly associated with mortality were dyspnea and malnutrition but not gender. CONCLUSION: Although women with COPD experience higher levels of dyspnea and anxiety than men at comparable levels of age and FEV1, these differences do not translate into variations in 3-year mortality rates. TRIAL REGISTRATION: 04-479.

Randomized controlled trials of pharmacological treatments to prevent COPD exacerbations: applicability to real-life patients.

BACKGROUND: In patients with chronic obstructive pulmonary disease, all efforts should be made to prevent exacerbations because each event modifies the trajectory of the disease. Treatment recommendations are mostly built on results from randomized controlled trials (RCTs) whose methodology ensure internal validity. However, their relevance may be compromised by the lack of generalizability, due to poor representability of study populations compared to real-life patients. In order to delimit to whom the results of studies on current and future treatments apply, we sought to identify and characterize the fraction of COPD population that would be eligible for inclusion into RCTs aiming at decreasing exacerbation risk. METHODS: We used the Initiatives-BPCO database, a French cohort of 1309 real-life COPD patients monitored in academic centers. We identified industry-sponsored phase III and IV trials that enrolled more than 500 patients, lasted at least one year and used exacerbations related endpoints. Eligibility criteria were extracted from each trial and applied to the patients. RESULTS: The eligibility criteria of 16 RCTs were applied to the 1309 patients. The most discriminating eligibility criteria were FEV1, minimum exacerbation rate in the previous year and smoking history, responsible for the exclusion of 39.9, 36.7 and 16.8% of patients, respectively. Altogether, 2.3 to 46.7% of our patients would have satisfied all eligibility criteria. CONCLUSION: These analyses confirm that an important gap exists between real-life patients and clinical trials populations in COPD, which limits the relevance of results and therefore should be considered when grading levels of evidence and designing future studies.

Predictors in routine practice of 6-min walking distance and oxygen desaturation in patients with COPD: impact of comorbidities.

Background: The 6-min walk test (6MWT) allows exercise tolerance to be assessed, and it has a significant prognostic value in COPD. The goal of this study was to analyse the determinants (obtained in routine practice) of a low 6-min walking distance (6MWD) and exercise-induced desaturation (EID) in COPD, including comorbidities. Methods: Patients were recruited from the real-life French COPD cohort "Initiatives BPCO". A low 6MWD was defined as <350 m. EID was defined by a minimum pulse oxygen saturation (SpO2)<90% and delta SpO2≥4% from baseline. Multivariate logistic regression analyses assessed the influence on 6MWD and EID of age, sex, obesity (body mass index, BMI >30 kg/m2), low BMI (BMI <18.5 kg/m2), modified Medical Research Council (mMRC) dyspnea scale, FEV1% pred, FVC % pred, hyperinflation and comorbidities including cardiovascular diseases. Results: Among 440 patients with available 6MWT data, a 6MWD <350 m was found in 146 patients (33%), which was positively associated in multivariate analyses with age and mMRC and negatively with resting SpO2 and FVC % pred (rescaled r2=0.34), whereas no comorbidity was associated with a low 6WMD. EID was found in 155 patients (35%). This was positively associated with hypertension and negatively with age, obesity, FEV1% pred and resting SpO2 (rescaled r2=0.37). Conclusion: 6MWD and EID exhibit different determinants in COPD with a minor impact of comorbidities limited to hypertension in EID and to obesity, which was unexpectedly associated with less EID. Other variables including age, routine resting lung function and SpO2 were weakly associated with 6MWD and EID. Altogether, these results suggest that 6MWT performance remains difficult to predict with routine clinical/functional parameters.

Cluster and CART analyses identify large subgroups of adults with cystic fibrosis at low risk of 10-year death.

Our goal was to identify subgroups of adults with cystic fibrosis (CF) at low risk of death within 10 years.Factor analysis for mixed data followed by Ward's cluster analysis was conducted using 25 variables from 1572 French CF adults in 2005. Rates of death by subgroups were analysed over 10 years. An algorithm was developed using CART (classification and regression tree) analysis to provide rules for the identification of subgroups of CF adults with low rates of death within 10 years. This algorithm was validated in 1376 Canadian CF adults.Seven subgroups were identified by cluster analysis in French CF adults, including two subgroups with low (∼5%) rates of death at 10 years: one subgroup (22% of patients) was composed of patients with nonclassic CF, the other subgroup (17% of patients) was composed of patients with classic CF but low rates of Pseudomonas aeruginosa infection and diabetes. An algorithm based on CART analysis of data in 2005 allowed us to identify most French adults with low rates of death. When tested using data from Canadian CF adults in 2005, the algorithm identified 287 out of 1376 (21%) patients at low risk (10-year death: 7.7%).Large subgroups of CF adults share low risk of 10-year mortality.

A simple algorithm for the identification of clinical COPD phenotypes.

This study aimed to identify simple rules for allocating chronic obstructive pulmonary disease (COPD) patients to clinical phenotypes identified by cluster analyses.Data from 2409 COPD patients of French/Belgian COPD cohorts were analysed using cluster analysis resulting in the identification of subgroups, for which clinical relevance was determined by comparing 3-year all-cause mortality. Classification and regression trees (CARTs) were used to develop an algorithm for allocating patients to these subgroups. This algorithm was tested in 3651 patients from the COPD Cohorts Collaborative International Assessment (3CIA) initiative.Cluster analysis identified five subgroups of COPD patients with different clinical characteristics (especially regarding severity of respiratory disease and the presence of cardiovascular comorbidities and diabetes). The CART-based algorithm indicated that the variables relevant for patient grouping differed markedly between patients with isolated respiratory disease (FEV1, dyspnoea grade) and those with multi-morbidity (dyspnoea grade, age, FEV1 and body mass index). Application of this algorithm to the 3CIA cohorts confirmed that it identified subgroups of patients with different clinical characteristics, mortality rates (median, from 4% to 27%) and age at death (median, from 68 to 76 years).A simple algorithm, integrating respiratory characteristics and comorbidities, allowed the identification of clinically relevant COPD phenotypes.

Relationship between blood eosinophils, clinical characteristics, and mortality in patients with COPD.

In patients with COPD, there is controversy regarding the association of blood eosinophil (Eos) levels with 1) exacerbation frequency and 2) the effect of inhaled corticosteroids for prevention of exacerbations. To determine whether Eos define subgroups of patients exhibiting attributes of COPD clinical phenotypes, we compared clinical features and mortality rates in COPD patients from the Initiatives BPCO French cohort categorized using different thresholds of blood Eos levels. The following data were collected at inclusion: medical and smoking history, occupational exposures, dyspnea, cough and sputum production, exacerbations in the previous year, history of allergy and asthma, nasal symptoms, body mass index, St George Respiratory Questionnaire (SGRQ) total score, post-bronchodilator spirometry, comorbidities, and medications. Three-year survival between groups was compared using Kaplan-Meier analysis. Three sets of analyses were performed to compare patients with ≥2% versus <2%, ≥3% versus <3%, and ≥4% versus <4% Eos. Eos was available in 458 patients (mean age: 62 years, 72% male, mean forced expiratory volume in 1 second: 51% pred), including 235 patients with Eos ≥2% (49%), 149 with Eos ≥3% (33%), and 90 with Eos ≥4% (20%). For all cutoffs, there was no difference between Eos+ and Eos- groups in univariate analyses except for diabetes and SGRQ score (more frequent and more impaired, respectively, in lower Eos categories). In particular, there was no difference in exacerbation rate, history of asthma, or three-year survival. In conclusion, regardless of the cutoff, Eos+ COPD patients exhibited no specific characteristic in terms of symptoms, lung function, exacerbation rate, and prognosis. These findings suggest that the association of higher Eos with exacerbations reported in previous studies could be population specific, which does not support generalizing the use of Eos as a biomarker for COPD phenotyping.

Impact of current cough on health-related quality of life in patients with COPD.

BACKGROUND: Cough and sputum production are frequent in chronic obstructive pulmonary disease (COPD). The objective of this study was to examine the relationship between cough and sputum production and health-related quality of life in COPD. METHODS: A cross-sectional study was conducted in the French Initiatives COPD cohort and assessed cough and sputum production within the past 7 days using the cough and sputum assessment questionnaire (CASA-Q), health-related quality of life, spirometry, smoking status, dyspnea, exacerbations, anxiety and depression, and comorbidities. RESULTS: One hundred and seventy-eight stable COPD patients were included (age, 62 [56-69] years, 128 male, forced expiratory volume in 1 second [FEV1]: 57 [37-72] % predicted) (median [Q1-Q3]). In univariate analyses, health-related quality of life (Saint George's respiratory questionnaire total score) was associated with each CASA-Q domain and with chronic bronchitis, exacerbations, dyspnea, FEV1, depression, and anxiety. All four domains introduced separately were independently associated with health-related quality of life. When introduced together in multivariate analyses, only the cough impact domain remained independently associated with health-related quality of life (R2=0.60). With chronic bronchitis (standard definition) instead of the CASA-Q, the R2 was lower (R2=0.54). CONCLUSION: This study provides evidence that current cough in the previous 7 days is an important determinant of health-related quality of life impairment in stable COPD patients.

Modified Medical Research Council scale vs Baseline Dyspnea Index to evaluate dyspnea in chronic obstructive pulmonary disease.

BACKGROUND: Assessment of dyspnea in COPD patients relies in clinical practice on the modified Medical Research Council (mMRC) scale, whereas the Baseline Dyspnea Index (BDI) is mainly used in clinical trials. Little is known on the correspondence between the two methods. METHODS: Cross-sectional analysis was carried out on data from the French COPD cohort Initiatives BPCO. Dyspnea was assessed by the mMRC scale and the BDI. Spirometry, plethysmography, Hospital Anxiety-Depression Scale, St George's Respiratory Questionnaire, exacerbation rates, and physician-diagnosed comorbidities were obtained. Correlations between mMRC and BDI scores were assessed using Spearman's correlation coefficient. An ordinal response model was used to examine the contribution of clinical data and lung function parameters to mMRC and BDI scores. RESULTS: Data are given as median (interquartile ranges, [IQR]). Two-hundred thirty-nine COPD subjects were analyzed (men 78%, age 65.0 years [57.0; 73.0], forced expiratory volume in 1 second [FEV1] 48% predicted [34; 67]). The mMRC grade and BDI score were, respectively, 1 [1-3] and 6 [4-8]. Both BDI and mMRC scores were significantly correlated at the group level (rho =-0.67; P<0.0001), but analysis of individual data revealed a large scatter of BDI scores for any given mMRC grade. In multivariate analysis, both mMRC grade and BDI score were independently associated with lower FEV1% pred, higher exacerbation rate, obesity, depression, heart failure, and hyperinflation, as assessed by the inspiratory capacity/total lung capacity ratio. The mMRC dyspnea grade was also associated with the thromboembolic history and low body mass index. CONCLUSION: Dyspnea is a complex symptom with multiple determinants in COPD patients. Although related to similar factors (including hyperinflation, depression, and heart failure), BDI and mMRC scores likely explore differently the dyspnea intensity in COPD patients and are clearly not interchangeable.

Phenotypes influencing low physical activity in maintenance dialysis.

OBJECTIVE: The "Pas à Pas" initiative aimed at evaluating the weekly physical activity (PA) and its determinants in a large cohort of dialysis patients. SETTING: Physical inactivity is a risk factor for mortality in maintenance dialysis patients and is still poorly documented in this population. DESIGN: A prospective national epidemiological study was performed. SUBJECTS: A total of 1,163 patients on maintenance dialysis (hemodialysis and peritoneal dialysis) were included. INTERVENTION AND MAIN OUTCOME MEASURE: PA was recorded during seven consecutive days using a pedometer to measure daily step numbers. RESULTS: Median age was 63 years (Q1 51-Q3 75). Sixty-three percent were sedentary (<5000 steps/day) with a median of 3,688 steps/day (1,866-6,271)]. PA level was similar between hemodialysis patients and those on peritoneal dialysis (3,693 steps [1,896-6,307] vs. 3,320 [1,478-5,926], P = .33). In hemodialysis patients, PA was lower on dialysis days compared with nondialysis days (2,912 [1,439-5,232] vs. 4,054 [2,136-7,108], respectively, P < .01). PA gradually decreased with age, 57% being sedentary between 50 and 65 years and 83% of patients after 80 years. Beyond this age effect, we identified, for the first time, specific phenotypes of patients with lower PA, such as inflammation, cardiovascular disease, protein energy wasting, obesity, and diabetes. By contrast, previous kidney transplantation and a higher muscle mass were associated with higher PA. CONCLUSIONS: Dialysis patients present a very low level of PA with high sedentary. Acting on patient's modifiable phenotypes may help to increase PA to improve morbidity, mortality, and quality of life.

Tiotropium might improve survival in subjects with COPD at high risk of mortality.

BACKGROUND: Inhaled therapies reduce risk of chronic obstructive pulmonary disease (COPD) exacerbations, but their effect on mortality is less well established. We hypothesized that heterogeneity in baseline mortality risk influenced the results of drug trials assessing mortality in COPD. METHODS: The 5706 patients with COPD from the Understanding Potential Long-term Impacts on Function with Tiotropium (UPLIFT®) study that had complete clinical information for variables associated with mortality (age, forced expiratory volume in 1 s, St George's Respiratory Questionnaire, pack-years and body mass index) were classified by cluster analysis. Baseline risk of mortality between clusters, and impact of tiotropium were evaluated during the 4-yr follow up. RESULTS: Four clusters were identified, including low-risk (low mortality rate) patients (n = 2339; 41%; cluster 2), and high-risk patients (n = 1022; 18%; cluster 3), who had a 2.6- and a six-fold increase in all-cause and respiratory mortality compared with cluster 2, respectively. Tiotropium reduced exacerbations in all clusters, and reduced hospitalizations in high-risk patients (p < 0.05). The beneficial effect of tiotropium on all-cause mortality in the overall population (hazard ratio, 0.87; 95% confidence interval, 0.75-1.00, p = 0.054) was explained by a 21% reduction in cluster 3 (p = 0.07), with no effect in other clusters. CONCLUSIONS: Large variations in baseline risks of mortality existed among patients in the UPLIFT® study. Inclusion of numerous low-risk patients may have reduced the ability to show beneficial effect on mortality. Future clinical trials should consider selective inclusion of high-risk patients.

Identification of clinical phenotypes using cluster analyses in COPD patients with multiple comorbidities.

Chronic obstructive pulmonary disease (COPD) is characterized by persistent airflow limitation, the severity of which is assessed using forced expiratory volume in 1 sec (FEV1, % predicted). Cohort studies have confirmed that COPD patients with similar levels of airflow limitation showed marked heterogeneity in clinical manifestations and outcomes. Chronic coexisting diseases, also called comorbidities, are highly prevalent in COPD patients and likely contribute to this heterogeneity. In recent years, investigators have used innovative statistical methods (e.g., cluster analyses) to examine the hypothesis that subgroups of COPD patients sharing clinically relevant characteristics (phenotypes) can be identified. The objectives of the present paper are to review recent studies that have used cluster analyses for defining phenotypes in observational cohorts of COPD patients. Strengths and weaknesses of these statistical approaches are briefly described. Description of the phenotypes that were reasonably reproducible across studies and received prospective validation in at least one study is provided, with a special focus on differences in age and comorbidities (including cardiovascular diseases). Finally, gaps in current knowledge are described, leading to proposals for future studies.