David B Rubin

Which patients with chronic obstructive pulmonary disease benefit from the addition of an inhaled corticosteroid to their bronchodilator? A cluster analysis

Objective To identify subsets of chronic obstructive pulmonary disease (COPD) patients who are more protected from exacerbations with the use of an inhaled corticosteroid/long-acting β2 agonist (ICS/LABA) combination, compared with the use of LABA monotherapy. Design Post hoc cluster analysis of patients from two randomised clinical trials of salmeterol/fluticasone propionate (SFC) and salmeterol (SAL) that had primary endpoints of moderate/severe exacerbation rates. Setting Centres in North America. Participants 1543 COPD patients were studied. Interventions SFC 50/250u2005µg or SAL 50u2005µg, twice daily. Primary and secondary outcome measures The analysis identified clusters of COPD patients more responsive to SFC versus SAL with respect to the annual rate of moderate/severe exacerbations and compared their baseline clinical characteristics. Results Overall, SFC significantly reduced the annual rate of moderate/severe exacerbations as compared with SAL alone (rate ratio (RR)=0.701, p<0.001). Three-patient clusters were identified: COPD patients receiving diuretics (RR=0.56, p<0.001); patients not receiving diuretics but with forced expiratory volume in 1 s (FEV1) reversibility ≥12% (RR=0.67, p<0.001) exhibited a substantial reduction in the annual rate of moderate/severe exacerbations relative to SAL. A third cluster, consisting of patients not receiving diuretics and without FEV1 reversibility, demonstrated no difference for SFC versus SAL. Patients receiving diuretics had a significantly higher prevalence of comorbid cardiovascular disease. Conclusions COPD patients receiving diuretics and those not receiving diuretics but with FEV1 reversibility >12% at baseline were significantly more likely to experience a reduction in COPD-associated exacerbations with SFC versus SAL alone. Trial registration NCT00115492, NCT00144911

The effect of ketoconazole on the pharmacokinetics and pharmacodynamics of inhaled fluticasone furoate and vilanterol trifenatate in healthy subjects

AIMnTo investigate the effects of the cytochrome P450 3A4 (CYP3A4) inhibitor ketoconazole on the pharmacokinetics (PK) and pharmacodynamics of fluticasone furoate (FF) and vilanterol trifenatate (VI).nnnMETHODSnTwo double-blind, randomized, placebo-controlled, two-way crossover studies in healthy subjects. In study 1, subjects received single doses of ketoconazole (400 mg) or placebo on days 1-6, with a single dose of inhaled VI (25 μg) on day 5. Pharmacodynamic and PK data were obtained up to 48 h following the VI dose. In study 2, subjects received once daily ketoconazole (400 mg) or placebo for 11 days, with FF/VI (200/25u2009μg) for the final 7 days. Pharmacodynamic and PK data were obtained up to 48 h following the day 11 dose.nnnRESULTSnIn study 1, there was no effect of co-administration of ketoconazole and VI on pharmacodynamic or PK parameters. In study 2, co-administration of ketoconazole and FF/VI had no effect on 0-4 h maximal heart rate or minimal blood potassium {treatment difference [90% confidence interval (CI)] -0.6 beats min(-1) (-5.8, 4.5) and 0.04 mmol l(-1) (-0.03, 0.11), respectively}, whilst there was a 27% decrease in 24 h weighted mean serum cortisol [treatment ratio (90% CI) 0.73 (0.62, 0.86)]. Co-administration of ketoconazole increased [percentage change (90% CI)] FF area under the curve (0-24) and maximal plasma concentration by 36% (16, 59) and 33% (12, 58), respectively, and VI area under the curve (0-t) and maximal plasma concentration by 65% (38, 97) and 22% (8, 38), respectively.nnnCONCLUSIONnCo-administration of FF/VI or VI with ketoconazole resulted in a less than twofold increase in systemic exposure to FF and VI. There was no increase in β-agonist systemic pharmacodynamic effects, while serum cortisol was decreased by 27%. Co-administration of FF/VI with strong CYP3A4 inhibitors has the potential to increase systemic exposure to both fluticasone furoate and vilanterol, which could lead to an increase in the potential for adverse reactions.

Effect of fluticasone propionate/salmeterol on arterial stiffness in patients with COPD

BACKGROUNDnCOPD is associated with increased arterial stiffness which may in part explain the cardiovascular morbidity observed in the disease. A causal relationship between arterial stiffness and cardiovascular events has not been established, though their strong association raises the possibility that therapies that reduce arterial stiffness may improve cardiovascular outcomes. Prior studies suggest that fluticasone propionate/salmeterol (FSC) may improve cardiovascular outcomes in COPD and we hypothesized that FSC would reduce arterial stiffness in these patients.nnnMETHODSnThis multicenter, randomized, double-blind, placebo-controlled study compared the effects of FSC 250/50 μg twice-daily and placebo on aortic pulse wave velocity (aPWV) as determined by ECG-gated carotid and femoral artery waveforms. The primary endpoint was aPWV change from baseline at 12-weeks (last measure for each patient).nnnRESULTSn249 patients were randomized; the mean FEV(1) in each group was similar (55% predicted) and 60% of patients reported a cardiovascular disorder. At 12-weeks, aPWV between FSC and placebo was -0.42 m/s (95%CI -0.88, 0.03; p = 0.065). A statistically significant reduction in aPWV between FSC and placebo was observed in those who remained on study drug throughout the treatment period [-0.49 m/s (95%CI -0.98, -0.01; p = 0.045)]. A post hoc analysis suggested the effect of FSC was greater in patients with higher baseline aPWV.nnnCONCLUSIONnFSC does not reduce aPWV in all patients with moderate to severe COPD, but may have effects in those with elevated arterial stiffness. Additional studies are required to determine if aPWV could serve as a surrogate for cardiovascular events in COPD.

Risk of pneumonia with inhaled corticosteroid/long-acting β2 agonist therapy in chronic obstructive pulmonary disease: a cluster analysis

Background Pneumonia poses a significant risk in patients with moderate to severe chronic obstructive pulmonary disease but data are limited on the disease phenotypes most susceptible to pneumonia. Methods Cluster analysis using a data-driven recursive partitioning algorithm was employed using baseline data from two pooled one-year randomized exacerbation trials (n=3,255) of fluticasone furoate/vilanterol or vilanterol alone to identify distinct patient groups at greatest risk of pneumonia or serious (hospitalization or death) pneumonia. Results Five clusters were identified. Patients at greater risk of first pneumonia had more severe obstruction (forced expiratory volume in one second/forced vital capacity <46%) and either a body mass index <19 kg/m2 (hazard ratio 7.8, 95% confidence interval 4.7–13.0; n=144) or a pneumonia history and greater comorbidities (hazard ratio 4.8, 95% confidence interval 3.0–7.7; n=374) relative to the cluster with the lowest pneumonia risk (reference; n=1310). Multiple comorbidities and use of psychoanaleptics also contributed to an increased risk of pneumonia in more obstructed patients. Independent of cluster, use of inhaled corticosteroids was associated with pneumonia (hazard ratio 1.89, 95% confidence interval 1.25–2.84) and serious pneumonia (hazard ratio 2.92, 95% confidence interval 1.40–6.01). Conclusion Cluster analysis can identify patient populations at risk for serious safety outcomes and inform risk management strategies to optimize patient management. The greatest risk for pneumonia was in subjects with multiple pneumonia risk factors.

Long-Acting Bronchodilators and Arterial Stiffness in Patients With COPD: A Comparison of Fluticasone Furoate/Vilanterol With Tiotropium

BACKGROUNDnIncreased arterial stiffness as measured by aortic pulse wave velocity (aPWV) predicts cardiovascular events and mortality and is elevated in patients with COPD. Prior investigation suggests that a long-acting β-agonist (LABA)/inhaled corticosteroid (ICS) lowers aPWV in patients with baseline aPWV ≥ 11 m/s. This study compared the effect of the ICS/LABA fluticasone furoate/vilanterol (FF/VI), 100/25 μg, delivered via the ELLIPTA dry powder inhaler, with tiotropium bromide (TIO), 18 μg, on aPWV.nnnMETHODSnThis multicenter, randomized, blinded, double-dummy, parallel-group, 12-week study compared FF/VI and TIO, both administered once daily. The primary end point was aPWV change from baseline at 12 weeks. Safety end points included adverse events (AEs), vital signs, and clinical laboratory tests.nnnRESULTSnTwo hundred fifty-seven patients with COPD and aPWV ≥ 11 m/s were randomized; 87% had prior cardiovascular events and/or risk. The mean difference in aPWV between FF/VI and TIO at week 12 was not significant (P = .484). Because the study did not contain a placebo arm, a post hoc analysis was performed to show that both treatments lowered aPWV by an approximate difference of 1 m/s compared with baseline. The proportion of patients reporting AEs was similar with FF/VI (24%) and TIO (18%). There were no changes in clinical concern for vital signs or clinical laboratory tests.nnnCONCLUSIONSnNo differences on aPWV were observed between FF/VI and TIO. However, further studies with a placebo arm are required to establish definitively whether long-acting bronchodilators lower aPWV. Both treatments demonstrated an acceptable tolerability profile.nnnTRIAL REGISTRYnClinicalTrials.gov; No.: NCT01395888; URL: www.clinicaltrials.gov.

Inhaled β-agonist does not modify sympathetic activity in patients with COPD

BackgroundNeurohumoral activation is present in COPD and might provide a link between pulmonary and systemic effects, especially cardiovascular disease. Because long acting inhaled β-agonists reduce hyperinflation, they could reduce sympathoexcitation by improving the inflation reflex. We aimed to evaluate if inhaled therapy with salmeterol reduces muscle sympathetic nerve activity (MSNA) evaluated by microneurography.MethodsMSNA, heart rate, blood pressure, and respiration were continually measured. After baseline recording of 20xa0minutes, placebo was administered; after further 45xa0minutes salmeterol (50xa0μg) was administered which was followed by a further 45xa0minutes of data recording. Additionally, lung function, plasma catecholamine levels, arterial pulse wave velocity, heart rate variability, and baroreflex sensitivity were evaluated. Following 4xa0weeks of treatment with salmeterol 50xa0μg twice daily, measurements were repeated without placebo administration.ResultsA total of 32 COPD patients were included. Valid MSNA signals were obtained from 18 patients. Change in MSNA (bursts/100 heart beats) following acute administration of salmeterol did not differ significantly from the change following placebo (-1.96u2009±u20099.81 vs. -0.65u2009±u20099.07; pu2009=u20090.51) although hyperinflation was significantly reduced. Likewise, no changes in MSNA or catecholamines were observed after 4xa0weeks. Heart rate increased significantly by 3.8u2009±u20094.2 (pu2009<u20090.01) acutely and 3.9u2009±u20094.3xa0bpm (pu2009<u20090.01) after 4xa0weeks. Salmeterol treatment was safe and well tolerated.ConclusionsBy using microneurography as a gold standard to evaluate sympathetic activity we found no change in MSNA following salmeterol inhalation. Thus, despite an attenuation of hyperinflation, the long acting β-agonist salmeterol does not appear to reduce nor incite sympathoexcitation.Trial registrationThis study was registered with the European Clinical Trials Database (EudraCT No. 2011-001581-18) and ClinicalTrials.gov (NCT01536587).

Predictors of pneumonia on routine chest radiographs in patients with COPD: a post hoc analysis of two 1-year randomized controlled trials

Background Patients with COPD are at risk for life-threatening pneumonia. Although anatomical abnormalities in the thorax may predispose to pneumonia, those abnormalities identified on routine chest X-rays (CXRs) in patients with COPD have not been studied to better understand pneumonia risk. Methods We conducted a post hoc exploratory analysis of data from two replicate year-long clinical trials assessing the impact of fluticasone furoate–vilanterol versus vilanterol alone on COPD exacerbations (GSK studies: HZC102871/NCT01009463 and HZC102970/NCT01017952). Abnormalities on baseline CXRs from 179 patients who developed pneumonia and 50 randomly selected patients who did not were identified by blinded consensus readings conducted by two radiologists. Positive and negative likelihood ratios and diagnostic odds ratios (ORs) were calculated to evaluate the markers for subsequent pneumonia development during the 1-year study period. Results Baseline characteristics distinguishing the pneumonia and non-pneumonia groups included a lower body mass index (24.9 vs 27.5 kg/m2, P=0.008), more severe airflow obstruction (mean post-bronchodilator forced expiratory volume in 1 second [FEV1]/forced vital capacity ratio: 42.3% vs 47.6%, P=0.003), and prior pneumonia (36% vs 20%, P=0.030). Baseline CXR findings with the highest diagnostic ORs were: elevated hemi-diaphragm (OR: 6.87; 95% CI: 0.90, 52.26), thick tracheal-esophageal stripe (OR: 4.39 [0.25, 78.22]), narrow cardiac silhouette (OR: 2.91 [0.85, 9.99]), calcified pleural plaque/mid-chest pleural thickening (OR: 2.82 [0.15, 53.76]), and large/prominent pulmonary artery shadow (OR: 1.94 [0.95, 3.97]). The presence of a narrow cardiac silhouette at baseline was associated with a statistically significant lower mean pre-bronchodilator FEV1 (P=0.040). There was also a trend for a lower mean pre-bronchodilator FEV1 in patients with a large/prominent pulmonary artery shadow at baseline (P=0.095). Conclusion Findings on routine CXR that relate to pathophysiological mechanisms of pneumonia could help determine pneumonia risk in patients with COPD.

A randomized trial of once-daily fluticasone furoate/vilanterol or vilanterol versus placebo to determine effects on arterial stiffness in COPD

Introduction Chronic obstructive pulmonary disease (COPD) is associated with increased cardiovascular morbidity and mortality. Elevated arterial stiffness, measured by aortic pulse wave velocity (aPWV), is a cardiovascular risk surrogate and is potentially modifiable by inhaled corticosteroid/long-acting beta2-agonist combinations in patients with COPD. Materials and methods The effects of once-daily inhaled fluticasone furoate/vilanterol (FF/VI) 100/25 µg, VI 25 µg, versus placebo on arterial stiffness in patients with COPD and baseline aPWV ≥11.0 m/s were investigated in a 24-week, multicenter, double-blind, randomized, stratified (by COPD exacerbation history), parallel-group, placebo-controlled trial. Eligible patients were ≥40 years old, with ≥10 pack-year smoking history, forced expiratory volume in 1 s (FEV1)/forced vital capacity ≤0.70, and post-bronchodilator FEV1 ≤70% of predicted. Patients with a major cardiovascular event in the previous 6 months/current severe heart failure/uncontrolled hypertension were excluded. Primary endpoint is change from baseline in aPWV after 24 weeks of treatment. Safety analyses included adverse events (AEs). Results The intent-to-treat population included 430 patients: FF/VI (n=135), VI (n=154), and placebo (n=141). Patients were predominantly male (79%) and Asian or White (each 48%), with a mean age of 68.5 years (standard deviation [SD] =7.9), percentage predicted post-bronchodilator FEV1 50.1% (SD =13.3), and aPWV 13.26 m/s (SD =2.22) at screening. At 24 weeks, mean (standard error [SE]) changes from baseline in aPWV were −1.75 m/s (SE =0.26, FF/VI), −1.95 m/s (SE =0.24, VI), and −1.97 m/s (SE =0.28, placebo). AEs occurred in 57% (FF/VI), 51% (VI), and 41% (placebo) of patients. Conclusion No differences were observed in aPWV-adjusted mean change from baseline for FF/VI 100/25 µg, compared with placebo.