Lungenentblähung mit Indacaterol/Glycopyrronium verbessert die kardiale Funktion bei COPD Patienten: Die CLAIM Studie

Einleitung: Kardiovaskuläre Erkrankungen sind bedeutende Komorbiditäten der COPD mit einem signifikanten Einfluss auf Morbidität und Mortalität. Dabei ist insbesondere Lungenüberblähung mit verminderten kardialen Volumina und reduziertem Herzzeitvolumen assoziiert. Die CLAIM Studie untersucht den Einfluss der Entblähung der Lunge mit dem dualen Bronchodilatator Indacaterol/Glycopyrronium (IND/GLY) auf die kardiale Funktion in COPD Patienten mit erhöhtem Residualvolumen. Methoden: CLAIM ist eine monozentrische, randomisierte, doppelt-blinde, Placebo-kontrollierte cross-over Studie. Patienten mit erhöhtem Residualvolumen (RVol) und ohne klinisch signifikante Kardiovaskuläre Erkrankungen wurden auf IND/GLY oder Placebo randomisiert. Primärer Endpunkt war die Veränderung im Linksventrikulären enddiatolischem Volumen (LV-EDV) gemessen mit MRI nach 14-tägiger Behandlung. Ergebnisse: 62 Patienten mit symptomatischer COPD (GOLD B: 87,1%) und erhöhtem Residualvolumen (mittleres Residualvolumen bei Einschluss 186% des Sollwerts) wurden randomisiert wovon 57 beide Behandlungsphasen durchliefen. IND/GLY führte zu einer signifikanten Verbesserung der Lungenfunktion und einer Verminderung des Residualvolumens um -0,75 l (95% CI: -0,93 bis -0,58; p < 0,0001). Damit einhergehend war eine signifikante Erhöhung des LV-EDV (relativ zur Körperoberfläche) um 5,23 ml/m2 (95% CI: 3,22 bis 7,25; p < 0,0001) und des Herzzeitvolumens (Δ CO: 0,18 l/min/m2; 95% CI: 0,06 bis 0,29; p = 0,003). Das Nebenwirkungsprofil von IND/GLY zeigte keine unerwarteten Ergebnisse. Schlussfolgerung: Die Behandlung von überblähten COPD Patienten mit IND/GLY führt zu einer deutlichen Verbesserung der Lungenfunktion und einer starken Verringerung der Überblähung. Die CLAIM Studie zeigt, dass die Entblähung der Lunge positive Auswirkungen auf die kardiale Funktion von überblähten COPD Patienten hat. Die Therapie der Überblähung durch duale Bronchodilatation kann auch bei Patienten mit moderater COPD und geringer Exazerbationswahrscheinlichkeit angebracht sein und möglicherweise negative kardiale Einschränkungen verhindern

Effect of lung deflation with indacaterol plus glycopyrronium on ventricular filling in patients with hyperinflation and COPD (CLAIM): A double-blind, randomised, crossover, placebo-controlled, single-centre trial

BACKGROUND: Pulmonary hyperinflation in chronic obstructive pulmonary disease (COPD) is associated with reduced biventricular end-diastolic volumes and increased morbidity and mortality. The combination of a long-acting beta agonist (LABA) and a muscarinic antagonist (LAMA) is more effective in reducing hyperinflation than LABA-inhaled corticosteroid combination therapy but whether dual bronchodilation improves cardiac function is unknown. METHODS: We did a double-blind, randomised, two-period crossover, placebo-controlled, single-centre study (CLAIM) at the Fraunhofer Institute of Toxicology and Experimental Medicine (Hannover, Germany), a specialty clinic. Eligible participants were patients aged at least 40 years with COPD, pulmonary hyperinflation (defined by a baseline residual volume >135% of predicted), a smoking history of at least ten pack-years, and airflow limitation (FEV1 <80% predicted and post-bronchodilator FEV1: forced vital capacity <0.7). Patients with stable cardiovascular disease were eligible, but those with arrhythmias, heart failure, unstable ischaemic heart disease, or uncontrolled hypertension were not. We randomly assigned participants (1:1) to either receive a combined inhaled dual bronchodilator containing the LABA indacaterol (110 mug as maleate salt) plus the LAMA glycopyrronium (50 mug as bromide salt) once per day for 14 days, followed by a 14-day washout, then a matched placebo for 14 days, or to receive the same treatments in reverse order. The randomisation was done using lists and was concealed from patients and investigators. The primary endpoint was the effect of indacaterol-glycopyrronium versus placebo on left-ventricular end-diastolic volume measured by MRI done on day 1 (visit 4) and day 15 (visit 5) in treatment period 1 and on day 29 (visit 6) and day 43 (visit 7) in treatment period 2 in the per-protocol population. Left-ventricular end-diastolic volume was indexed to body surface area. Safety was assessed in all participants who received at least one dose of the study drug. This study is registered with ClinicalTrials.gov, number NCT02442206. FINDINGS: Between May 18, 2015, and April 20, 2017, we randomly assigned 62 eligible participants to treatment; 30 to indacaterol-glycopyrronium followed by placebo and 32 to placebo followed by indacaterol-glycopyrronium. The 62 randomly assigned patients were included in the intent-to-treat analysis. There were two protocol violations and therefore 60 were included in the per-protocol analysis. 57 patients completed both treatment periods. After indacaterol-glycopyrronium treatment, left-ventricular end-diastolic volume increased from a mean 55.46 mL/m(2) (SD 15.89) at baseline to a least-squares (LS) mean of 61.76 mL/m(2) (95% CI 57.68-65.84), compared with a change from 56.42 mL/m(2) at baseline (13.54) to 56.53 mL/m(2) (52.43-60.62) after placebo (LS means treatment difference 5.23 mL/m(2) [95% CI 3.22 to 7.25; p<0.0001]). The most common adverse events reported with indacaterol-glycopyrronium were cough (in nine patients [15%] of 59) and throat irritation (in seven [12%]). With placebo, the most common adverse events reported were headache (in five patients [8%] of 61) and upper respiratory tract infection (in four [7%]). Two patients had serious adverse events: one (2%) after indacaterol-glycopyrronium (endometrial cancer) and one (2%) after placebo (myocardial infarction); these were not thought to be treatment related. No patients died during the study. INTERPRETATION: This is the first study to analyse the effect of LABA-LAMA combination therapy on cardiac function in patients with COPD and lung hyperinflation. Dual bronchodilation with indacaterol-glycopyrronium significantly improved cardiac function as measured by left-ventricular end-diastolic volume. The results are important because of the known association of cardiovascular impairment with COPD, and support the early use of dual bronchodilation in patients with COPD who show signs of pulmonary hyperinflation. FUNDING: Novartis Pharma GmbH

Influence of physicians’ risk perception on switching treatments between high- efficacy and non–high-efficacy disease‑modifying therapies in multiple sclerosis

Background: The decision of initiating treatment for multiple sclerosis (MS) with a high-efficacy DMT (HE DMT) or non-high-efficacy DMT (non-HE DMT) is influenced by several factors, including risk perception of patients and physicians. Objective: Investigate the influence of physicians' risk perception on decision-making when switching treatments for MS and the reasons for switching. Methods: Data were drawn from the Adelphi Real-World MS Disease-Specific Program (a retrospective survey) and analysis included people with RMS identified between 2017- 2021. Results: Of 4129 patients with reasons for switch available, 3538 switched from non-HE DMT and 591 from HE DMT. Overall, 4.7% of patients were switched treatment by their physicians due to the risk of malignancies and infections including PML risk. The proportion of switches that were made due to the risk of PML were 23.9% in the HE DMT and 0.5% in the non-HE DMT groups. The top reasons for switching were relapse frequency (non-HE DMT vs HE-DMT: 26.8% vs 15.2%), lack of efficacy (20.9 vs 11.7) and increased number of MRI lesions (20.3% vs 12.4%). Conclusions: Physicians' risk perception of malignancies and infection excluding PML was not a leading factor when switching treatment. The risk of PML was a key factor, especially for switching patients from HE DMTs. In both groups, lack of efficacy was the key contributing factor for switching. Initiating the treatment with HE DMTs may potentially reduce the number of switches due to sub-optimal efficacy. These findings might help physicians to engage more in discussions with patients about the benefit/risk profile of DMTs

Lung deflation and improvement of cardiac end-diastolic volumes with indacaterol/glycopyrronium reduce dyspnea and improve health status in hyperinflated COPD patients: The CLAIM study

Rationale Cardiovascular diseases such as heart failure are common comorbidities of chronic obstructive pulmonary disease (COPD) and have a significant impact on morbidity and mortality. Lung hyperinflation detrimentally affects cardiac function in COPD patients and pharmacological deflation of the lung improves lung function and cardiac end-diastolic volumes. Here we show the effect of lung deflation and subsequent improvement of cardiac function on patient reported outcomes such as health status and symptoms in hyperinflated COPD patients. Methods In this randomized, double-blind, single-center, placebo-controlled, 2 period cross-over trial, COPD patients with increased residual volume (RV > 135 % pred.) and without relevant cardiovascular disease were enrolled. Primary outcome was the change in left-ventricular end-diastolic volume (LVEDV) measured with MRI after 14 days of treatment with indacaterol/glycopyrronium (IND/GLY, 110/50 µg q.d.) or placebo. Health status was assessed using the COPD assessment test (CAT) score and dyspnea was assessed with the baseline/transition dyspnea index (BDI/TDI) score. Results 62 patients were randomized, of which 57 completed both treatment periods. Treatment with IND/GLY significantly increased cardiac end-diastolic volumes, cardiac output and lung function measures vs. placebo. Improvement of end-diastolic volumes and lung function was associated with a statistical significant and clinically relevant increase in CAT and TDI scores. Changes in both scores remarkably exceeded the minimal clinically important difference after 14 days of treatment with LS means treatment differences versus placebo of -3.6 points (95% CI: -5.1, -2.2; P<0.0001) in CAT score and +3.7 points (95% CI: 2.5, 4.8; P<0.0001) in TDI. The safety profile of IND/GLY was comparable to placebo. Conclusion Lung deflation with dual bronchodilation using IND/GLY substantially improved cardiac function with increase in right- and left-ventricular end-diastolic volumes and cardiac output in hyperinflated COPD patients. This study is the first to show that lung deflation and improvement in cardiac function translate into a clinically relevant reduction of disease burden and dyspnea. Our findings argue for the early use of dual bronchodilation in patients with COPD who show signs of hyperinflation

Lungenentblähung mit Indacaterol/Glycopyrronium verbessert die kardiale Funktion von COPD Patienten: Die CLAIM Studie

Einleitung: Kardiovaskuläre Erkrankungen sind bedeutende Komorbiditäten der COPD mit einem signifikanten Einfluss auf Morbidität und Mortalität. Dabei ist insbesondere Lungenüberblähung mit verminderten kardialen Volumina und reduziertem Herzzeitvolumen assoziiert. Die CLAIM Studie untersucht den Einfluss der Entblähung der Lunge mit dem dualen Bronchodilatator Indacaterol/Glycopyrronium (IND/GLY) auf die kardiale Funktion bei COPD Patienten mit erhöhtem Residualvolumen. Methoden: CLAIM ist eine monozentrische, randomisierte, doppelt-blinde, Placebo-kontrollierte cross-over Studie. COPD Patienten mit erhöhtem Residualvolumen und ohne klinisch signifikante kardiovaskuläre Erkrankungen wurden auf eine von zwei möglichen Behandlungssequenzen (IND/GLY 110/50 µg inhalativ q.d. gefolgt von Placebo oder umgekehrt) randomisiert. Primärer Endpunkt war die Veränderung im linksventrikulären enddiastolischen Volumen (LVEDV) gemessen mittels MRI nach 14-tägiger Behandlung. Ergebnisse: Von 62 randomisierten Patienten mit symptomatischer COPD und erhöhtem Residualvolumen durchliefen 57 beide Behandlungsphasen. IND/GLY führte zu einer klinisch relevanten und statistisch signifikanten Verbesserung der Lungenfunktion und des Residualvolumens (-0.75 L [95% CI: -0,93 bis -0,58;

Indacaterol/Glycopyrronium improves pulmonary ventilation and ventilation inhomogeneity in the CLAIM Study

Background: Ventilation of the lungs is disturbed in COPD. Bronchodilator treatment reduces airway obstruction and improves airflow in the lung. Analysis of lung ventilation might help to further characterize COPD patients and assess treatment effects. Objectives: The objective was to analyze treatment effects of indacaterol/glycopyrronium (IND/GLY) on regional lung ventilation. Methods: CLAIM was a randomized, double-blind, single-center, placebo-controlled, 2 period cross-over trial. 62 hyperinflated COPD patients were enrolled to receive IND/GLY (110/50 μg q.d.) for 14 days followed by placebo or vice versa. Regional lung ventilation was measured under free breathing conditions in three coronal slices and in left and right sagittal slices using phase-resolved functional lung (PREFUL)-MRI. Results: Analysis of coronal lung slices showed that treatment with IND/GLY increased total fractional ventilation (FV) in the lung by 12.4% vs. placebo (relative LS Mean difference, p=0.0114) at day 14. Increase in total FV was associated with a reduction of hypoventilated areas (volume defect percentage) by 16.6% (p=0.0002) and an increase in homogeneity of lung ventilation by 12.4% (p<0.0001) vs. placebo, measured as reduction of the variation coefficient of FV. Similar results were obtained for sagittal slices, thereby supporting the validity of these results for the entire lung. Conclusion: IND/GLY improved lung ventilation in hyperinflated COPD patients. Importantly, this was associated with a reduction of hypoventilated areas and increased homogeneity. Improved regional lung ventilation might contribute to the reduction in dyspnea reported earlier for the CLAIM study