Search strategies yielded 201 unique references, of which five met the eligibility criteria. In addition, reports of two more unpublished studies were identified in ICTRP (Fig. 1: Flow diagram of study selection). We identified a total of 10 RCT involving 10,918 participants that were eligible for the review: ANHELTO 1 & 2 (published in one article) [14], ENERGITO [15], MORACTO 1 & 2 [16, 17], OTEMTO 1 & 2 [18, 19], TONADO 1 & 2 [20, 21] and VIVACITO [22]. We identified one additional RCT that has been completed published only as a protocol [23, 24] (PHYSACTO), and one more trial that is still ongoing (DYNAGITO) [25].

Fig. 1 Flow diagram of study selection Full size image

Another two RCT assessing the combined treatment with TIO/OLO were excluded due to the short follow up period (4 weeks) [26], or the lack of a comparison with any of the mono-components or an active control (TORRACTO) [27].

Description of the studies

Details on the characteristics of the included studies are provided in Table 1 (Characteristics of the included studies: summary) and Additional file 2: Table S1.

Table 1 Characteristics of the included studies: summary Full size table

Six studies had a parallel group design, with a sample size ranging from 607 and 1577 participants, whereas the other four had a crossover design that included between 219 and 295 participants (mean 1091; median 809). All studies except ANHELTO 1 & 2 (which were conducted exclusively in the US) were multinational with a wide range of participating countries. Treatment duration was 6 weeks (4 studies), 12 weeks (4 studies) and 24 weeks (2 studies), with an additional extension up to 54 weeks in the later ones.

All trials (except ANHELTO 1 & 2) assessed once-daily TIO/OLO FDC, which was administered with the use of a single inhaler (Respimat®). By contrast, in ANHELTO 1&2, the combination treatment TIO + OLO was administered using two different inhalers (HandiHaler® and Respimat®). Regarding the dosing of TIO in the combined treatment, ANHELTO 1 & 2 used TIO 18 μg, whereas all the rest assessed two different FDC using high and low doses of TIO (5 μg and 2.5 μg). OLO was always administered at the same dose of 5 μg. For the purposes of this review, only data from TIO/OLO FDC arms where high dose of TIO (5 μg) were used have been included, as the low dose (2.5 μg) is not marketed.

Nine studies had a control group with TIO (5 or 18 μg), and five a control group with OLO (5 μg). Only one study compared the combined therapy with TIO/OLO versus the combined therapy with salmeterol plus fluticasone at two different dose combination (50/500 μg or 50/250 μg) [15].

Overall, the inclusion criteria and populations’ characteristics of the studies were very homogeneous. Participants were aged ≥40 years, current or ex-smokers with a smoking history of more than 10 pack-years, mostly with moderate to severe COPD; only TONADO 1 & 2 included participants with very severe disease (FEV 1 < 30% predicted, 10.8% of the participants). All studies required participants to be able to inhale medication in a competent manner from the Respimat® or HandiHaler® inhalers as well as to perform technically acceptable pulmonary function tests, and maintain records (paper diary) as required.

Risk of bias of the included studies

Risk of bias was deemed low for all domains evaluated in all included trials (details in Additional file 3: Figure S1 and Additional file 4: Figure S2). Risk of bias was assessed according the criteria outlined in the Cochrane Handbook. Where no sufficient details were provided in the article (i.e. allocation concealment), these were requested to the sponsor who provided further details.

Efficacy of the intervention

Trough FEV 1 was reported in eight of the RCT [14, 15, 18,19,20,21,22]. Overall, the combined therapy proved to be superior to the mono-components in all studies (Fig. 2: Trough FEV 1 ). TIO/OLO was associated with significantly higher trough FEV 1 when compared with TIO (MD 0.06 [0.04 to 0.07], I2 = 33%) (5 RCT with 3101 patients) or OLO (MD 0.09 [0.07–0.10], I2 = 0%) (3 RCT with 2313 patients). TIO/OLO showed a statistically significant greater improvement in trough FEV 1 after 6 weeks of treatment compared to both doses of salmeterol plus fluticasone (with an improvement ranging between 42 and 58 mL). When treatment was administered in separate inhalers, TIO + OLO (18/5 μg) resulted in significant improvements over TIO (18 μg) in trough FEV 1 (treatment differences: 62 mL [P < 0.001] in ANHELTO 1; 40 mL [P = 0.0029] in ANHELTO 2) [14].

Fig. 2 Trough FEV 1 Full size image

TIO/OLO was associated with an improved quality of life compared to TIO (MD -1.56 [−2.41 to −0.71], I2 = 0%) in 4 RCT with 2697 participants [14, 18, 19] or OLO (−1.69 [−2.77 to −0.61]) in 2 RCT with 1933 participants [20, 21] (Fig. 3: Quality of life SGRQ: change from baseline). More participants receiving TIO/OLO had a clinically meaningful difference in SGRQ compared to TIO [14, 18, 19] (RR 1.21 [1.12 to 1.30], I2 = 0%) or OLO [20, 21] (RR 1.28 [1.18 to 1.40]) (Fig. 4: Quality of life SGRQ: responders).

Fig. 3 Quality of life SGRQ: change from baseline Full size image

Fig. 4 Quality of life SGRQ: responders Full size image

Similar results were found for TIO + OLO (18/5 μg) vs TIO, both in the SGRQ total score change [14] (MD: -1.90 [−2.80 to −1.00]) and SGRQ responders rate (RR 1.16 [1.06 to 1.27]) (Figs. 3 and 4).

Four studies measured the Mahler Transition Dyspnea Index (TDI) [18,19,20,21]. TIO/OLO led to improved TDI compared to TIO (MD 0.43 [0.22 to 0.65], I2 = 1%) and OLO (RR 0.42 [0.16 to 0.68]) (Fig. 5: Symptoms TDI: change from baseline). More participants receiving TIO/OLO had a clinically meaningful difference in TDI score (≥1.0 unit) compared to TIO (RR 1.17 [1.07 to 1.28], I2 = 75%) or OLO (RR 1.14 [1.01 to 1.28]) (Fig. 6: Symptoms TDI: responders).

Fig. 5 Symptoms TDI: change from baseline Full size image

Rescue medication usage was lower with TIO + OLO (18/5 μg) than with TIO [14, 18,19,20,21]. On average, TIO + OLO reduced the number of days using rescue medication by 8.5 days (95% CI 4.2, 12.8) in ANHELTO 1 and by 7.2 days (95% CI 3 to 11.49) in ANHELTO 2. In OTEMTO 1 & 2, the use of rescue medication over 24 h was lower in patients receiving TIO/OLO compared to TIO after 12 weeks (P < 0.05) (post-hoc analysis). In TONADO 1 & 2, TIO/OLO provided reductions in adjusted weekly mean daily (24-h) rescue medication use compared to the mono-components throughout the 52-week treatment period.

MORACTO 1 & 2 trials showed a trend over increased endurance time for TIO/OLO compared to TIO (MD 8.06 [−13.76 to 29.87], I2 = 99%) or OLO (MD 23.67 [−21.34 to 68.69], I2 = 100%); however, these results are limited by the significant heterogeneity between the two included trials.

Regarding safety, no differences were observed in the frequency of general and serious adverse events between TIO/OLO and the mono-components. All adverse events were reported in ANHELTO 1 & 2, OTEMTO 1 & 2, TONADO 1 & 2, VIVACITO and ENERGITO trials. No significant differences between groups were observed when comparing TIO/OLO versus mono-components (RR 0.99 [0.96 to 1.02], I2 = 0%) or versus salmeterol fluticasone (RR 1.02 [0.85 to 1.23]) (Fig. 7: All adverse events). Serious adverse events were assessed in ANHELTO 1 & 2, OTEMTO 1 & 2, TONADO 1 & 2, VIVACITO and ENERGITO trials. A similar between group distribution was observed between participants receiving TIO/OLO versus mono-components or placebo (RR 0.99 [0.88 to 1.11], I2 = 49%). Also, ENERGITO trial concluded similar number of serious adverse events were observed between participants receiving TIO/OLO versus fluticasone/salmeterol (RR 0.80 [0.39 to 1.65]).