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Long-acting bronchodilators and arterial stiffness in patients with COPD
D.B. Rubin(1), J.-L. Pepin(2), J.R. Cockcroft(3), D. Midwinter(4), S. Sharma(1), S. Andreas(5)
(1)GlaxoSmithKline - Research Triangle Park/US; (2)Joseph Fourier University and Grenoble University Hospital - Grenoble/FR; (3)Wales Heart Research Institute - Cardiff/UK; (4)GlaxoSmithKline - Stockley Park/UK; (5)Georg-August-Universitat Gottingen - Gottingen/DE
Increased arterial stiffness as measured by aortic pulse wave velocity (aPWV) independently predicts cardiovascular (CV) events and mortality(1) and is elevated in COPD patients.(2)
A post-hoc analysis of a clinical trial with Advair/Seretide (250/50mcg) suggested that a long-acting beta agonist/inhaled corticosteroid (LABA/ICS) lowers aPWV in patients with baseline aPWV values >11 meters per second (m/s)(3) (Figure 1). These results prompted the current investigation.
As LABA/ICS and tiotropium (TIO) may have a different impact on CV events, the purpose of this study was to compare the effect of fluticasone furoate/vilanterol (FF/VI) with TIO on aPWV.
This multicenter, randomized, double-blind, double-dummy, parallel group study compared FF/VI 100/25mcg and TIO 18mcg both once daily over 12 weeks.
aPWV was measured by sequentially recording ECG-gated carotid and femoral artery waveforms.
The primary endpoint was aPWV change from baseline at 12 weeks. Other endpoints included trough FEV1 and St. George Respiratory Questionnaire for COPD (SGRQ-C). Primary analysis was intent-to-treat (ITT).
Table 1. Screening/baseline characteristics (ITT)*
| N=257 | ||
| Demographics | ||
| Age, years | 67.3 (7.28) | |
| Female sex, % | 14 | |
| White race, % | 100 | |
| Smoking history | ||
| Smoking pack years | 43.6 (22.55) | |
| Current smokers at screening, % | 46 | |
| Cardiovascular history/risk factors, % | 87 | |
| aPWV at screening (m/s) | 12.91 (1.902) | |
| Augmentation index at screening (%) | 26.3 (10.76) | |
| Lung function at screening | ||
| Pre-bronchodilator FEV 1 (L) | 1.271 (0.4559) | |
| Percent predicted post-bronchodilator FEV 1 (%) | 46.5 (14.15) | |
| Percent reversibility in FEV 1 (%) | 8.5 (12.56) | |
| Post-bronchodilator FEV 1 /FVC (%) | 51.3 (11.13) | |
| Proportion reversible (%) | 16 | |
| Inspiratory capacity at baseline (L) | 2.123 (0.6499) |
Data are mean (SD) and from the baseline visit unless otherwise stated
*There were no differences in characteristics between patients randomized to FF/VI vs TIO
Table 2. Change from baseline in FEV1 (L) (ITT)
| Trough FEV 1 (L) at Day 84 | FF/VI 100/25 N=127 | TIO N=130 | ||
| n[1] | 117 | 122 | ||
| n[2] | 112 | 112 | ||
| LS mean | 1.406 | 1.368 | ||
| LS mean change (SE for mean/mean change) | 0.117 (0.0221) | 0.080 (0.0219) | ||
| FF/VI versus TIO Difference (95% CI) P-value | 0.037 (-0.024, 0.099) 0.232 |
n[1] = number of subjects with analyzable data for one or more time points
n[2] = number of subjects with analyzable data at the given time point
Table 3. Change in SGRQ (ITT)
| SGRQ* | FF/VI 100/25 N=127 | TIO N=130 | ||
| Total, n[1] : n[2] Mean baseline (SD) Mean change from baseline (SD) | 123 : 106 50.36 (18.582) 6.03 (13.235) | 128 : 108 47.97 (18.150) 4.97 (11.503) | ||
| Symptoms Domain, n[1] : n[2] Mean baseline (SD) Mean change from baseline (SD) | 126 : 108 66.79 (21.338) 8.57 (17.983) | 130 : 112 64.12 (19.204) 5.09 (17.303) | ||
| Activity Domain, n[1] : n[2] Mean baseline (SD) Mean change from baseline (SD) | 125 : 108 59.99 (20.063) 4.72 (16.412) | 129 : 109 58.75 (19.715) 3.43 (14.631) | ||
| Impacts Domain, n[1] : n[2] Mean baseline (SD) Mean change from baseline (SD) | 126 : 110 39.33 (20.443) 5.84 (14.481) | 129 : 111 36.90 (20.171) 5.70 (12.863) |
n[1] = number of subjects with baseline data
n[2] = number of subjects with Day 84 and baseline data
*SGRQ scores derived from SGRQ-C questionnaire
Post-hoc analysis indicates both FF/VI and TIO lower aPWV ~1m/s, a MCID, without an impact on MAP.
Responders (>1m/s) did not reveal distinguishing characteristics.
Mean arterial pressure (MAP) was unchanged over the trial and including the MAP in the statistical model did not change the magnitude of the treatment effect.
There was an inconsistent treatment difference for current smokers compared with former smokers over time
at Days 56 and 84, the treatment difference numerically favored FF/VI for former smokers, whereas the reverse was true for current smokers
at Day 28 there was no apparent difference between groups for current smokers.
FF/VI and TIO have similar impact on reduction of aPWV.
The COPD phenotype selected by the inclusion criterion of a aPWV >11m/s is associated with a history and/or risk of cardiovascular disease.
HYPOTHESIS: We speculate that bronchodilators lower aortic stiffness by improving the inflation reflex that lowers vascular sympathetic tone.(4) Further studies exploring this mechanism are warranted.
(1) Eur Heart J 2006;27:2588.
(2) Am J Respir Crit Care Med 2007;176:1208.
(3) Resp Med 2011;105:1322.
(4) Chest 2005;128:3618.
The presenting author, David Rubin, is employed by and holds stock in GlaxoSmithKline.
Funded by GlaxoSmithKline (HZC115247, NCT013958888).
Editorial support (in the form of assembling tables) was provided by David Cutler, PhD at Gardiner-Caldwell Communications (Macclesfield, UK) and was funded by GlaxoSmithKline.
Presented at the American Thoracic Society Annual Congress, Philadelphia, PA, USA, 17 22 May 2013