This post hoc analysis showed that dual bronchodilation with tiotropium/olodaterol at the initiation of therapy in maintenance-naïve patients with COPD results in greater improvements in lung function, health status and dyspnoea than treatment with tiotropium alone, without any increased safety risk. These combined data from the TONADO and OTEMTO trials enabled a large population of maintenance-naïve patients with a range of disease severities to be analysed. As there is a lack of RCT data in this population, these data provide clinically important information regarding the optimal initial treatment approach for these individuals and support the use of LAMA/LABA treatment as initial pharmacotherapy.
In maintenance-naïve patients, the mean treatment differences observed with tiotropium/olodaterol versus tiotropium were generally in line with previously published results for the overall TONADO and OTEMTO study populations [8, 9]. In the TONADO trials, for example, significant improvements in trough FEV1, SGRQ and TDI were observed with tiotropium/olodaterol versus tiotropium .
In the current study, clinically relevant improvements from baseline were observed for both tiotropium/olodaterol and tiotropium in maintenance-naïve patients, but these were significantly greater in patients treated with tiotropium/olodaterol versus tiotropium alone. In patients with GOLD 2 COPD (characterised by moderate airflow obstruction) or GOLD 3 COPD (more severe COPD), the change from baseline was also beyond that of the thresholds for an MCID in trough FEV1 (> 0.1 L), SGRQ score (≥ 4 units) and TDI score (≥ 1 unit) in patients receiving tiotropium/olodaterol. However, this was not the case for all the endpoints in GOLD 2/3 patients treated with tiotropium. In patients with GOLD 2 COPD, tiotropium/olodaterol provided significant improvements compared with tiotropium alone. Hence, combination therapy could be beneficial in patients at this earlier stage of COPD, as well as in patients with more severe COPD (GOLD 3).
It is worth noting that the validated thresholds used to assess clinically relevant improvements have largely been established for comparisons of active treatment against placebo, whereas this analysis compares two active treatments . The mean differences between active treatments are therefore unlikely to exceed thresholds for an MCID, as was the case here. The responder analysis is, however, a valuable alternative approach to compare the two active treatments . In maintenance-naïve patients, the likelihood of achieving an MCID in trough FEV1 (> 0.1 L), quality of life (SGRQ score ≥ 4 units) or dyspnoea severity (TDI score ≥ 1 unit) was increased by 81%, 54% and 43%, respectively, with tiotropium/olodaterol versus tiotropium. When the data were combined, patients treated with tiotropium/olodaterol were 60% more likely to experience an MCID in at least one of the three assessed outcomes compared with tiotropium alone. In agreement with the current analysis, previous studies have demonstrated the benefits of alternative LAMA/LABA combinations, including umeclidinium/vilanterol and indacaterol/glycopyrronium, as well as tiotropium/olodaterol, in bronchodilator-naïve patients [15,16,17]. For example, in a post hoc analysis of umeclidinium/vilanterol versus tiotropium, dual therapy resulted in superior lung function and a reduction in short-term deterioration . Similarly, in a pooled analysis of the ARISE, SHINE and SPARK trials, indacaterol/glycopyrronium demonstrated greater improvements in lung function and patient-reported outcomes versus tiotropium or glycopyrronium monotherapy . This finding has been supported more recently by preliminary data from a 24-week RCT that reported a potential benefit of umeclidinium/vilanterol as initial maintenance therapy versus LAMA and LABA monotherapy with umeclidinium and salmeterol, respectively .
The symptoms of COPD can pose a major challenge for patients. The burden of symptoms makes it difficult to complete daily activities, and is associated with poor quality of life, declining health status and poor prognosis [18, 19]. COPD is underdiagnosed, with patients often not being diagnosed until their COPD has progressed to more advanced stages of the disease . The fastest decline in lung function is seen in the initial stages of COPD ; as such, treating patients at earlier stages of the disease could help them achieve control of respiratory symptoms sooner . In addition, use of dual bronchodilators has been shown to improve symptoms during physical activity [22, 23]; therefore, treatment of patients while they have more preserved lung function (i.e. at earlier GOLD stages) may allow patients to improve their health status and remain active so they are able to continue their daily activities for longer . Taking all these arguments into account, our results support first-line use of tiotropium/olodaterol in treatment-naïve patients with COPD.
It is worth noting that there is wide variability in how individual patients respond to treatment with long-acting bronchodilators . Not all patients will benefit from dual bronchodilator therapy, and clinical trial data, such as those presented here, cannot predict the response of every individual patient . Different approaches exist regarding whether patients should be treated according to group mean results or whether a more personalised approach, to identify responders versus non-responders, should be used . Nevertheless, our results suggest that tiotropium/olodaterol can provide additional benefits versus tiotropium monotherapy for most patients, without compromising safety.
The key strength of this analysis was the large size of the TONADO and OTEMTO trials, which permitted analysis of the maintenance-naïve subpopulations. This is one of the largest analyses to be conducted in treatment-naïve patients with COPD and, to our knowledge, is the largest analysis of treatment-naïve patients initiating dual bronchodilation therapy. Restricted options in the collection of patients’ medical history are a potential limitation of this analysis—the TONADO and OTEMTO trials only recorded whether patients were receiving LAMA, LABA or ICS treatment at study entry (i.e. when they signed the informed consent); hence, it is possible that some of the patients may have received maintenance treatment at some point previously. In addition, in the TONADO and OTEMTO studies, CAT and mMRC data were not collected; therefore, stratification of patients into GOLD A–D groups was not possible. This may be helpful in future studies to better establish the utility of the data in the real-world clinical setting. Also, given the 12-week duration of the OTEMTO trial, exacerbations were not a primary or secondary outcome. As the current analysis is also performed at 12 weeks, there were too few events to investigate any effect of exacerbations, although this could be of interest for future research.