Table 1—

Characteristics of randomised controlled trials included in the analysis of cardiovascular(CV) events and mortality

Study [Ref.]LocationTreatment duration weeksCOPD criteriaPrimary outcomeConcomitant cardiac conditions and exclusionsDrugMaleAge yrsFEV1 % predPrior ICS useCurrent smokers
Aaron 15#27 centres in Canada52FEV1/FVC <70%COPD exacerbationHTN: 41.4 %; CAD: 22.8%; CHF: 3.5%Salmeterol/fluticasone combination 50/500 μg b.i.d.57.967.5±8.939.4±11.970.832.4
HTN: 43.9%; CAD: 21.0%; CHF: 1.4% Excluded CHF with LV dysfunctionSalmeterol xinafoate 50 μg57.467.6±8.238.0±13.178.824.3
Burge 1618 UK hospitals156FEV1/FVC <70%Decline in FEV1NAFluticasone propionate 500 μg b.i.d.7563.7±7.150.3±14.951.136.4
Calverley 17196 centres in 25 countries52ERSFEV1NASalmeterol/fluticasone combination 50/500 μg b.i.d.7562.7±8.744.8±14.75052
Salmeterol xinafoate 50 μg b.i.d.7063.2±8.644.3±13.84951
Fluticasone propionate 500 μg b.i.d.7063.5±8.545±13.65453
Calverley 19109 centres in 15 countries52GOLDFEV1 and HRQoLNAFormoterol 9 μg/budesonide 400 μg b.i.d.7864±NA36±104733
Excluded any CV disorderFormoterol 9 μg b.i.d.7563±NA36±104836
Budesonide 400 μg b.i.d.7464±NA36±105139
Calverley 1844 centres in 42 countries156ERSMortalityNASalmeterol/fluticasone combination 50/500 μg b.i.d.7565±8.344.3±12.34743
Salmeterol xinafoate 50 μg7665.1±8.243.6±12.64543
Fluticasone propionate 500 μg b.i.d.7565±8.444.1±12.34743
Ferguson 2094 centres in North America52ATSRate of exacerbationsNASalmeterol/fluticasone combination 50/250 μg b.i.d.58.364.9±9.039.8±13.91540
Salmeterol xinafoate 50 μg b.i.d.52.065.0±9.150.6±15.41838
FLTA3025 2155 centres in the USA24ATSFEV1NAFluticasone propionate 500 μg b.i.d.6663.3±101301±500+NANA
Fluticasone propionate 250 μg b.i.d.7265.2±8.71240±486+NANA
Hanania 2676 centres in the USA24ATSFEV1Excluded abnormal ECGSalmeterol/fluticasone combination 50/250 μg b.i.d.6163±NA41±112343
Salmeterol xinafoate 50 μg b.i.d.5864±NA42±122051
Fluticasone propionate 250 μg b.i.d.6663±NA42±112848
Kardos 2795 centres in Germany52GOLDCOPD exacerbationsNASalmeterol/fluticasone combination 50/500 μg b.i.d.7463.8±8.340.4±8.940.649.7
Salmeterol xinafoate 50 μg b.i.d.77.664±8.240.3±8.544.449.9
Lung Health Study 2910 centres160FEV1/FVC <70 %Rate of decline in FEV1Excluded recent MITriamcinolone 600 μg b.i.d.6456.2±6.864.9±13.5NA90.5
Lofdahl 2839 centres in 9 EU countries156FEV1/FVC <70 %Rate of decline in FEV132 (15 on budesonide, 15 on placebo with previous ischaemic cardiac events)Budesonide 400 μg b.i.d.73.552.5±7.576.8±12.4NA39.4 pack-yrs
Placebo72.252.4±7.776.9±13.2NA39.2 pack-yrs
Mahler 30Multicentre trial in the USA24ATSFEV1 and TDINASalmeterol/fluticasone combination 50/500 μg b.i.d.6261.9±NA41±NA2846
Salmeterol xinafoate 50 μg b.i.d.6463.5±NA40±NA3146
Fluticasone propionate 500 μg b.i.d.6164.4±NA41±NA2546
Paggiaro 3113 European centres24ERSExacerbationsNAFluticasone propionate 500 μg b.i.d.9962±NA59±18NA49
Rennard 32237 centres in 9 countries52FEV1/FVC <70%FEV1HTN 41.6%Budesonide 160/ formoterol 4.5 μg b.i.d.62.363.2±8.933.8±11.4NA34.8
Cardiac disease 17.7%Budesonide 80/ formoterol 4.5 μg b.i.d.62.863.6±9.234.5±11.5NA37.0
Cardiac failure 2.9%Formoterol 4.5 μg b.i.d.65.362.9±9.133.7±11.2NA41.2
SCO100250 2298 centres in the USA and Canada52FEV1/FVC <70%Rate of exacerbationsNASalmeterol/fluticasone combination 50/250 μg b.i.d.5165.4±NA<50§NANA
Salmeterol xinafoate 50 μg b.i.d.5765.3±NA<50§NANA
SCO100470 24135 centres in Europe and Asia-Pacific24GOLDFEV1 and TDI scoreNASalmeterol/fluticasone combination 50/250 μg b.i.d.78.363.5±9.31654±459+NA42
Salmeterol xinafoate 50 μg b.i.d.77.263.7±9.01681±465+NA44
SCO40041 2331 centres in the USA156GOLDBone mineral densityNASalmeterol/fluticasone combination 50/250 μg b.i.d.59.765.4±8.36<70%NANA
Salmeterol xinafoate 50 μg b.i.d.62.765.9±9.52<70%NANA
SFCT01/SCO30002 2549 centres in Italy and Poland52FEV1/VC <88%Time to exacerbationsNAFluticasone propionate 500 μg b.i.d.83.964.6±8.7NANANA
Szafranski 3389 centres in 11 countries52GOLDNumber of severe exacerbations and FEV1NABudesonide/formoterol 160/4.5 μg 2 inhalations b.i.d.7664±NA36±NA2630
Excluded if relevant CV disorderFor 4.5 μg 2 inhalations b.i.d.7663±NA36±NA2838
Budesonide 200 μg 2 inhalations b.i.d.8064±NA37±NA2436
Tashkin 34194 sites in 5 countries26FEV1/FVC <70%FEV1NABudesonide 320/ formoterol 9 μg b.i.d.67.963±NA33.7±11.8NA40.8
Budesonide 160/ formoterol 9 μg64.463±NA34.1±10.9NA39.5
Budesonide 160 μg + formoterol 4.5 μg74.264±NA33.5±10.7NA37.3
Budesonide 160 μg67.663±NA33.5±10.8NA40.0
Formoterol 4.5 μg65.564±NA33.6±11.3NA38.4
van der Valk 35Pulmonary clinics26ATSExacerbations and HRQoLCardiac insufficiency excludedFluticasone propionate 500 μg b.i.d.85.464.1±6.857.5±
Vestbo 36Community in Denmark156FEV1/VC<70%Rate of FEV1 declineNABudesonide 400 μg b.i.d.58.659.0±8.386.2±20.6NA75.9
Wouters 3739 centres in the Netherlands52FEV1/VC <88%Rate of FEV1 declineExcluded if they had MI, angina or heart failure 3 months prior to entrySalmeterol/fluticasone combination 50/500 μg b.i.d.7363±7.947.4±13.98539
Salmeterol xinafoate 50 μg b.i.d.7564±7.748.2±12.98735
  • Data are presented as % or mean±sd, unless otherwise stated. COPD: chronic obstructive pulmonary disease; FEV1: forced expiratory volume in 1 s; % pred: % predicted; ICS: inhaled corticosteroid; FVC: forced vital capacity; HTN: hypertension; CAD: coronary artery disease; CHF: chronic heart failure; LV: left ventricle; NA: not available; ERS: European Respiratory Society; GOLD: Global Initiative for Chronic Obstructive Lung Disease; HRQoL: health-related quality of life; ATS; American Thoracic Society; EU: European Union; ECG: electrocardiogram; MI: myocardial infarction; TDI: transitional dyspnoea index; VC: vital capacity. #: treatment with tiotropium bromide 18 μg·day−1 in both arms and an additional tiotropium arm; : also had an additional salmeterol/fluticasone combination arm; +: reported in mL as % pred; §: FEV1 <50% pred, exact mean and sd data were unavailable.