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Original Research: COPD |

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

Jean-Louis Pepin, MD, PhD; John R. Cockcroft, MD; Dawn Midwinter, MSc; Sanjay Sharma, BSc; David B. Rubin, MD; Stefan Andreas, MD
Author and Funding Information

From University Grenoble Alpes (Prof Pepin) and Grenoble University Hospital (Prof Pepin), Grenoble, France; Wales Heart Research Institute (Dr Cockcroft), Cardiff University, Cardiff, Wales; GlaxoSmithKline (Ms Midwinter), Stockley Park, England; GlaxoSmithKline (Mr Sharma and Dr Rubin), Research Triangle Park, Durham, NC; and Georg-August-Universitat Göttingen (Dr Andreas), Göttingen, Germany.

CORRESPONDENCE TO: Stefan Andreas, MD, Lungenfachklinik, Immenhausen, Krs. Kassel, Robert-Koch-Straße 3, 34376 Immenhausen, Universitätsmedizin Göttingen, Göttingen, Germany; e-mail: stefan.andreas@med.uni-goettingen.de


FUNDING/SUPPORT: This study was funded by GlaxoSmithKline.

This is an open access article distributed under the terms of the Creative Commons Attribution-Noncommercial License (http://creativecommons.org/licenses/by-nc/3.0/), which permits unrestricted use, distribution, and reproduction to noncommercial entities, provided the original work is properly cited. Information for reuse by commercial entities is available online.


Chest. 2014;146(6):1521-1530. doi:10.1378/chest.13-2859
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BACKGROUND:  Increased 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.

METHODS:  This 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.

RESULTS:  Two 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.

CONCLUSIONS:  No 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.

TRIAL REGISTRY:  ClinicalTrials.gov; No.: NCT01395888; URL: www.clinicaltrials.gov.

Figures in this Article

Patients with COPD are at increased risk of death and disability from extrapulmonary complications.13 In patients with COPD, cardiovascular diseases (CVDs) are the most common comorbidities3 and one of the leading causes of hospitalization and death4; COPD and CVDs complicate the prognosis of each other.5 In patients with cardiovascular risk, identifying cardiovascular changes before the occurrence of major clinical events is critical. For this purpose, several markers of subclinical CVD have been validated.

Among the markers of cardiovascular risk, arterial stiffness has a predictive value for cardiovascular events beyond traditional clinical cardiovascular risk factors6 and is suited for use in clinical practice. In COPD, arterial stiffness is independently associated with severity of emphysema7 and airflow obstruction8 and is elevated compared with healthy patients matched for age, BMI, and smoking history. Inflammation, oxidative stress, and high sympathetic tone, linked to the severity of airway obstruction, are suspected mechanisms by which COPD leads to the development of increased arterial stiffness and cardiovascular events.9,10

Early results from interventions that may reduce arterial stiffness in patients with COPD have been reviewed recently11 and a post hoc analysis of a randomized clinical trial with salmeterol/fluticasone propionate11,12 suggested that a long-acting β-agonist (LABA)/inhaled corticosteroid (ICS) lowers aortic pulse wave velocity (aPWV) in patients with baseline aPWV ≥ 11 m/s. Different classes of inhaled bronchodilators may impact cardiovascular events in patients with COPD,13,14 and their safety as related to cardiovascular mortality is a topic of some discussion.15 Assessing the impact of different inhaled bronchodilators on arterial stiffness may help increase understanding of cardiovascular benefit/risk. We hypothesized that although different classes of bronchodilators may induce decreases in arterial stiffness in patients with elevated baseline values, this decrease would be larger in subjects randomized to fluticasone furoate/vilanterol (FF/VI). Therefore, we compared the effects of a LABA/ICS, FF/VI delivered via the ELLIPTA dry powder inhaler, and tiotropium bromide (TIO) on arterial stiffness over 12 weeks.

Study Design

The primary objective was to evaluate the effect of treatment with once-daily FF/VI, 100/25 μg, compared with once-daily TIO, 18 μg, on arterial stiffness measured as aPWV in patients with COPD and aPWV ≥ 11.0 m/s. This was a phase 3b comparator, blinded, double-dummy, randomized, parallel-group, multicenter study conducted at 46 centers in seven countries. Further details of the blinding procedure are provided in e-Appendix 1.

At screening, male or nonpregnant female patients aged ≥ 40 years with a history of COPD, a current or prior history of ≥ 10 pack-years of cigarette smoking, a post-albuterol/salbutamol FEV1 ≤ 70% of predicted normal, a FEV1/FVC ratio ≤ 0.70, and a measured aPWV ≥ 11.0 m/s were eligible. Exclusion criteria and details of concomitant medications are presented in e-Appendix 2.

After a 2-week, single-blind, placebo run-in period, during which COPD stability and protocol compliance were assessed, eligible patients were randomized (1:1) to treatment with FF/VI, 100/25 μg (via ELLIPTA device; GlaxoSmithKline), or TIO, 18 μg (via HandiHaler device; Boehringer Ingelheim GmbH), for 12 weeks. Salbutamol/albuterol was provided to use as needed throughout the run-in and treatment periods. A follow-up phone call was made approximately 7 days after the final clinic visit.

At baseline, hemodynamic parameters, including aPWV, peripheral and central pulse pressure, and augmentation index (AIx), were recorded. Carotid-femoral aPWV was measured using tonometers positioned transcutaneously at the base of the common carotid artery and over the femoral artery by using the SphygmoCor CPV system (AtCor Medical Inc). Peripheral pulse pressure, defined as the difference between peripheral systolic BP and diastolic BP, was measured using a sphygmomanometer on the upper arm. Central (aortic) pulse pressure (measured using the SphygmoCor CPV system) is different from the pulse pressure in distributing arteries because of reflective waves from vessel branching and from decreased arterial compliance, which leads to characteristic changes in the systolic, diastolic, and mean pressures. AIx was derived from measures of the pulse waves at the carotid and radial arteries and represents the time of pressure wave reflection in relation to left-ventricular systolic pressure. It is defined as the difference between the second and first systolic peaks and was measured using the SphygmoCor CPV system.

Efficacy Assessments

Carotid-femoral aPWV was measured at screening and on days 28, 56, and 84. Other efficacy end points included change from baseline in trough FEV1 and trough inspiratory capacity (prebronchodilator and predose) at the end of the treatment period (day 84). Additionally, central pulse pressure and AIx were evaluated by the SphygmoCor CPV system. All hemodynamic and vital sign measurements were performed between 6:00 am and 10:00 am. Health outcome assessments were conducted on days 1 and 84 (e-Appendix 3).

Safety Assessments

Safety end points were the proportion of patients reporting adverse events (AEs) and serious AEs (SAEs), including pneumonia. Vital signs (BP and pulse rate) were recorded at all study visits, including the prescreening visit if aPWV was also obtained. Clinical laboratory tests were performed at screening and at baseline (predose on day 1) and included liver function tests that were also performed on day 84. Abnormal oropharyngeal examinations were reported as AEs, and COPD exacerbation information was recorded at each clinic visit.

Statistical Methods

Data from a prior study1 indicated that a reasonable estimate of SD of mean change from baseline in aPWV was 2.2 m/s. One hundred two patients per treatment group were estimated to provide 90% power to detect a treatment difference of 1 m/s in change from baseline in aPWV after 12 weeks at a significance level of .05, based on a two-sample, two-sided t test. Two hundred forty-eight patients were planned, and no multiplicity adjustments were required.

All efficacy and safety end points were summarized using the intent-to-treat (ITT) population (patients randomized and treated with at least one dose of drug) unless otherwise stated. The primary analysis was performed using mixed-model repeated-measures (MMRMs) analysis of covariance with terms for visit, treatment, age, sex, smoking status at screening, geographical region, baseline aPWV, and interaction terms of baseline by visit and treatment by visit. The per-protocol population (patients in the ITT population not identified as major protocol deviations) was used to confirm the primary end point analysis only. A sensitivity analysis tested the interaction of covariates with treatment. If an interaction was observed, further investigation was conducted by fitting a treatment-by-covariate-by-day interaction term to the model to evaluate whether there was an inconsistent treatment response on day 84.

A post hoc analysis of aPWV compared with baseline values was also conducted, using the last observation carried forward (LOCF) aPWV values for each patient; LOCF was considered an appropriate model for this exploratory analysis and was considered to be more powerful than an analysis of completers only (ie, patients with available results at week 12). This was analyzed separately for each treatment group using MMRM with the response variable of aPWV and the repeated explanatory variable of visit (baseline and LOCF visit only).

This study was conducted in accordance with the International Conference of Harmonisation: Guidance for Good Clinical Practice,16 the Declaration of Helsinki 2008,17 and all applicable subject privacy requirements; approvals from Institutional Review Boards are presented in e-Table 1. Written informed consent was obtained from each patient prior to the performance of any study-specific procedures.

Patient Disposition

The most common reason for failing screening was aPWV < 11 m/s. Two hundred sixty patients were randomized; three patients were determined not to meet the entry criteria prior to dispensing of the study drug. Accordingly, 257 patients were included in the ITT population (Fig 1). The most common reason for withdrawal was AEs. Use of concomitant medication was stable throughout the course of the study.

Figure Jump LinkFigure 1 –  Subject disposition for this study. See Results section for further detail. FF/VI = fluticasone furoate/vilanterol; TIO = tiotropium bromide.Grahic Jump Location

Demographics and baseline characteristics were comparable between the two treatment groups (Tables 1, 2, e-Table 2). In this population with moderate to severe airflow obstruction, the mean aPWV at screening was 12.91 m/s, and 87% had cardiovascular history/risk. All patients were white and mostly men, who tended to be overweight and mildly hypertensive.

Table Graphic Jump Location
TABLE 1 ]  Baseline Demographics and Pulmonary Characteristics (ITT Population)

Data are presented as mean (SD) unless indicated otherwise. ACE = angiotensin-converting enzyme inhibitor; FF/VI = fluticasone furoate/vilanterol; ITT = intent-to-treat; TIO = tiotropium bromide.

a 

Assessed at screening visit, prior to 2-wk fluticasone propionate/salmeterol run-in period.

b 

Assessed at baseline visit, following 2-wk fluticasone propionate/salmeterol run-in period and prior to first dose of study drug.

c 

Medication classes were selected because they reflect cardiovascular risk and/or disease and, with the exception of anticoagulants, have been shown to modify arterial stiffness.

Table Graphic Jump Location
TABLE 2 ]  Baseline Hemodynamic Indexes, Cardiovascular History, and Risk History (ITT Population)

Data are presented as mean (SD) unless indicated otherwise. aPWV = aortic pulse wave velocity. See Table 1 legend for expansion of other abbreviations.

a 

Assessed at screening visit, prior to 2-wk fluticasone propionate/salmeterol run-in period.

Efficacy

During the treatment period, mean changes from baseline in aPWV were similar between treatment groups (Fig 2). At day 84, the adjusted mean change from baseline was −0.859 m/s with FF/VI and −1.118 m/s with TIO, with an FF/VI vs TIO treatment difference of 0.259 m/s, which was not statistically significant. Results were similar for the per-protocol population (data not shown).

Figure Jump LinkFigure 2 –  LS mean change from baseline in aortic pulse wave velocity (aPWV) (m/s) (intent-to-treat population). Analysis was performed using a repeated-measures model with covariates of treatment, visit, age, sex, smoking status at screening, geographical region, baseline aPWV, and interaction terms of baseline by visit and treatment by visit. LS = least squares. See Figure 1 legend for expansion of other abbreviations.Grahic Jump Location

The interaction of treatment with smoking status at screening and baseline systolic BP were significant at the 10% level (P = .029 and P = .046, respectively); interactions with sex, center grouping, and age were nonsignificant. There was no differential treatment response on day 84 by baseline systolic BP, and no evidence of a consistent response for smoking status at screening. The numerical treatment difference was in favor of TIO in current smokers and favored FF/VI in former smokers. This numerical difference was also observed at day 56, but not day 28. There were no statistically significant differences in the change of hemodynamic variables between study arms or in the changes over time (e-Table 3).

Adjusted mean changes from baseline in trough FEV1 ranged from 0.093 to 0.117 L with FF/VI and from 0.032 to 0.084 L with TIO over the course of treatment, with the greatest improvements in both treatment groups at day 84 (Table 3). Differences in adjusted mean changes from baseline in trough FEV1 and trough inspiratory capacity between FF/VI and TIO groups at day 84 were small (0.037 L and 0.070 L, respectively). FVC data are presented in e-Table 4. The assessment of health outcome results demonstrated no statistically significant differences between FF/VI and TIO group (e-Table 5).

Table Graphic Jump Location
TABLE 3 ]  Pulmonary Function at End of Trial (Day 84) (ITT Population)

Analysis performed using a repeated-measures model with covariates of treatment, age, sex, smoking status, geographical region, baseline aPWV, FEV1, or inspiratory capacity (as applicable), and interaction terms of baseline by visit and treatment by visit. LS = least squares. See Table 1 and 2 legends for expansion of other abbreviations.

a 

No. patients with analyzable data for one or more time points.

b 

No. patients with analyzable data at day 84.

Safety

The proportion of patients who reported on-treatment AEs (e-Table 6) was similar with FF/VI (n = 31 [24%]; treatment-related, n = 4 [3%]) and TIO (n = 34 [26%]; treatment-related, n = 7, [5%]). Fifteen patients (5%) withdrew because of AEs (run-in, n = 1; FF/VI, n = 8; TIO, n = 6). The most frequently reported AEs (≥ 3% in either treatment group) were COPD worsening/exacerbation, nasopharyngitis, and headache (Table 4); supraventricular extrasystoles (FF/VI, n = 1; TIO, n = 3) and headache (FF/VI, n = 1; TIO, n = 1) were the only treatment-related AEs reported by more than one patient. On-treatment SAEs were reported by seven patients (6%) with FF/VI and by eight patients (6%) with TIO; one was considered to be treatment-related (TIO: COPD exacerbation) and two were fatal but were not considered to be treatment-related (both TIO: one pulmonary embolism after abcessectomy and one car accident). AEs of special interest included pneumonia reported as an SAE (FF/VI: on-treatment, n = 2; posttreatment, n = 1), cardiovascular events (FF/VI, n = 3; TIO, n = 4) and local steroid effects (FF/VI, n = 3); additionally, hand fracture (n = 1), bronchitis (n = 1), and cataract (n = 1) were reported by patients in the FF/VI group only. There were no statistically significant changes in vital signs. Few patients in either treatment group (n ≤ 4 [3%]) had changes from baseline to any postbaseline visit that were outside the normal range for any liver chemistry parameter; none of the changes was of clinical concern.

Table Graphic Jump Location
TABLE 4 ]  Summary of Most Frequent On-Treatment Adverse Events (ITT Population)

Data are presented as No. (%). See Table 1 legend for expansion of abbreviations.

a 

In each treatment group.

Post Hoc Analysis

Because raw mean values of aPWV fell by approximately 1 m/s from baseline in both treatment groups (Fig 3), post hoc analyses that compared LOCF values with baseline values were conducted. Both treatments lowered aPWV compared with baseline to a level approximating a meaningful clinical difference of 1 m/s (FF/VI: −0.9 m/s, P = .0024; TIO: −1.1 m/s, P = .0006). To determine whether patient characteristics related to aPWV responsiveness to bronchodilators, a responder analysis was conducted.

Figure Jump LinkFigure 3 –  Raw mean change from baseline in aortic pulse wave velocity (m/s) (intent-to-treat population). A post hoc analysis was performed using a mixed model repeated-measures for each treatment group separately. Raw mean changes from baseline data are presented graphically; however, the analysis showed that the adjusted mean difference from the last observation carried forward visit to the baseline visit for FF/VI was −0.9 m/s (P = .0024) and for TIO was −1.1 m/s (P = .0006). See Figure 1 and 2 legends for expansion of abbreviations.Grahic Jump Location

The following screening and/or baseline characteristics were explored for responders (≥ 1 m/s reduction of aPWV from baseline) as compared with nonresponders (< 1 m/s reduction from baseline or missing): (1) lung function, (2) central and peripheral pressure measures, (3) aPWV, (4) cardiovascular risk/history, and (5) concomitant medications. No characteristics of responders were identified except for a slightly better pulmonary function in the responders (e-Table 7).

The change from baseline in aPWV was significantly correlated to the change from baseline for both central mean arterial pressure (MAP) (Pearson correlation coefficient: 0.26613, P = .0002) and peripheral MAP (Pearson correlation coefficient: 0.22751, P = .0010) (e-Table 8); however, the change from baseline central and peripheral MAP contributed to only 7% and 5%, respectively, of aPWV variability. The results from the analysis of covariance, adjusting for post baseline MAP at each visit, do not impact the conclusions drawn from the primary MMRM analysis (e-Table 9).

No statistically significant treatment difference between FF/VI and TIO was observed for the primary end point of aPWV. Our study included patients with an elevated arterial stiffness (aPWV ≥ 11 m/s); thus, it was not surprising that 87% of patients reported cardiovascular history/risk. Given the strong, independent association of arterial stiffness with CVD,7 and because CVDs are common and the most important comorbidities in COPD,18,19 it is important that our post hoc analysis suggesting effects of inhaled COPD therapy on aPWV be confirmed by further randomized controlled trials that include a placebo arm.

Arterial stiffness is a sign of early cardiovascular damage and predisposes damage of other organs such as the heart, brain, and kidneys.7,20,21 Noninvasive measurement of carotid-femoral pulse wave velocity is a surrogate for aPWV and is the “gold standard” for assessment of arterial stiffness.7,20 In a previous meta-analysis,21 aPWV was a strong predictor of future cardiovascular events and all-cause mortality. The elevation of aPWV in COPD8,9 relates to emphysema severity independent of smoking, age, sex, FEV1% predicted, and other cardiovascular risk factors.7 In a large study, an independent correlation between lung function and arterial stiffness was present,22 and in a multiethnic study of > 3,500 patients, small- and large-artery elasticity were associated with FVC and FEV1 measured 5 years later.23 Furthermore, the SphygmoCor system, as used in this study, has excellent reproducibility24 and has been used in a number of large studies, including the Anglo Cardiff Collaborative Study (ACCT)25 and the Chronic Renal Insufficiency Cohort (CRIC).26

Clinical trials suggest that bronchodilator therapy may reduce mortality and cardiovascular events,4 and one of the mechanisms that may influence this is lowering arterial stiffness. Treatment with fluticasone propionate/salmeterol, 250/50 μg bid, over 12 weeks decreased aPWV by 0.42 m/s, but this was not significant compared with placebo.12 However, in a post hoc analysis, the effect was statistically significant in patients with high baseline aPWV; accordingly, the current study targeted this population.

Tobacco consumption,27,28 BP, and antihypertensive medications20,29 are the main determinants of aPWV. In our study, BP did not change and correction for central artery pressure did not impact the findings. Furthermore, smoking prevalence and medications were stable during the study. Thus, our results are not explained by changes in smoking prevalence, BP, or cardiovascular medications. A large body of epidemiologic evidence demonstrates that an increase of aPWV of approximately 1 m/s will occur in a decade of life,30 increasing cardiovascular mortality by approximately 15%.21 Despite this, we cannot be certain that a reduction in aPWV of 1 m/s would be clinically meaningful because there are no available outcome studies specific to COPD. However, preliminary data from the Assessment of Risk in Chronic Airways Disease Evaluation (ARCADE) study has shown an increase in aPWV of 0.7 m/s over 2 years in patients with COPD relative to matched control subjects who showed no increase over the same period.31 Such an increase would be expected to increase the frequency of cardiovascular events, suggesting that, if sustained, a reduction of 1 m/s would be clinically relevant. Data from the ongoing Study to Understand Mortality and Morbidity in COPD (SUMMIT), assessing mortality and morbidity in COPD,32 in which aPWV is being measured with the SphygmoCor system, in a subset of subjects, may provide evidence of clinical usefulness.

Although, mechanistically, stroke volume may influence aPWV, heart rate and, most importantly, path-length measurement, are the major sources of error.33 There were no significant differences in heart rate, and we used the subtraction method, which has been validated invasively, to measure path length.34 Although we did not measure cardiac output, a change in cardiac output substantial enough to produce a decrease in aPWV of 1 m/s is highly unlikely.

Another driver of arterial stiffness in COPD that is thought to increase smooth muscle tone is neurohumoral activation,35,36 which enhances the inflammatory response and is probably linked to the systemic disease related to COPD.4,37,38 We speculate that bronchodilators could lower arterial stiffness by improving the inflation reflex3739 or hypoxemia37 that can drive neurohumoral activation in patients with COPD; however, we did not measure inflammatory biomarkers in this study. The safety profiles of FF/VI and TIO were similar, and there was no indication that FF/VI was related to a higher frequency of AEs, although this was only a 12-week study. Cardiovascular events have been associated with the administration of LABAs, such as VI, and with long-acting muscarinic antagonists, such as TIO; in this study, the frequency of cardiovascular events was low (≤ 3% in either treatment group), which is noteworthy because of the high frequency of CVD comorbidities reported by patients.

As expected for ICS-containing therapies, local steroid effects were reported only by patients in the FF/VI group. Only one SAE (COPD exacerbation) was considered to be related to TIO treatment, and no fatalities were considered to be treatment related. The three cases of pneumonia reported as SAEs with FF/VI (two on-treatment; one posttreatment) were not considered to be treatment related; however, previous observations have shown that ICS use can increase the risk of pneumonia in patients with COPD.40,41 There were no changes in clinical concern related to vital signs or clinical laboratory measurements in either treatment group.

Strength and Limitations

To the best of our knowledge, this is the largest randomized clinical controlled trial to date in patients with COPD and elevated aPWV specifically comparing the effects on arterial stiffness of two inhaled therapies that have different modes of action for altering airway tone. A potential limitation is that our study cannot prove the causality of associations that we describe. Furthermore, because we included patients with aPWV above a certain threshold, regression to the mean may explain the observed decrease in aPWV; the inclusion of a placebo arm would have allowed us to reduce or eliminate this effect. Further studies should prospectively investigate the impact of bronchodilators on aPWV.

No statistically significant differences in aPWV were observed between FF/VI and TIO. However, the results from the post hoc analysis suggest that long-acting bronchodilators may lower aPWV in patients with COPD and baseline elevated values. If replicated in a placebo-controlled study, our results may be of importance when considering ways to improve the increased cardiovascular morbidity and mortality of patients with COPD. Overall, both FF/VI and TIO were well tolerated in this 12-week study.

Author contributions: S. A. is the guarantor of the content of this manuscript, had full access to all the data in the study, and takes responsibility for the integrity of the data and the accuracy of the data analysis. D. M., S. S., D. B. R., and S. A. contributed to the study conception and design; J.-L. P., D. M., S. S., D. B. R., and S. A. contributed to the acquisition of the data; and J.-L. P., J. R. C., D. M., S. S., D. B. R., and S. A. contributed to the data analysis/interpretation, critical review of the manuscript, and approval of the final version to be published.

Financial/nonfinancial disclosures: The authors have reported to CHEST the following conflicts of interest: Dr Pepin has received investigator support from GlaxoSmithKline for this study. Prof Cockcroft has received grant support from GlaxoSmithKline for the Assessment of Risk in Chronic Airways Disease Evaluation (ARCADE) study, is on the steering committee of the GlaxoSmithKline-funded Airflow Limitation and Cardiovascular disease in Europe (ALICE) study, and has received honoraria for serving on GlaxoSmithKline advisory boards. Ms Midwinter, Mr Sharma, and Dr Rubin are employees of and hold stock in GlaxoSmithKline. Dr Andreas received support from GlaxoSmithKline to conduct this study and also received a recent grant for a clinical COPD study, as well as fees for serving on advisory boards from GlaxoSmithKline, Pfizer Inc, and Almirall, and fees for lectures from GlaxoSmithKline, Almirall, Boehringer-Ingelheim, Novartis, Nycomed, and Pfizer Inc. ELLIPTA is a trademark of the GlaxoSmithKline group of companies.

Role of sponsors: Employees of the sponsor GlaxoSmithKline (D. M., S. S., D. R.) were involved in the conception and design of the study, acquisition of data and analysis and interpretation of data, and developed the manuscript. The sponsor did not place any restriction on authors about the statements made in the final article. Editorial support (in the form of development of the final draft in consultation with the authors, collating author comments, assembly of tables and figures, copyediting, fact checking, referencing, and graphic services) was provided by Laura Maguire, MChem, Gardiner-Caldwell Communications, an Ashfield company (Macclesfield, England) and was funded by GlaxoSmithKline. The fee for open access was paid by GlaxoSmithKline.

Other contributions: The authors would like to acknowledge Farshid Hamayoun-Valiani, PhD, from GlaxoSmithKline for her contribution to the study.

Additional information: The e-Appendixes and e-Tables can be found in the Supplemental Materials section of the online article.

AE

adverse event

AIx

augmentation index

aPWV

aortic pulse wave velocity

CVD

cardiovascular disease

FF/VI

fluticasone furoate/vilanterol

ICS

inhaled corticosteroid

ITT

intent-to-treat

LABA

long-acting β-agonist

LOCF

last observation carried forward

MAP

mean arterial pressure

MMRM

mixed-model repeated-measure

SAE

serious adverse event

TIO

tiotropium bromide

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ICH tripartite guideline: guidance for good clinical practice E6 (R1). International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use website. http://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Efficacy/E6_R1/Step4/E6_R1__Guideline.pdf. Accessed July 24, 2014.
 
WMA declaration of Helsinki—ethical principles for medical research involving human subjects.. World Medical Association, Inc website. http://www.wma.net/en/30publications/10policies/b3/index.html. Updated October 2008. Accessed July 24, 2014.
 
Sin DD, MacNee W. Chronic obstructive pulmonary disease and cardiovascular diseases: a “vulnerable” relationship. Am J Respir Crit Care Med. 2013;187(1):2-4. [CrossRef] [PubMed]
 
Rutten FH, Hoes AW. Chronic obstructive pulmonary disease: a slowly progressive cardiovascular disease masked by its pulmonary effects? Eur J Heart Fail. 2012;14(4):348-350. [CrossRef] [PubMed]
 
Laurent S, Cockcroft J, Van Bortel L, et al; European Network for Non-invasive Investigation of Large Arteries. Expert consensus document on arterial stiffness: methodological issues and clinical applications. Eur Heart J. 2006;27(21):2588-2605. [CrossRef] [PubMed]
 
Ben-Shlomo Y, Spears M, Boustred C, et al. Aortic pulse wave velocity improves cardiovascular event prediction: an individual participant meta-analysis of prospective observational data from 17,635 subjects. J Am Coll Cardiol. 2014;63(7):636-646. [CrossRef] [PubMed]
 
Brunner EJ, Shipley MJ, Witte DR, et al. Arterial stiffness, physical function, and functional limitation: the Whitehall II Study. Hypertension. 2011;57(5):1003-1009. [CrossRef] [PubMed]
 
Duprez DA, Hearst MO, Lutsey PL, et al. Associations among lung function, arterial elasticity, and circulating endothelial and inflammation markers: the multiethnic study of atherosclerosis. Hypertension. 2013;61(2):542-548. [CrossRef] [PubMed]
 
Wimmer NJ, Townsend RR, Joffe MM, Lash JP, Go AS; Chronic Renal Insufficiency Cohort Study Investigators. Correlation between pulse wave velocity and other measures of arterial stiffness in chronic kidney disease. Clin Nephrol. 2007;68(3):133-143. [PubMed]
 
McEniery CM, Yasmin, Hall IR, Qasem A, Wilkinson IB, Cockcroft JR; ACCT Investigators. Normal vascular aging: differential effects on wave reflection and aortic pulse wave velocity: the Anglo-Cardiff Collaborative Trial (ACCT). J Am Coll Cardiol. 2005;46(9):1753-1760. [CrossRef] [PubMed]
 
Townsend RR, Wimmer NJ, Chirinos JA, et al. Aortic PWV in chronic kidney disease: a CRIC ancillary study. Am J Hypertens. 2010;23(3):282-289. [CrossRef] [PubMed]
 
Mahmud A, Feely J. Effect of smoking on arterial stiffness and pulse pressure amplification. Hypertension. 2003;41(1):183-187. [CrossRef] [PubMed]
 
Doonan RJ, Hausvater A, Scallan C, Mikhailidis DP, Pilote L, Daskalopoulou SS. The effect of smoking on arterial stiffness. Hypertens Res. 2010;33(5):398-410. [CrossRef] [PubMed]
 
Maclay JD, McAllister DA, Rabinovich R, et al. Systemic elastin degradation in chronic obstructive pulmonary disease. Thorax. 2012;67(7):606-612. [CrossRef] [PubMed]
 
Reference Values for Arterial Stiffness’ Collaboration. Determinants of pulse wave velocity in healthy people and in the presence of cardiovascular risk factors: ‘establishing normal and reference values’. Eur Heart J. 2010;31(19):2338-2350. [CrossRef] [PubMed]
 
Albarrati AM, Gale NS, Munnery MM, et al. Rapid progression of central arterial stiffness in COPD: preliminary 2 year follow-up data from the ARCADE study. J Am Soc Hypertens. 2014;8(4):e4-e5. [CrossRef]
 
Vestbo J, Anderson J, Brook RD, et al. The Study to Understand Mortality and Morbidity in COPD (SUMMIT) study protocol. Eur Respir J. 2013;41(5):1017-1022. [CrossRef] [PubMed]
 
Wilkinson IB, McEniery CM, Schillaci G, et al. ARTERY Society guidelines for validation of non-invasive haemodynamic measurement devices: part 1, arterial pulse wave velocity. Artery Res. 2010;4(2):34-40. [CrossRef]
 
Weber T, Ammer M, Rammer M, et al. Noninvasive determination of carotid-femoral pulse wave velocity depends critically on assessment of travel distance: a comparison with invasive measurement. J Hypertens. 2009;27(8):1624-1630. [CrossRef] [PubMed]
 
Dinenno FA, Jones PP, Seals DR, Tanaka H. Age-associated arterial wall thickening is related to elevations in sympathetic activity in healthy humans. Am J Physiol Heart Circ Physiol. 2000;278(4):H1205-H1210. [PubMed]
 
Swierblewska E, Hering D, Kara T, et al. An independent relationship between muscle sympathetic nerve activity and pulse wave velocity in normal humans. J Hypertens. 2010;28(5):979-984. [CrossRef] [PubMed]
 
Andreas S, Anker SD, Scanlon PD, Somers VK. Neurohumoral activation as a link to systemic manifestations of chronic lung disease. Chest. 2005;128(5):3618-3624. [CrossRef] [PubMed]
 
Fatouleh R, Macefield VG. Respiratory modulation of muscle sympathetic nerve activity is not increased in essential hypertension or chronic obstructive pulmonary disease. J Physiol. 2011;589(Pt 20):4997-5006. [PubMed]
 
Macklem PT. Therapeutic implications of the pathophysiology of COPD. Eur Respir J. 2010;35(3):676-680. [CrossRef] [PubMed]
 
Crim C, Calverley PM, Anderson JA, et al. Pneumonia risk in COPD patients receiving inhaled corticosteroids alone or in combination: TORCH study results. Eur Respir J. 2009;34(3):641-647. [CrossRef] [PubMed]
 
Global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease. GOLD website. http://www.goldcopd.org/uploads/users/files/GOLD_Report_2014_Jun11.pdf. Updated 2013. Accessed July 24, 2014.
 

Figures

Figure Jump LinkFigure 1 –  Subject disposition for this study. See Results section for further detail. FF/VI = fluticasone furoate/vilanterol; TIO = tiotropium bromide.Grahic Jump Location
Figure Jump LinkFigure 2 –  LS mean change from baseline in aortic pulse wave velocity (aPWV) (m/s) (intent-to-treat population). Analysis was performed using a repeated-measures model with covariates of treatment, visit, age, sex, smoking status at screening, geographical region, baseline aPWV, and interaction terms of baseline by visit and treatment by visit. LS = least squares. See Figure 1 legend for expansion of other abbreviations.Grahic Jump Location
Figure Jump LinkFigure 3 –  Raw mean change from baseline in aortic pulse wave velocity (m/s) (intent-to-treat population). A post hoc analysis was performed using a mixed model repeated-measures for each treatment group separately. Raw mean changes from baseline data are presented graphically; however, the analysis showed that the adjusted mean difference from the last observation carried forward visit to the baseline visit for FF/VI was −0.9 m/s (P = .0024) and for TIO was −1.1 m/s (P = .0006). See Figure 1 and 2 legends for expansion of abbreviations.Grahic Jump Location

Tables

Table Graphic Jump Location
TABLE 1 ]  Baseline Demographics and Pulmonary Characteristics (ITT Population)

Data are presented as mean (SD) unless indicated otherwise. ACE = angiotensin-converting enzyme inhibitor; FF/VI = fluticasone furoate/vilanterol; ITT = intent-to-treat; TIO = tiotropium bromide.

a 

Assessed at screening visit, prior to 2-wk fluticasone propionate/salmeterol run-in period.

b 

Assessed at baseline visit, following 2-wk fluticasone propionate/salmeterol run-in period and prior to first dose of study drug.

c 

Medication classes were selected because they reflect cardiovascular risk and/or disease and, with the exception of anticoagulants, have been shown to modify arterial stiffness.

Table Graphic Jump Location
TABLE 2 ]  Baseline Hemodynamic Indexes, Cardiovascular History, and Risk History (ITT Population)

Data are presented as mean (SD) unless indicated otherwise. aPWV = aortic pulse wave velocity. See Table 1 legend for expansion of other abbreviations.

a 

Assessed at screening visit, prior to 2-wk fluticasone propionate/salmeterol run-in period.

Table Graphic Jump Location
TABLE 3 ]  Pulmonary Function at End of Trial (Day 84) (ITT Population)

Analysis performed using a repeated-measures model with covariates of treatment, age, sex, smoking status, geographical region, baseline aPWV, FEV1, or inspiratory capacity (as applicable), and interaction terms of baseline by visit and treatment by visit. LS = least squares. See Table 1 and 2 legends for expansion of other abbreviations.

a 

No. patients with analyzable data for one or more time points.

b 

No. patients with analyzable data at day 84.

Table Graphic Jump Location
TABLE 4 ]  Summary of Most Frequent On-Treatment Adverse Events (ITT Population)

Data are presented as No. (%). See Table 1 legend for expansion of abbreviations.

a 

In each treatment group.

References

Sin DD, Van Eeden S, Leipsic J, Man SF. Reply: beneficial effects of angiotensin receptor blockade in chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 2013;187(3):328. [CrossRef] [PubMed]
 
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Lee HM, Lee J, Lee K, Luo Y, Sin DD, Wong ND. Relation between COPD severity and global cardiovascular risk in US adults. Chest. 2012;142(5):1118-1125. [CrossRef] [PubMed]
 
Laurent S, Alivon M, Beaussier H, Boutouyrie P. Aortic stiffness as a tissue biomarker for predicting future cardiovascular events in asymptomatic hypertensive subjects. Ann Med. 2012;44(suppl 1):S93-S97. [CrossRef] [PubMed]
 
McAllister DA, Maclay JD, Mills NL, et al. Arterial stiffness is independently associated with emphysema severity in patients with chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 2007;176(12):1208-1214. [CrossRef] [PubMed]
 
Sabit R, Bolton CE, Edwards PH, et al. Arterial stiffness and osteoporosis in chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 2007;175(12):1259-1265. [CrossRef] [PubMed]
 
Fabbri LM, Luppi F, Beghé B, Rabe KF. Complex chronic comorbidities of COPD. Eur Respir J. 2008;31(1):204-212. [CrossRef] [PubMed]
 
Macnee W, Maclay J, McAllister D. Cardiovascular injury and repair in chronic obstructive pulmonary disease. Proc Am Thorac Soc. 2008;5(8):824-833. [CrossRef] [PubMed]
 
Vivodtzev I, Tamisier R, Baguet JP, Borel JC, Levy P, Pépin JL. Arterial stiffness in COPD. Chest. 2014;145(4):861-875. [CrossRef] [PubMed]
 
Dransfield MT, Cockcroft JR, Townsend RR, et al. Effect of fluticasone propionate/salmeterol on arterial stiffness in patients with COPD. Respir Med. 2011;105(9):1322-1330. [CrossRef] [PubMed]
 
Calverley PM, Anderson JA, Celli B, et al; TORCH Investigators. Cardiovascular events in patients with COPD: TORCH study results. Thorax. 2010;65(8):719-725. [CrossRef] [PubMed]
 
Löfdahl CG, Postma DS, Pride NB, Boe J, Thorén A. Possible protection by inhaled budesonide against ischaemic cardiac events in mild COPD. Eur Respir J. 2007;29(6):1115-1119. [CrossRef] [PubMed]
 
Dong YH, Lin HH, Shau WY, Wu YC, Chang CH, Lai MS. Comparative safety of inhaled medications in patients with chronic obstructive pulmonary disease: systematic review and mixed treatment comparison meta-analysis of randomised controlled trials. Thorax. 2013;68(1):48-56. [CrossRef] [PubMed]
 
ICH tripartite guideline: guidance for good clinical practice E6 (R1). International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use website. http://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Efficacy/E6_R1/Step4/E6_R1__Guideline.pdf. Accessed July 24, 2014.
 
WMA declaration of Helsinki—ethical principles for medical research involving human subjects.. World Medical Association, Inc website. http://www.wma.net/en/30publications/10policies/b3/index.html. Updated October 2008. Accessed July 24, 2014.
 
Sin DD, MacNee W. Chronic obstructive pulmonary disease and cardiovascular diseases: a “vulnerable” relationship. Am J Respir Crit Care Med. 2013;187(1):2-4. [CrossRef] [PubMed]
 
Rutten FH, Hoes AW. Chronic obstructive pulmonary disease: a slowly progressive cardiovascular disease masked by its pulmonary effects? Eur J Heart Fail. 2012;14(4):348-350. [CrossRef] [PubMed]
 
Laurent S, Cockcroft J, Van Bortel L, et al; European Network for Non-invasive Investigation of Large Arteries. Expert consensus document on arterial stiffness: methodological issues and clinical applications. Eur Heart J. 2006;27(21):2588-2605. [CrossRef] [PubMed]
 
Ben-Shlomo Y, Spears M, Boustred C, et al. Aortic pulse wave velocity improves cardiovascular event prediction: an individual participant meta-analysis of prospective observational data from 17,635 subjects. J Am Coll Cardiol. 2014;63(7):636-646. [CrossRef] [PubMed]
 
Brunner EJ, Shipley MJ, Witte DR, et al. Arterial stiffness, physical function, and functional limitation: the Whitehall II Study. Hypertension. 2011;57(5):1003-1009. [CrossRef] [PubMed]
 
Duprez DA, Hearst MO, Lutsey PL, et al. Associations among lung function, arterial elasticity, and circulating endothelial and inflammation markers: the multiethnic study of atherosclerosis. Hypertension. 2013;61(2):542-548. [CrossRef] [PubMed]
 
Wimmer NJ, Townsend RR, Joffe MM, Lash JP, Go AS; Chronic Renal Insufficiency Cohort Study Investigators. Correlation between pulse wave velocity and other measures of arterial stiffness in chronic kidney disease. Clin Nephrol. 2007;68(3):133-143. [PubMed]
 
McEniery CM, Yasmin, Hall IR, Qasem A, Wilkinson IB, Cockcroft JR; ACCT Investigators. Normal vascular aging: differential effects on wave reflection and aortic pulse wave velocity: the Anglo-Cardiff Collaborative Trial (ACCT). J Am Coll Cardiol. 2005;46(9):1753-1760. [CrossRef] [PubMed]
 
Townsend RR, Wimmer NJ, Chirinos JA, et al. Aortic PWV in chronic kidney disease: a CRIC ancillary study. Am J Hypertens. 2010;23(3):282-289. [CrossRef] [PubMed]
 
Mahmud A, Feely J. Effect of smoking on arterial stiffness and pulse pressure amplification. Hypertension. 2003;41(1):183-187. [CrossRef] [PubMed]
 
Doonan RJ, Hausvater A, Scallan C, Mikhailidis DP, Pilote L, Daskalopoulou SS. The effect of smoking on arterial stiffness. Hypertens Res. 2010;33(5):398-410. [CrossRef] [PubMed]
 
Maclay JD, McAllister DA, Rabinovich R, et al. Systemic elastin degradation in chronic obstructive pulmonary disease. Thorax. 2012;67(7):606-612. [CrossRef] [PubMed]
 
Reference Values for Arterial Stiffness’ Collaboration. Determinants of pulse wave velocity in healthy people and in the presence of cardiovascular risk factors: ‘establishing normal and reference values’. Eur Heart J. 2010;31(19):2338-2350. [CrossRef] [PubMed]
 
Albarrati AM, Gale NS, Munnery MM, et al. Rapid progression of central arterial stiffness in COPD: preliminary 2 year follow-up data from the ARCADE study. J Am Soc Hypertens. 2014;8(4):e4-e5. [CrossRef]
 
Vestbo J, Anderson J, Brook RD, et al. The Study to Understand Mortality and Morbidity in COPD (SUMMIT) study protocol. Eur Respir J. 2013;41(5):1017-1022. [CrossRef] [PubMed]
 
Wilkinson IB, McEniery CM, Schillaci G, et al. ARTERY Society guidelines for validation of non-invasive haemodynamic measurement devices: part 1, arterial pulse wave velocity. Artery Res. 2010;4(2):34-40. [CrossRef]
 
Weber T, Ammer M, Rammer M, et al. Noninvasive determination of carotid-femoral pulse wave velocity depends critically on assessment of travel distance: a comparison with invasive measurement. J Hypertens. 2009;27(8):1624-1630. [CrossRef] [PubMed]
 
Dinenno FA, Jones PP, Seals DR, Tanaka H. Age-associated arterial wall thickening is related to elevations in sympathetic activity in healthy humans. Am J Physiol Heart Circ Physiol. 2000;278(4):H1205-H1210. [PubMed]
 
Swierblewska E, Hering D, Kara T, et al. An independent relationship between muscle sympathetic nerve activity and pulse wave velocity in normal humans. J Hypertens. 2010;28(5):979-984. [CrossRef] [PubMed]
 
Andreas S, Anker SD, Scanlon PD, Somers VK. Neurohumoral activation as a link to systemic manifestations of chronic lung disease. Chest. 2005;128(5):3618-3624. [CrossRef] [PubMed]
 
Fatouleh R, Macefield VG. Respiratory modulation of muscle sympathetic nerve activity is not increased in essential hypertension or chronic obstructive pulmonary disease. J Physiol. 2011;589(Pt 20):4997-5006. [PubMed]
 
Macklem PT. Therapeutic implications of the pathophysiology of COPD. Eur Respir J. 2010;35(3):676-680. [CrossRef] [PubMed]
 
Crim C, Calverley PM, Anderson JA, et al. Pneumonia risk in COPD patients receiving inhaled corticosteroids alone or in combination: TORCH study results. Eur Respir J. 2009;34(3):641-647. [CrossRef] [PubMed]
 
Global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease. GOLD website. http://www.goldcopd.org/uploads/users/files/GOLD_Report_2014_Jun11.pdf. Updated 2013. Accessed July 24, 2014.
 
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