Supplementary material
Clinical assessment of endothelial function in patients with chronic obstructive pulmonary disease:
a systematic review with meta-analysis.
at
Salvatore Iervolino, MD, PhD2 Alberto De Felice, MD2 Nicola Pappone, MD2
Antonio Storino, MD2,3 Matteo Nicola Dario Di Minno, MD, PhD4
*The two Authors equally contributed to this study.
1Department of Clinical Medicine and Surgery, Federico II University, Naples, Italy;
2ICS Maugeri SpA SB, Scientific Institute of Telese Terme - IRCCS, Telese Terme (BN), Italy;
3Department of Public Health, Federico II University, Naples, Italy;
4Department of Advanced Biomedical Sciences, Division of Cardiology, Federico II University, Naples, Italy.
Table of contents:
Supplemental Table 1 / Quality of studies assessment (Newcastle-Ottawa scale) for 8 included studies.Supplemental Table 2 / Measures of disease severity and disease activity in patients with chronic obstructive pulmonary disease in included studies.
Supplemental Table 3 / Concomitant use of medications in patients with chronic obstructive pulmonary disease (COPD) and controls in included studies.
Supplemental Table 4 / Meta-regression analyses. Impact of major clinical and demographic variables on flow-mediated dilatation (FMD) in chronic obstructive pulmonary disease patients (COPD) patients and controls.
Supplemental Figure 1 / Funnel plots of effect size (mean difference) versus precision (1/standard error of the mean difference) for studies evaluating flow-mediated dilatation (FMD) in patients with chronic obstructive pulmonary disease (COPD) and in control subjects using fixed effect (Panel A) and random effect (Panel B).
Supplemental Figure 2 / Meta-regression analyses. Impact of age (Panel A) and FEV1 (Panel B) on the mean difference in flow-mediated dilatation (FMD) in chronic obstructive pulmonary disease patients (COPD) patients and controls.
Supplemental Table 1.Quality of studies assessment (Newcastle-Ottawa scale) for 8 included studies.
Study / Definition of cases / Representativeness of cases / Selection of controls / Definition of controls / Comparability of cases and controls / Ascertainment of exposure / Same method of ascertainment / Non-response rate / QualityBlum 2014 [16] / / / / - / - / / / / 6
Costanzo 2016 [18] / / - / - / - / - / / / / 4
de Matthaeis 2014 [17] / / / - / - / - / / / / 5
Eickhoff 2014 [25] / / / / / - / / / / 7
Hartmann 2016 [26] / / - / / / / / / / 7
Ives 2014 [27] / / / / / - / / / / 7
Moro 2008 [28] / / / / / / / / / 8
Özben 2010 [19] / / / - / / / / / / 7
Supplemental Table 2. Measures of disease severity and disease activity in patients with chronic obstructive pulmonary disease in included studies.
Study / Patients(n) / FEV1
(% predicted) / FEV1/FVC / GOLD I
(%) / GOLD II
(%) / GOLD III
(%) / GOLD IV
(%) / CRP
(mg/l) / IL6
(pg/ml)
Blum 2014 [16] / 23 / 45 / 59 / - / - / - / - / - / -
Costanzo 2016 [18] / 41 / 61.9 / 55.7 / - / - / - / - / 2.4 / 4.1
de Matthaeis 2014 [17] / 96 / - / - / - / - / - / - / - / -
Eickhoff 2014* [25] / 60 / 41 / 43 / - / - / - / - / 4.0 / 2.5
Hartmann 2016 [26] / 10 / 60 / 46 / - / - / - / - / - / -
Ives 2014 [27] / 30 / 55 / 45 / 10 / 43.3 / 26.7 / 20 / - / -
Moro 2008 [28] / 44 / - / - / - / - / - / - / - / -
Özben 2010 [19] / 30 / 51 / 57 / - / - / - / - / - / -
FEV1: forced expiratory volume in 1 second; FVC: forced vital capacity; GOLD: Global Initiative for Chronic Obstructive Lung Disease scoring system; CRP: C-reactive protein; IL6: interleukin-6. FEV1, FEV1/FVC, GOLD score, CRP and IL6 levels are expressed as mean values, unless otherwise indicated.
*IL6 levels are expressed as median value.
Supplemental Table 3. Concomitant use of medications in patients with chronic obstructive pulmonary disease (COPD) and controls in included studies.
Study / Patients(n) / Aspirin
(%) / Statins
(%) / ACE-I
(%) / ARBs
(%) / β-blockers
(%) / CCB
(%) / β-agonists
(%) / Anticholinergics
(%) / CCS
(%) / Oxygen
(%)
Blum 2014 [16] / COPD / 23 / - / - / - / - / - / - / - / - / - / -
Controls / 22 / - / - / - / - / - / - / - / - / - / -
Costanzo 2016 [18] / COPD / 41 / - / 20 / 54 / - / 15 / - / 68 / 44 / - / 0
Controls / 35 / - / 17 / 60 / - / 11 / - / 0 / 0 / 0 / 0
de Matthaeis 2014 [17] / COPD / 96 / 31.3 / - / 43.8 / 21.9 / 18.8 / 28.1 / - / - / - / 66.7
Controls / 76 / - / - / - / - / - / - / - / - / - / 0
Eickhoff 2014 [25] / COPD / 60 / - / - / - / - / - / - / Bronchodilators in 100% / 75 / 23
Controls / 40 / - / - / - / - / - / - / - / - / 0 / 0
Hartmann 2016 [26] / COPD / 10 / - / - / - / - / - / - / - / - / - / 0
Controls / 10 / - / - / - / - / - / - / - / - / - / 0
Ives 2014 [27] / COPD / 30 / - / 16.7 / 33.3 / 6.7 / 13.3 / 30 / 46.6 / 23.3 / 36.6 / 23.3
Controls / 30 / - / 20 / 6.7 / 3.3 / 6.7 / 6.7 / 3.3 / 0 / 0 / 0
Moro 2008 [28] / COPD / 44 / 52.3 / 20.4 / 47.7 / 11.4 / 11.4 / - / - / - / - / 0
Controls / 48 / 60.4 / 33.3 / 66.7 / 8.3 / 22.9 / - / - / - / - / 0
Özben 2010 [19] / COPD / 30 / - / - / - / - / - / - / - / - / - / -
Controls / 20 / - / - / - / - / - / - / - / - / - / -
ACE-I: angiotensin converting enzyme-inhibitors; ARBs: angiotensin receptor blockers; CCB: calcium channel blockers; CCS: corticosteroids.
Supplemental Table 4. Meta-regression analyses. Impact of major clinical and demographic variables on flow-mediated dilation (FMD) in chronic obstructive pulmonary disease patients (COPD) patients and controls.
Independent variable / FMD% of males / Z=-1.83; P=0.067
Age / Z=3.51; P<0.001
Diabetes mellitus / Z=0.198; P=0.842
BMI / Z=1.57; P=0.117
Hypertension / Z=1,49; P=0.135
Smoking history / Z=1.67; P=0.100
Pack-years / Z=-1.29; P=0.198
Hyperlipidemia / N/A
FEV1 (% predicted) / Z=3.76; P<0.001
FEV1/FVC / Z=-0.53; P=0.596
GOLD I / N/A
GOLD II / N/A
GOLD III / N/A
GOLD IV / N/A
CRP / N/A
IL6 / N/A
Aspirin / N/A
Statin / Z=-0.48; P=0.629
ACE-I / Z=0.54; P=0.586
ARBs / N/A
β-blockers / Z=-0.06; P=0.952
CCB / N/A
β-agonists / N/A
Anticholinergics / N/A
CCS / N/A
Oxygen / Z=-0.40; P=0.689
BMI: body mass index; FEV1: forced expiratory volume in 1 second; FVC: forced vital capacity; GOLD: Global Initiative for Chronic Obstructive Lung Disease scoring system; CRP: C-reactive protein; ACE-I: angiotensin converting enzyme-inhibitors; ARBs: angiotensin receptor blockers; CCB: calcium channel blockers; N/A: not assessed because of the limited number of studies reporting this co-variate.
Supplemental Figure 1. Funnel plots of effect size (mean difference) versus precision (1/standard error of the mean difference) for studies evaluating flow-mediated dilatation (FMD) in patients with chronic obstructive pulmonary disease (COPD) and in control subjects using fixed effect (Panel A) and random effect (Panel B).
Panel A: Fixed effect
Observed studies are represented by empty circles, imputed studies by black circles.
Egger’s regression intercept / Intercept / 0.77831Standard error / 2.91914
95% lower limit / -6.36457
95% upper limit / 7.92120
t-value / 0.26662
P value / 0.79869
Begg and Mazumdar / Kendall’s S statistic (P-Q) / -8.00000
Kendall’s tau without continuity correction
tau / -0.28571
Z-value for tau / 0.98974
P-value / 0.32230
Kendall’s tau with continuity correction
tau / -0.25000
Z-value for tau / 0.86603
P-value / 0.38648
Duvall and Tweedie’s trim and fill / Studies
trimmed / Point
estimate / Lower
limit / Upper
limit / Q value
Observed values / - / -3.15231 / -3.38654 / -2.91807 / 186.14909
Adjusted values (on the right) / 0 / -3.15231 / -3.38654 / -2.91807 / 186.14909
Adjusted values (on the left) / 1 / -3.17682 / -3.41049 / -2.94315 / 194.90637
Panel B: Random effects
Observed studies are represented by empty circles, imputed studies by black circles.
Egger’s regression intercept / Intercept / 0.77831Standard error / 2.91914
95% lower limit / -6.36457
95% upper limit / 7.92120
t-value / 0.26662
P value / 0.79869
Begg and Mazumdar / Kendall’s S statistic (P-Q) / -8.00000
Kendall’s tau without continuity correction
tau / -0.28571
Z-value for tau / 0.98974
P-value / 0.32230
Kendall’s tau with continuity correction
tau / -0.25000
Z-value for tau / 0.86603
P-value / 0.38648
Duvall and Tweedie’s trim and fill / Studies
trimmed / Point
estimate / Lower
limit / Upper
limit / Q value
Observed values / - / -3.15672 / -4.88786 / -1.42558 / 186.14909
Adjusted values (on the right) / 0 / -3.15672 / -4.88786 / -1.42558 / 186.14909
Adjusted values (on the left) / 2 / -4.33838 / -6.01752 / -2.65925 / 225.43494
Supplemental Figure 2. Meta-regression analyses. Impact of age (Panel A) and FEV1 (Panel B) on the mean difference in flow-mediated dilation (FMD) in chronic obstructive pulmonary disease patients (COPD) patients and controls.
FEV1: forced expiratory volume in 1 second.
The area of each circle is proportional to the study weight in the meta-regression. An increasing age and increasing values of FEV1 are associated with a lower difference in FMD between COPD patients and controls.