Characteristics of randomised controlled trials included in the analysis of cardiovascular(CV) events and mortality
| Study [Ref.] | Location | Treatment duration weeks | COPD criteria | Primary outcome | Concomitant cardiac conditions and exclusions | Drug | Male | Age yrs | FEV1 % pred | Prior ICS use | Current smokers |
| Aaron 15# | 27 centres in Canada | 52 | FEV1/FVC <70% | COPD exacerbation | HTN: 41.4 %; CAD: 22.8%; CHF: 3.5% | Salmeterol/fluticasone combination 50/500 μg b.i.d. | 57.9 | 67.5±8.9 | 39.4±11.9 | 70.8 | 32.4 |
| HTN: 43.9%; CAD: 21.0%; CHF: 1.4% Excluded CHF with LV dysfunction | Salmeterol xinafoate 50 μg | 57.4 | 67.6±8.2 | 38.0±13.1 | 78.8 | 24.3 | |||||
| Burge 16 | 18 UK hospitals | 156 | FEV1/FVC <70% | Decline in FEV1 | NA | Fluticasone propionate 500 μg b.i.d. | 75 | 63.7±7.1 | 50.3±14.9 | 51.1 | 36.4 |
| Placebo | 74.2 | 63.8±7.1 | 50.0±14.9 | 57.0 | 39.2 | ||||||
| Calverley 17 | 196 centres in 25 countries | 52 | ERS | FEV1 | NA | Salmeterol/fluticasone combination 50/500 μg b.i.d. | 75 | 62.7±8.7 | 44.8±14.7 | 50 | 52 |
| Salmeterol xinafoate 50 μg b.i.d. | 70 | 63.2±8.6 | 44.3±13.8 | 49 | 51 | ||||||
| Fluticasone propionate 500 μg b.i.d. | 70 | 63.5±8.5 | 45±13.6 | 54 | 53 | ||||||
| Placebo | 75 | 63.4±8.6 | 44.2±13.7 | 52 | 47 | ||||||
| Calverley 19 | 109 centres in 15 countries | 52 | GOLD | FEV1 and HRQoL | NA | Formoterol 9 μg/budesonide 400 μg b.i.d. | 78 | 64±NA | 36±10 | 47 | 33 |
| Excluded any CV disorder | Formoterol 9 μg b.i.d. | 75 | 63±NA | 36±10 | 48 | 36 | |||||
| Budesonide 400 μg b.i.d. | 74 | 64±NA | 36±10 | 51 | 39 | ||||||
| Placebo | 75 | 65±NA | 36±10 | 46 | 30 | ||||||
| Calverley 18 | 44 centres in 42 countries | 156 | ERS | Mortality | NA | Salmeterol/fluticasone combination 50/500 μg b.i.d. | 75 | 65±8.3 | 44.3±12.3 | 47 | 43 |
| Salmeterol xinafoate 50 μg | 76 | 65.1±8.2 | 43.6±12.6 | 45 | 43 | ||||||
| Fluticasone propionate 500 μg b.i.d. | 75 | 65±8.4 | 44.1±12.3 | 47 | 43 | ||||||
| Placebo | 76 | 65±8.2 | 44.1±12.3 | 51 | 43 | ||||||
| Ferguson 20 | 94 centres in North America | 52 | ATS | Rate of exacerbations | NA | Salmeterol/fluticasone combination 50/250 μg b.i.d. | 58.3 | 64.9±9.0 | 39.8±13.9 | 15 | 40 |
| Salmeterol xinafoate 50 μg b.i.d. | 52.0 | 65.0±9.1 | 50.6±15.4 | 18 | 38 | ||||||
| FLTA3025 21 | 55 centres in the USA | 24 | ATS | FEV1 | NA | Fluticasone propionate 500 μg b.i.d. | 66 | 63.3±10 | 1301±500+ | NA | NA |
| Fluticasone propionate 250 μg b.i.d. | 72 | 65.2±8.7 | 1240±486+ | NA | NA | ||||||
| Placebo | 70 | 64.8±9.5 | 1221±502+ | NA | NA | ||||||
| Hanania 26 | 76 centres in the USA | 24 | ATS | FEV1 | Excluded abnormal ECG | Salmeterol/fluticasone combination 50/250 μg b.i.d. | 61 | 63±NA | 41±11 | 23 | 43 |
| Salmeterol xinafoate 50 μg b.i.d. | 58 | 64±NA | 42±12 | 20 | 51 | ||||||
| Fluticasone propionate 250 μg b.i.d. | 66 | 63±NA | 42±11 | 28 | 48 | ||||||
| Placebo | 58 | 65±NA | 42±12 | 30 | 47 | ||||||
| Kardos 27 | 95 centres in Germany | 52 | GOLD | COPD exacerbations | NA | Salmeterol/fluticasone combination 50/500 μg b.i.d. | 74 | 63.8±8.3 | 40.4±8.9 | 40.6 | 49.7 |
| Salmeterol xinafoate 50 μg b.i.d. | 77.6 | 64±8.2 | 40.3±8.5 | 44.4 | 49.9 | ||||||
| Lung Health Study 29 | 10 centres | 160 | FEV1/FVC <70 % | Rate of decline in FEV1 | Excluded recent MI | Triamcinolone 600 μg b.i.d. | 64 | 56.2±6.8 | 64.9±13.5 | NA | 90.5 |
| Placebo | 62.1 | 56.4±6.8 | 63.4±13.2 | NA | 89.8 | ||||||
| Lofdahl 28 | 39 centres in 9 EU countries | 156 | FEV1/FVC <70 % | Rate of decline in FEV1 | 32 (15 on budesonide, 15 on placebo with previous ischaemic cardiac events) | Budesonide 400 μg b.i.d. | 73.5 | 52.5±7.5 | 76.8±12.4 | NA | 39.4 pack-yrs |
| Placebo | 72.2 | 52.4±7.7 | 76.9±13.2 | NA | 39.2 pack-yrs | ||||||
| Mahler 30 | Multicentre trial in the USA | 24 | ATS | FEV1 and TDI | NA | Salmeterol/fluticasone combination 50/500 μg b.i.d. | 62 | 61.9±NA | 41±NA | 28 | 46 |
| Salmeterol xinafoate 50 μg b.i.d. | 64 | 63.5±NA | 40±NA | 31 | 46 | ||||||
| Fluticasone propionate 500 μg b.i.d. | 61 | 64.4±NA | 41±NA | 25 | 46 | ||||||
| Placebo | 75 | 64±NA | 41±NA | 18 | 54 | ||||||
| Paggiaro 31 | 13 European centres | 24 | ERS | Exacerbations | NA | Fluticasone propionate 500 μg b.i.d. | 99 | 62±NA | 59±18 | NA | 49 |
| Placebo | 78 | 64±NA | 55±17 | NA | 49 | ||||||
| Rennard 32 | 237 centres in 9 countries | 52 | FEV1/FVC <70% | FEV1 | HTN 41.6% | Budesonide 160/ formoterol 4.5 μg b.i.d. | 62.3 | 63.2±8.9 | 33.8±11.4 | NA | 34.8 |
| Cardiac disease 17.7% | Budesonide 80/ formoterol 4.5 μg b.i.d. | 62.8 | 63.6±9.2 | 34.5±11.5 | NA | 37.0 | |||||
| Cardiac failure 2.9% | Formoterol 4.5 μg b.i.d. | 65.3 | 62.9±9.1 | 33.7±11.2 | NA | 41.2 | |||||
| Placebo | 65.3 | 62.9±9.1 | 35.5±11.9 | NA | 39.5 | ||||||
| SCO100250 22 | 98 centres in the USA and Canada | 52 | FEV1/FVC <70% | Rate of exacerbations | NA | Salmeterol/fluticasone combination 50/250 μg b.i.d. | 51 | 65.4±NA | <50§ | NA | NA |
| Salmeterol xinafoate 50 μg b.i.d. | 57 | 65.3±NA | <50§ | NA | NA | ||||||
| SCO100470 24 | 135 centres in Europe and Asia-Pacific | 24 | GOLD | FEV1 and TDI score | NA | Salmeterol/fluticasone combination 50/250 μg b.i.d. | 78.3 | 63.5±9.3 | 1654±459+ | NA | 42 |
| Salmeterol xinafoate 50 μg b.i.d. | 77.2 | 63.7±9.0 | 1681±465+ | NA | 44 | ||||||
| SCO40041 23 | 31 centres in the USA | 156 | GOLD | Bone mineral density | NA | Salmeterol/fluticasone combination 50/250 μg b.i.d. | 59.7 | 65.4±8.36 | <70% | NA | NA |
| Salmeterol xinafoate 50 μg b.i.d. | 62.7 | 65.9±9.52 | <70% | NA | NA | ||||||
| SFCT01/SCO30002 25¶ | 49 centres in Italy and Poland | 52 | FEV1/VC <88% | Time to exacerbations | NA | Fluticasone propionate 500 μg b.i.d. | 83.9 | 64.6±8.7 | NA | NA | NA |
| Placebo | 80 | 65.7±9.0 | NA | NA | NA | ||||||
| Szafranski 33 | 89 centres in 11 countries | 52 | GOLD | Number of severe exacerbations and FEV1 | NA | Budesonide/formoterol 160/4.5 μg 2 inhalations b.i.d. | 76 | 64±NA | 36±NA | 26 | 30 |
| Excluded if relevant CV disorder | For 4.5 μg 2 inhalations b.i.d. | 76 | 63±NA | 36±NA | 28 | 38 | |||||
| Budesonide 200 μg 2 inhalations b.i.d. | 80 | 64±NA | 37±NA | 24 | 36 | ||||||
| Placebo | 83 | 65±NA | 36±NA | 26 | 34 | ||||||
| Tashkin 34 | 194 sites in 5 countries | 26 | FEV1/FVC <70% | FEV1 | NA | Budesonide 320/ formoterol 9 μg b.i.d. | 67.9 | 63±NA | 33.7±11.8 | NA | 40.8 |
| Budesonide 160/ formoterol 9 μg | 64.4 | 63±NA | 34.1±10.9 | NA | 39.5 | ||||||
| Budesonide 160 μg + formoterol 4.5 μg | 74.2 | 64±NA | 33.5±10.7 | NA | 37.3 | ||||||
| Budesonide 160 μg | 67.6 | 63±NA | 33.5±10.8 | NA | 40.0 | ||||||
| Formoterol 4.5 μg | 65.5 | 64±NA | 33.6±11.3 | NA | 38.4 | ||||||
| Placebo | 69.0 | 63±NA | 34.6±10.5 | NA | 36.0 | ||||||
| van der Valk 35 | Pulmonary clinics | 26 | ATS | Exacerbations and HRQoL | Cardiac insufficiency excluded | Fluticasone propionate 500 μg b.i.d. | 85.4 | 64.1±6.8 | 57.5±14.1 | 86.2 | 22.0 |
| Placebo | 83.5 | 64±6.7 | 56.1±14.8 | 80.2 | 33.0 | ||||||
| Vestbo 36 | Community in Denmark | 156 | FEV1/VC<70% | Rate of FEV1 decline | NA | Budesonide 400 μg b.i.d. | 58.6 | 59.0±8.3 | 86.2±20.6 | NA | 75.9 |
| Placebo | 62.1 | 59.1±9.7 | 86.9±21.1 | NA | 77.2 | ||||||
| Wouters 37 | 39 centres in the Netherlands | 52 | FEV1/VC <88% | Rate of FEV1 decline | Excluded if they had MI, angina or heart failure 3 months prior to entry | Salmeterol/fluticasone combination 50/500 μg b.i.d. | 73 | 63±7.9 | 47.4±13.9 | 85 | 39 |
| Salmeterol xinafoate 50 μg b.i.d. | 75 | 64±7.7 | 48.2±12.9 | 87 | 35 |
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.