Effects of chronic obstructive pulmonary disease (COPD) treatments on cardiovascular (CV) risk

Author/studyDesign and participantsDurationPopulationTreatment(s)Primary outcomeKey resultsOther findings
 Suissa (2003) [71]Population-based, nested case–control
(n=12 090)
Follow-up to 1999Newly diagnosed patients with COPD aged >55 years (identified from the Saskatchewan Health Services databases, 1980–1997)SABAsCases of acute MI occurring during cohort follow-up1127 evaluable patients identified with fatal or non-fatal acute MI
SABA use not associated with increased risk of acute MI (rate ratio for any use: 1.06, 95% CI 0.92–1.23)
No significant increase in risk when analysis is restricted to patients with CV risk factors
 Salpeter (2004) [72]Meta-analysis of randomised and placebo-controlled trials
13 RCTs of single-dose treatment (n=232)
20 trials of longer treatment duration (n=6623)
Mean of 4.7 months (range: 3 days to 1 year)Patients with obstructive airway disease (COPD or asthma)
Mean age 56.6 years (single-dose) and 52.2 years (longer treatment studies)
β2-agonists versus placeboShort-term effect on heart rate and potassium concentrations
Long-term effect on adverse CV events
Single-dose β2-agonist versus placebo increased heart rate by 9.12 bpm and reduced potassium concentration by 0.36 mmol·L−1
Longer β2-agonist treatment significantly increased risk for CV events (relative risk 2.54, 95% CI 1.59–4.05)
The relative risk for sinus tachycardia was 3.06 (95% CI 1.70–5.50)
For all other events, relative risk was 1.66 (95% CI 0.76–3.6)
 Cazzola (2007) [27]Randomised, double blind, double dummy (n=20)COPD and sPAP >20 mmHg (rest)Salmeterol 50 µg
Formoterol 12 µg
Acute haemodynamic responseMean sPAP significantly decreased versus baseline at 15, 30 and 60 min post-inhalation (p<0.05)No correlation between maximum increase in FEV1 and maximum decrease in sPAP after inhalation of salmeterol or formoterol
 Santus (2015) [73]Randomised, double blind, placebo controlled, crossover (n=40)COPD (FEV1 ≤70% pred; RV ≥135% pred)
Absence of CV comorbidities
Age 50–85 years
Indacaterol 150 µg versus placebo (1:1)Effect of reduction of right-ventricular and FRC on right heart systolic/diastolic functional indicesSignificant improvements in right-ventricular compliance/cardiac performance with indacaterol versus placebo (p≤0.05 after 180 min treatment) as follows:
1) TAPSE: 0.41 mm versus 0.02 mm
2) DT-TR: 11.9 ms versus 3.8 ms
3) ≤Heart rate: −2 bpm versus 0.6 bpm
Indacaterol associated with significant (p<0.05) increases versus placebo in FEV1, VC and IC
Muscarinic antagonists
 Kesten 2006 [74]Pooled safety analysis of 19 randomised, double blind, placebo controlled trials (including two asthma trials) (n=7819)COPD diagnosis with airflow limitation
Age ≥40 years
Smoking history ≥10 pack-years
Tiotropium 18 µg once daily (n=4435)
Placebo (n=3384)
AEs occurring during the studyTiotropium not associated with increased risk of serious cardiac events versus placebo. Data as follows:
1) CV mortality (relative risk 0.57, 95% CI 0.26–1.26)
2) Cardiac arrest (relative risk 0.90, 95% CI 0.26–3.15)
3) MI (relative risk 0.74, 95% CI 0.26–2.07)
Relative risk of tachycardia with tiotropium versus placebo: 1.68 (95% CI 0.69–4.11)
 Travers (2007) [75]Randomised, double blind, placebo controlled, crossover (n=18)7–10 day treatment period + 35 day washout periodCOPD (FEV1 ≤65% pred; FRC ≥120% pred; modified baseline dyspnoea index score ≤6)Tiotropium 18 µg once daily versus placeboEffect of tiotropium on CV response to exerciseTiotropium improved cardiac function during exercise versus placebo:
1) Significantly reduced heart rate (105 bpm versus 112 bpm, p<0.05)
2) Higher O2 pulse (10.9 mL·beat−1 versus 10.1 mL·beat−1, p<0.05)
3) Lower SBP (148 mmHg versus 156 mmHg, p<0.05)
Tiotropium significantly improved measures of dynamic hyperinflation during exercise: IRV was significantly greater with tiotropium versus placebo (0.60 L versus 0.44 L, p<0.05)
 Singh (2008) [76]Systematic review and meta-analysis (17 RCTs; 12 on tiotropium, 5 on ipratropium) (n=14 783)COPD of any severityTiotropium or ipratropium (n=7472) versus control (placebo/active control) (n=7311)Composite of non-fatal MI, non-fatal stroke and CV deathTiotropium or ipratropium significantly increased risk of CV death, MI or stroke versus control (1.8% versus 1.2%; relative risk 1.58 (95% CI 1.21–2.06), p<0.001)Tiotropium or ipratropium did not significantly increase risk of all-cause mortality versus control (2.0% versus 1.6%; relative risk 1.26 (95% CI 0.99–1.61), p=0.06)
 Rodrigo (2009) [77]Systematic review and meta-analysis (19 RCTs) (n=18111)7 trials (28–48 months)
12 trials (8 weeks–6 months)
Patients with COPD (average baseline FEV1: 41% pred normal)
Mean age 64.8 years
Tiotropium versus placebo (n=15#),
SFC (n=2#),
salmeterol (n=1#),
salmeterol/placebo (n=1#)
Composite of MACE, CV mortality and non-fatal MI or strokeNo difference in incidence of MACE versus control groups (relative risk 0.96, 95% CI 0.82–1.12)Compared with control groups, tiotropium did not significantly increase risk of:
1) CV death (relative risk 0.93, 95% CI 0.73–1.20)
2) Non-fatal MI (relative risk 0.84, 95% CI 0.64–1.09)
3) Non-fatal stroke (relative risk 1.04, 95% CI 0.78–1.39)
 Celli (2009, UPLIFT) [78]Multicentre, randomised, double blind, placebo-controlled, parallel group (n=5993)
Mortality analysis
4 yearsPatients aged >40 years with COPD (post-bronchodilator FEV1 ≤70% pred normal; FEV1/FVC ≤70%)Tiotropium (n=2987)
Placebo (n=3006)
Effect of tiotropium on survivalReduced risk of cardiac mortality with tiotropium versus placebo (HR 0.86, 95% CI 0.75–0.99)Reduced risk of all-cause mortality for tiotropium versus placebo (HR 0.84 (95% CI 0.73–0.97), p=0.016)
 Nojiri 2012 [79]Single-centre, prospective, pilot (n=21)12 weeksPatients with COPD (FEV1/FVC <0.70) and prior (≥1 year) pulmonary resection for lung cancer
ECOG status 1
>20 pack-year smoking history
Tiotropium 18 µg once dailyPulmonary function and left-ventricular diastolic dysfunction (E/e′ ratio)Significant improvements after tiotropium (versus before tiotropium) in:
1) FEV1 (1.84 L versus 1.60 L, p<0.001)
2) E/e′ ratio (7.59 versus 8.97, p<0.001)
No significant differences before/after tiotropium in BP, heart rate, FVC, left-ventricular mass and LVEF
Significant improvement in PASP versus before tiotropium (33.0 mmHg versus 38.5 mmHg, p<0.01)
 Pepin (2014) [80]Multicentre, randomised, double dummy, parallel group, blinded (n=257)12 weeksCOPD patients aged ≥40 years
Smoking history ≥10 pack-years
Post-bronchodilator FEV1 ≤70% pred normal
FEV1/FVC ≤0.70
aPWV ≥11 m·s−1
Tiotropium 18 µg once daily (n=130) versus fluticasone furoate/vilanterol combination 100 µg/25 µg once daily (n=127)Change from baseline in arterial stiffness (aPWV)+ at 12 weeksAt 12 weeks there was a comparable reduction from baseline in aPWV with tiotropium (−1.118 m·s−1) and fluticasone furoate/vilanterol combination (−0.859 m·s−1, p=ns)No significant differences between tiotropium and fluticasone furoate/vilanterol combination for change from baseline in trough FEV1 (0.080 L versus 0.117 L) or IC (0.019 L versus 0.089 L)
 Suissa (2017) [65]UK observational, population-based prior ICS-matched cohort analysis (primary care, CPRD) (n=115 397, base cohort (new users of a long-acting bronchodilator); n=70 550, sub-cohort (linked to HES database))1 yearNew users of long-acting bronchodilators (LABA or tiotropium) for COPD
Aged >55 years
≥2 years medical history
First LABA/tiotropium prescription on/after September 25, 2003
Full cohort (matched by propensity score): tiotropium (n=26 442), LABA (n=26 442)
HES sub-cohort: tiotropium (n=15 427), LABA (n=15 427)
Incidence of acute MI, stroke, HF (full cohort) and incidence of arrhythmia and pneumonia (HES sub-cohort) following 1 year of treatment with tiotropium versus LABANo difference between tiotropium versus LABA in CV events, as follows:
1) Acute MI: HR 1.10 (95% CI 0.88–1.38)
2) Stroke: HR 1.02 (95% CI 0.78–1.34)
3) Heart failure: HR 0.90 (95% CI 0.79–1.02)
4) Arrhythmia: HR 0.81 (95% CI 0.60–1.09)
Risk of pneumonia significantly reduced with tiotropium versus LABA (HR 0.81, 95% CI 0.72–0.92)
β2-agonists and muscarinic antagonists
 Berton (2010) [81]Double-blind, placebo-controlled, crossover (n=12)Moderate-to-severe COPD (FEV1/FVC <0.7; post-bronchodilator FEV1 <60% pred)
Resting PaO2 >60 mmHg
Salbutamol 120 µg + ipratropium 20 µg/actuation versus placeboKey determinants of O2 delivery and uptake during high-intensity, constant work rate cycling exerciseCompared with placebo, bronchodilators accelerated central haemodynamic response at exercise onset, as follows:
1) t1/2QT: 75.9±10.3 s
versus 58.9±18.9 s (p=0.02)
2) t1/2heart rate:
78.2±13.0 s versus
62.5±15.5 s (p=0.03)
3) t1/2SV: 51.0±8.1 s
versus 40.6±10.3 s (p=0.02)
Bronchodilators led to lung deflation and increased exercise tolerance versus placebo (454±131 s versus 321±140 s; p<0.05)
 Wilchesky (2012–part 1) [82]Retrospective, cohort (healthcare databases, Province of Saskatchewan, Canada) (n= 6018)COPD patients aged ≥55 years
Newly treated COPD (three or more prescriptions for a bronchodilator, on two different dates, within any 1-year period)
Ipratropium bromide
Rate of cardiac arrhythmiasRate of arrhythmia increased with new use of:
1) ipratropium (relative risk 2.4, 95% CI 1.4–4.0)
2) LABA (relative risk 4.5, 95% CI 1.4–14.4)
Rate of arrhythmia was not increased with new use of:
1) SABA (relative risk 0.9, 95% CI 0.5–1.6)
2) Methylxanthines (relative risk 1.6, 95% CI 0.7–3.7)
 Wilchesky (2012–part 2) [83]Retrospective, cohort (healthcare databases, Quebec, Canada) (n=76 661)COPD patients aged ≥67 years
Newly treated COPD (three or more prescriptions for a bronchodilator, on two different dates between January 01, 1990 and December 31, 2002)
Ipratropium bromide
Rate of cardiac arrhythmiasRate of arrhythmia increased with new use of:
1) SABA (relative risk 1.27, 95% CI 1.03–1.57)
2) LABA (relative risk 1.47, 95% CI 1.01–2.15)
Rate of arrhythmia slightly (not significantly) increased with new use of:
1) ipratropium bromide (relative risk 1.23, 95% CI 0.95–1.57)
2) Methylxanthines (relative risk 1.28, 95% CI 0.93–1.77)
 Gershon (2013) [84]Population-based, nested case–control analysis of a retrospective study (n=191 005)COPD patients aged ≥66 years
Receiving treatment (September 2003–March 2009)
53 532 had a CV event
26 628 matched to control§
Hospitalisation or ED visit for a CV eventNew users of LABAs and LAMAs more likely versus non-users to have a CV-related hospitalisation/ED visit
LABAs: OR 1.31 (95% CI 1.12–1.52), p<0.001
LAMAs: OR 1.14 (95% CI 1.01–1.28), p=0.03
No significant difference in CV events between LABAs and LAMAs (OR 1.15 (95% CI 0.95–1.38), p=0.16)
 Wang (2018) [123]Nested case-control study (healthcare database, Taiwan) (n=284 229)COPD patients aged ≥40 years
37 719 had a CV event
Matched with 146 139 randomly selected controls
Inpatient or ED visit for CAD, HF, ischaemic stroke or arrhythmiaNew LABA and LAMA use were associated with an increased risk of a CV event within 30 days (OR 1.50 (95% CI 1.35–1.67), p<0.001 and OR 1.52 (95% CI 1.28–1.80), p<0.001, respectively). The risk was absent, or even reduced, with prevalent useNo difference in risk was observed between individual LABA agents, LAMA dosage forms, or concomitant COPD regimens
LABA/LAMA combinations
 Suissa (2017) [66]UK observational, population-based cohort analysis (primary care, CPRD) (n=463 899, base cohort)
31 174 patients on combined bronchodilator therapy matched to 31 174 patients on bronchodilator monotherapy
1 yearNew users of long-acting bronchodilators (LABA or tiotropium) for COPD
Aged >55 years
≥2 years medical history
First LABA/tiotropium prescription on/after September 25, 2002
LABA/tiotropium initiation + second long-acting bronchodilator (n=31 174)
Bronchodilator monotherapy (n=31 174)
Incidence of acute MI, stroke, HF and arrhythmia following 1 year of treatmentCombination of two long-acting bronchodilators was not associated with increased risk of:
1) Acute MI (HR 1.12, 95% CI 0.92–1.37)
2) Stroke (HR 0.87, 95% CI 0.69–1.10)
3) Arrhythmia (HR 1.05, 95% CI 0.81–1.36)
Two long-acting bronchodilators in combination were associated with increased risk of HF (HR 1.16, 95% CI 1.03–1.30)
 Samp (2017) [85]Retrospective, observational cohort (using health insurance claims data) (n=19 078 matched patients)Patients with COPD initiating LABA/LAMA or ICS/LABALABA/LAMA (n=3844)
ICS/LABA (n=15 234)
CCV outcomes: hospitalisations for ACS, HF, cardiac dysrhythmia, stroke, or TIALABA/LAMA treatment was associated with fewer CV events versus ICS/LABA treatment (HR 0.794, 95% CI 0.623–0.997)No difference between treatments in cerebrovascular events (HR 1.166, 95% CI 0.653–1.959)
 Hohlfeld (2017) [86]Randomised, double-blind, single centre, placebo-controlled, two period, crossover (n=62)Patients with COPD and increased RV (>135% predicted) without CVDIndacaterol/glycopyrronium 110 µg/50 µg once daily
Change in LVEDV measured with MRI on day 14Compared with placebo, indacaterol/glycopyrronium resulted in a significant increase in LVEDV (10.27 mL, p<0.0001) and QT (0.337 L·min−1, p=0.0032)Compared with placebo, indacaterol/glycopyrronium was associated with:
1) Improved lung function (peak FEV1 increased by 0.42 L, p<0.0001)
2) Reduced lung hyperinflation (RV −0.75 L, p<0.0001)
ICS and ICS/LABA combinations
 Huiart (2005) [87]Nested case–control analysis (health services databases, Saskatchewan, Canada) (n=5648)Follow-up until first MIPatients ≥55 years with new-onset COPD who had not received any bronchodilator, anti-asthma drug or nasal/ICS in the previous 5 yearsICSFirst fatal or non-fatal acute MIResults based on 371 cases with first acute MI matched to 1864 controls
Low-dose ICS (50–200 µg·day−1) significantly reduced risk of acute MI by 32% (rate ratio 0.68, 95% CI 0.47–0.99)
Overall, current use of ICS was not associated with a significant decrease in risk of acute MI (rate ratio 0.82, 95% CI 0.57–1.16)
 Loke (2010) [88]Systematic review of 23 RCTs (n=23 396) and 12 observational studiesRCTs ≥24 weeksPatients with COPD of any severityICS versus placebo or ICS/LABA versus LABARisk of fatal and non-fatal MI and CV deathFindings from RCTs indicated that ICS were not associated with significantly reduced risk of MI (relative risk 0.95, 95% CI 0.73–1.23), CV death (relative risk 1.02, 95% CI 0.81–1.27) or mortality (relative risk 0.96, 95% CI 0.86–1.07)Findings from observational studies indicated that ICS use was associated with a significant reduction in CV death (two studies: relative risk 0.79 (95% CI 0.72–0.86), p<0.0001) and mortality (11 studies: relative risk 0.78 (95% CI 0.75–0.80), p<0.0001)
 Calverley (2010, TORCH) [89]Multicentre, randomised, double-blind, placebo-controlled, parallel group (post hoc analysis) (n=6184)3 yearsPatients (current/former smokers) with COPD (pre-bronchodilator FEV1 <60% pred and FEV1/FVC ≤0.70)
Aged 40–80 years
Salmeterol/fluticasone propionate combination 50 µg/500 µg (n=1546)
Salmeterol 50 µg (n=1542)
Fluticasone propionate 500 µg (n=1552)
Placebo (n=1544) (all twice daily)
CV AEs and SAEsThe probability of patients having a CV AE by 3 years was lowest for salmeterol/fluticasone propionate combination (20.8%) versus placebo (24.2%), salmeterol (22.7%) and fluticasone propionate (24.3%)Treatment with salmeterol/fluticasone propionate combination was associated with a significant reduction versus placebo in probability of a CV AE by 3 years in patients receiving CV therapy at baseline (27.9% versus 33.5%, respectively; p<0.05)
 Dransfield (2011) [90]Multicentre, randomised, double-blind, placebo-controlled (n=249)12 weeksPatients with COPD (post-bronchodilator FEV1 <80% pred and FEV1/FVC ratio ≤0.70)
Aged ≥50 years
Smoking history of ≥10 pack-years
Salmeterol/fluticasone propionate combination 50 µg/250 µg twice daily (n=123)
Placebo (n=126)
(Both arms received open label tiotropium 18 µg once daily for 4 weeks after a 12 week treatment period)
aPWV change from baseline at 12 weeksFor patients that remained on treatment for 12 weeks (n=96 in each group), salmeterol/fluticasone propionate combination was associated with a significant reduction in aPWV versus placebo (−0.49 m·s−1, p=0.045)No significant changes in aPWV for salmeterol/fluticasone propionate combination + tiotropium versus tiotropium from 12–16 weeks (mean change 0.18 m·s−1)
 Stone (2016) [91]Single-centre, randomised, double-blind, placebo-controlled, crossover (n=45)Two 7-day treatment periods separated by a 7±2-day washout periodCOPD (FEV1 <70% pred)
Smoking history ≥15 pack-years
Aged >40 years
MRC score >1
Lung hyperinflation (RV >120% pred) which improved ≥7.5% after salbutamol
Fluticasone furoate/vilanterol combination 100 µg/25 µg once daily
Change in RVEDVI from baseline versus placebo after 7 days treatment (maximum 14 days)Mean increase in change from baseline in RVEDVI of 5.8 mL·m−2 (95% CI 2.74–8.91), p<0.001 versus placeboImproved lung hyperinflation and airflow limitation from baseline with fluticasone furoate/vilanterol combination relative to placebo, as follows:
1) RV: 429 mL reduction (p<0.001)
2) Increased IC, IC/TLC, FEV1 and FVC (261 mL, 4.6%, 220 mL and 350 mL, respectively; all p<0.001)
 Vestbo (2016, SUMMIT) [92]Multicentre, randomised, double-blind, placebo-controlled, parallel group, event-driven (n=16 485)Maximum follow-up was 4 yearsCOPD (post-bronchodilator FEV1 50–70% pred and FEV1/FVC ≤0.70)
Smoking history ≥10 pack-years
mMRC dyspnoea scale ≥2
History/increased risk of CVD
Fluticasone furoate/vilanterol combination 100 µg/25 µg once daily (n=4121)
Fluticasone furoate 100 µg once daily (n=4135)
Vilanterol 25 µg once daily (n=4118)
Placebo (n=4111)
All-cause mortalityAll-cause mortality did not differ significantly between fluticasone furoate/vilanterol combination and placebo (HR 0.88 (95% CI 0.74–1.04); 12% relative reduction, p=0.137) or componentsFluticasone furoate/vilanterol combination had no effect on composite CV events (CV death, MI, stroke, unstable angina, TIA) compared with placebo (HR 0.93, 95% CI 0.75–1.14)
 Bhatt (2017) [93]Multicentre, randomised, double-blind, parallel group, placebo-controlled (stratified by COPD exacerbation history) (n=430)24 weeksPatients aged ≥40 years with a history of COPD
≥10 pack-year smoking history
FEV1/FVC ≤0.70
Post-bronchodilator FEV1 ≤70% pred
aPWV ≥11 m·s−1
Fluticasone furoate/vilanterol combination 100 µg/25 µg once daily (n=135)
Vilanterol 25 µg once daily (n=154)
Placebo (n=141)
Change from baseline in aPWV after 24 weeks with fluticasone furoate/vilanterol combination versus placeboNo significant difference in mean change from baseline in aPWV at 24 weeks with fluticasone furoate/vilanterol combination (−1.75 m·s−1) versus placebo (−1.97 m·s−1)Post-hoc analysis indicated a greater proportion of respondersƒ in the fluticasone furoate/vilanterol combination versus placebo groups when withdrawn patients were classified as non-responders (50% versus 36%, respectively)
Other COPD pharmacological treatments
 Suissa (1996) [94]Population-based cohort from Saskatchewan, Canada (n=12 301)Patients with asthma aged 5–54 yearsTheophylline and β-agonists versus controlIdentified 30 CV deaths in which acute asthma did not appear to be a contributing factorRate of CV death was greater with theophylline (rate ratio 2.7, 95% CI 1.2–6.1) and β-agonists administered orally or by nebuliser (rate ratio 2.4, 95% CI 1.0–5.4)Rate of CV death was not greater with β-agonists administered by MDI (rate ratio 1.2, 95% Cl 0.5–2.7)
 Huerta (2005) [95]Nested case-control (population-based cohort, UK General Practice Research Database after January 01, 1994) (n=5710)Patients aged 10–79 years with asthma or COPD (710 cases and 5000 controls)Theophylline (and other therapies: β-agonists, oral steroids, ICS)Rhythm disordersShort-term theophylline use was weakly associated with:
1) Arrhythmia (relative risk 1.8, 95% CI 1.0–3.3)
2) AF (relative risk 1.8, 95% CI 0.9–3.7)
Short-term theophylline use was associated with supraventricular tachycardia (relative risk 4.0, 95% CI 0.9–18.1)
 White (2013) [96]Pooled analysis of 14 intermediate and long-term trials (n=12 054)Range: 12–52 weeksPatients with moderate-to-very-severe COPDRoflumilast (n=6563)
Placebo (n=5491)
MACE (CV death, non-fatal MI and stroke)MACE composite rate was significantly lower with roflumilast versus placebo (HR 0.65 (95% CI 0.45–0.93), p=0.019)MACE experienced by 14.3/1000 patient-years (roflumilast) and by 22.3/1000 patient-years (placebo)

ACS: acute coronary syndrome; AE: adverse event; AF: atrial fibrillation; aPWV: aortic pulse wave velocity; BP: blood pressure; CAD: coronary artery disease; CCV: cardiovascular and cerebrovascular; CPRD: Clinical Practice Research Datalink; CVD: cardiovascular disease; DT-TR: tricuspid E-wave deceleration time; ECOG: Eastern Cooperative Oncology Group; ED: emergency department; E/e′: ratio of peak early diastolic mitral flow velocity to peak early diastolic mitral annual movement velocity; FEV1: forced expiratory volume in 1 s; FRC: functional residual capacity; FVC: forced vital capacity; HES: hospital episode statistics; HF: heart failure; HR: hazard ratio; IC: inspiratory capacity; ICS: inhaled corticosteroid; IRV: inspiratory reserve volume; LABA: long-acting β2-agonist; LAMA: long-acting muscarinic antagonist; LVEDV: left-ventricular end-diastolic volume; LVEF: left-ventricular ejection fraction; MACE: major adverse cardiovascular event; MDI: metered dose inhaler; MI: myocardial infarction; mMRC: modified Medical Research Council; MRI: magnetic resonance imaging; ns: not significant; OR: odds ratio; PaO2: arterial oxygen tension; PASP: pulmonary arterial systolic pressure; QT: cardiac output; RCT: randomised controlled trial; RVEDVI: right-ventricular end-diastolic volume index; RV: residual volume; SABA: short-acting β2-agonist; SAE: serious adverse event; SFC: salmeterol/fluticasone combination; SBP: systolic blood pressure; sPAP: systolic pulmonary arterial pressure; SV: stroke volume; TAPSE: tricuspid annular plane systolic excursion; TIA: transient ischaemic attack; TLC: total lung capacity; VC: vital capacity. #: number of studies; : increases with elevation of left-ventricular filling pressure that occurs due to impaired left-ventricular diastolic function; +: marker of CV risk; §: for each case, one control was randomly selected, matched for age (±1 year), sex, duration of COPD, HF and history of hospitalisation for ACS, HF, ischaemic stroke, cardiac arrhythmia and acute respiratory disease (acute exacerbation of COPD, pneumonia, influenza, or acute bronchitis); ƒ: patients with aPWV reduction from baseline of ≥1 m·s−1 on day 168.