Benefits of Tiotropium/Olodaterol Compared with Tiotropium in Patients with COPD Receiving only LAMA at Baseline: Pooled Analysis of the TONADO^® and OTEMTO^® Studies

Chronic obstructive pulmonary disease (COPD) is a leading cause of mortality and morbidity [1‐4]. In 2016, COPD was the third leading cause of death worldwide, a trend that is anticipated to continue through 2020 [5, 6]. Additionally, patients with COPD continue to report reduced quality of life [7].

The current Global Initiative for Chronic Obstructive Lung Disease (GOLD) strategy report recommends a stepwise pharmacological treatment plan for patients with COPD that begins with a long-acting bronchodilator monotherapy (long-acting muscarinic antagonists [LAMAs] or long-acting β₂-agonists [LABAs]) as first-line maintenance treatment for most patients, with escalation to dual bronchodilation as the next step [8]. In line with these recommendations, many patients receive initial treatment with LAMAs or, less commonly, LABAs; despite this, many patients treated with monotherapy remain symptomatic [9‐13]. The mechanism of action for LAMAs involves blocking the bronchoconstriction effect of acetylcholine, whereas LABAs relax airway smooth muscle by activating β₂-receptors [9]. Therefore, combining these therapies can have complementary and additive effects. Accordingly, the American Thoracic Society 2020 clinical practice guidelines recommend dual LAMA/LABA bronchodilator therapy over LABA or LAMA monotherapy for patients with COPD with dyspnoea or exercise intolerance [14]. Additionally, the National Institute for Health and Care Excellence recommends dual LAMA/LABA therapy for patients with no indication of asthmatic features or corticosteroid responsiveness, who remain breathless or have exacerbations despite optimised non-pharmacological management and use of short-acting bronchodilators [15].

Tiotropium, a once-daily LAMA, has been shown to provide long-term improvements in lung function, quality of life and exercise capacity, along with a reduced risk of exacerbations [7, 10, 16]. Olodaterol, a once-daily LABA with high selectivity for the β₂-adrenoceptor [17], has been combined with tiotropium as a dual therapy (tiotropium/olodaterol) for COPD delivered using the Respimat^® inhaler [2, 10, 17, 18]. The combination of tiotropium/olodaterol has been assessed in multiple trials and across different disease severities, demonstrating improvements in lung function, symptoms and quality of life, which has led to its approval for use in many countries worldwide [17‐21].

TONADO^® 1&2 and OTEMTO^® 1&2 were paired, replicate, double-blind, parallel-group, active-controlled, multicentre, randomised, Phase III studies that included patients with moderate-to-severe (OTEMTO) or moderate-to-very-severe (TONADO) COPD [10, 22]. TONADO previously showed improvements in lung function with acceptable safety profiles over a 52-week period when patients were treated with tiotropium/olodaterol compared with tiotropium or olodaterol monotherapies [10]. OTEMTO also demonstrated improvements in lung function, with an acceptable safety profile in patients treated with tiotropium/olodaterol compared with tiotropium monotherapy or placebo [22].

Previous studies comparing LAMA/LABA with their monotherapies included patients on a range of background therapies [10, 23], making it difficult to truly assess the clinical benefit of treatment escalation from one to two long-acting bronchodilators. In this pooled analysis, we focused specifically on patients with moderate-to-severe COPD treated with LAMA monotherapy at baseline to assess the effects of treatment escalation to dual-bronchodilator therapy on lung function, symptoms and safety profiles [10, 22].

Long-acting bronchodilators remain a key first-line therapy for COPD maintenance [8, 27], but many patients remain symptomatic on monotherapy [9‐13]. This post hoc analysis focused on a subset of patients from the TONADO and OTEMTO studies with moderate-to-severe COPD who were treated with only LAMA monotherapy at baseline [10, 22]. Patients were excluded if they were currently on any other maintenance treatment. After 12 weeks, optimisation of treatment with tiotropium/olodaterol dual-bronchodilator therapy provided greater improvements in lung function (trough FEV₁), health status (SGRQ) and dyspnoea severity (TDI) compared with continuing LAMA monotherapy. These results support treatment escalation from LAMA monotherapy to dual-bronchodilator treatment (as recommended in the GOLD management strategy [8]) to optimise lung function, achieve better symptom control and improve patient quality of life.

We observed a greater likelihood of achieving an MCID in at least one of the outcomes (i.e., any trough FEV₁, SGRQ or TDI improvements) in patients treated with tiotropium/olodaterol compared with patients treated with tiotropium monotherapy (odds ratio 2.43 ± 0.77, indicating a relative increase of 143% in the likelihood of achieving an FEV₁, TDI or SGRQ response with tiotropium/olodaterol versus tiotropium; P = 0.0046). Data from the current analysis are consistent with the results from the overall populations reported in the individual study publications, suggesting that the benefits of tiotropium/olodaterol compared with tiotropium are observed across a range of COPD patients, including those previously treated with LAMA monotherapy prior to study entry [10, 22].

Despite the effectiveness shown with LAMA or LABA monotherapy, many patients remain symptomatic on these treatments [9‐13], which can in turn impact daily living activities. Avoidance of physical activity to prevent dyspnoea can lead to deconditioning, thus further reducing patient activity and causing a downward spiral associated with worse patient outcomes [28, 29]. Patients with COPD who have some level of regular physical activity have lower risks of COPD-related hospital admissions and mortality [29]. Patient evaluations should include exploration of symptoms by incorporating specialised tools, such as a short patient-centred questionnaire, to assess symptom severity, activity limitation and health-related quality of life [30]. In clinical practice, the COPD Assessment Test is currently one of the most useful and practical questionnaires [30]. Using the results from these tools, individual patient treatment plans should be reassessed and additional therapies added to optimise treatment [12].

In support of the current study, similar findings have been shown in other studies comparing LAMA monotherapy with LAMA/LABA in patients with COPD [2, 19, 20, 23, 31]. In a recent systematic literature review and meta-analysis by Han et al. [32], patients treated with LAMA/LABA showed a 0.127 l (95% CI 0.108, 0.145; P < 0.01) improvement in FEV₁ area under the time curve 0–3 h post-dose at 12 weeks versus tiotropium. LAMA/LABA therapy also significantly improved the SGRQ total score at 12 weeks compared with tiotropium (improvement of 1.87 points; 95% CI − 2.72, − 1.02; P < 0.01) and increased the SGRQ responder rate by 19% [32]. However, the studies in this meta-analysis included patients on different background therapies, such as ICS, which could influence the overall results [32]. In the current analysis, the confounding effects of previous therapies are removed, enabling a cleaner comparison of the impact of escalation from one bronchodilator to two bronchodilators and indicating significant improvements in trough FEV₁, SGRQ and TDI after 12 weeks with tiotropium/olodaterol compared with tiotropium monotherapy.

Post hoc analyses of clinical trials have been conducted comparing LAMA/LABA combinations to long-acting bronchodilator monotherapies and also in various patient subgroups, including ‘treatment-naïve’ COPD patients who were previously not receiving any inhaled maintenance treatment. These analyses have shown similar results to the overall study population, with additional benefits for LAMA/LABA treatment across a range of lung function endpoints and patient-reported outcomes [33‐36]. Such analyses have been used to provide evidence in the debate of whether to start COPD therapy with a LAMA/LABA or monotherapy [33‐36]. The current analysis utilises large clinical trial data sets to address a question that is relevant to clinical practice; namely, what is the clinical benefit of treatment escalation from LAMA to LAMA/LABA?

Donohue et al. reported that only approximately one-third of patients displayed a pronounced lung function response to both long-acting bronchodilator classes, highlighting the between-patient variation in response to different bronchodilators [37]. The current analysis provides information from a large pooled data set for treatment escalation responses on lung function and patient-reported outcomes, and the responder analysis supports the escalation step from LAMA to LAMA/LABA. However, as in the study by Donohue et al. [37], clinical benefit will vary between individuals.

Previously, some safety concerns have been raised with use of dual bronchodilation in COPD [38‐40]. However, our analysis of the TONADO and OTEMTO studies identified comparable safety profiles for the tiotropium and tiotropium/olodaterol treatment arms, presenting no specific concerns and indicating that stepping up from monotherapy to dual therapy is not met with an adverse safety profile. This is in agreement with previous studies evaluating the safety of tiotropium/olodaterol [2, 9, 10, 22, 41‐43]. In the individual studies, no increase in major adverse cardiac events was observed between tiotropium/olodaterol and its monocomponents [10, 41]. In a previous pooled analysis of TONADO and OTEMTO, the incidence of AEs was similar between treatment groups [2]; in OTEMTO, more AEs leading to treatment discontinuation were present in the placebo groups compared with the treatment groups, while in TONADO, AEs were similar across the treatment groups, ranging from 73% to 77% [2]. In a separate pooled analysis of these studies, no additional safety concerns were identified in older patients using tiotropium/olodaterol [44].

The current analysis pools data from four clinical trials, representing a large, clinically relevant patient population and allowing analysis of patients with COPD who were using LAMA monotherapy at baseline. However, these results have limitations due to the post hoc nature of the analysis and are therefore not powered for statistical comparisons, but nevertheless provide clinical value in the absence of any prospective data. At baseline, significant differences between the treatment arms were identified for weight and smoking status, but sensitivity analyses controlling for these covariates did not alter the presented results. This analysis also focuses on a subgroup of patients from the original studies that may not be fully representative of a wider COPD population.

Stepping up treatment to once-daily tiotropium/olodaterol led to significant improvements in lung function, dyspnoea severity and health status compared with tiotropium alone in patients with COPD who were receiving LAMA therapy at baseline. This shows that patients benefitted from maximising bronchodilation and treatment optimisation with tiotropium/olodaterol. Dual bronchodilation could provide additional benefits for patients with COPD currently on LAMA monotherapy and can be considered at initiation of maintenance therapy for patients with COPD.