Effects of Tiotropium/Olodaterol on Activity-Related Breathlessness, Exercise Endurance and Physical Activity in Patients with COPD: Narrative Review with Meta-/Pooled Analyses

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A comprehensive set of studies with large study populations (over 16,000 patients combined) investigated the role of tiotropium/olodaterol on lung function and health status/quality of life. Long-term phase III clinical trials established that tiotropium/olodaterol improves airflow obstruction compared with its monocomponents, as well as improving health status/quality of life [20‐22]. Improvements in St. George’s Respiratory Questionnaire scores (a measure of impact on overall health, daily life and patient-perceived well-being in people with obstructive airways disease) and Mahler Transition Dyspnoea Index focal score (a measure of breathlessness in daily life) provided evidence that the observed improvements with tiotropium/olodaterol translate into patient-reported improvements in health status/quality of life and activity-related breathlessness [20, 22]. Given the importance of these findings, the effects of tiotropium/olodaterol treatment on activity-related breathlessness were studied in more detail in several trials during the tiotropium/olodaterol clinical programme.

In COPD, forced expiratory volume in 1 s (FEV₁) is a commonly used endpoint as a measure of treatment efficacy [23]. However, the relationship between FEV₁ and daily physical activity is relatively modest, suggesting that the decrease in physical activity with COPD does not depend only on the severity of airflow limitation measured at rest, but may also depend on other factors, including dynamic hyperinflation [24]. In clinical practice and research, the degree of hyperinflation at rest and exercise may be tracked by measuring IC [25, 26]. A progressive reduction in IC during exercise is a sign of ongoing gas trapping [26]. There are many studies demonstrating that bronchodilator treatment leading to lung deflation (i.e. an increase in IC) is associated with clinically important improvements in breathlessness and in the level of patients’ exercise endurance [26, 27].

Tiotropium/olodaterol treatment has been repeatedly found to improve lung function and reduce hyperinflation compared with either of the monocomponents or with placebo in patients with COPD [21, 28‐30]. In the VIVACITO incomplete-crossover study, 6 weeks’ treatment with tiotropium/olodaterol increased IC ± standard error (SE) at 2.5 h post treatment (tiotropium/olodaterol 5/5 µg: 0.351 ± 0.038 L; placebo: 0.016 ± 0.040 L; P < 0.0001 for tiotropium/olodaterol versus placebo) (Table 1) [21]. This was further supported by a significant decrease in functional residual capacity with tiotropium/olodaterol versus placebo (tiotropium/olodaterol 5/5 µg: − 0.547 L; placebo: − 0.052 L; P < 0.0001) [21]. Residual volume also decreased significantly with tiotropium/olodaterol (P < 0.0001 versus placebo) [21]. In the MORACTO study, IC prior to exercise was greater after 6 weeks of treatment with tiotropium/olodaterol 5/5 µg compared with placebo (mean ± SD 0.254 ± 0.019 L; P < 0.0001; Table 1); mean IC also increased in TORRACTO with tiotropium/olodaterol compared with placebo after 6 and 12 weeks (descriptive statistics, nominal P < 0.05 at both time points) [28, 29]. More recently, in the OTIVATO study, which was conducted in patients with evidence of hyperinflation and breathlessness during everyday activities, tiotropium/olodaterol 5/5 µg increased mean resting IC ± SE from baseline by 0.489 ± 0.049 L after 6 weeks of treatment, with a treatment difference versus tiotropium monotherapy of 0.218 L (95% confidence interval [CI] 0.121 L, 0.314 L; P < 0.0001) (Table 1) [30].

In order to summarise previously published data, we also performed a meta-analysis/pooled analysis evaluating the effect of tiotropium/olodaterol on inspiratory capacity at rest in MORACTO 1 and 2, TORRACTO, VIVACITO and OTIVATO (see Box 1 for details).

Exercise endurance tests are often used in clinical trials to evaluate exercise capacity. These tests generally involve walking on a level surface or cycling on a stationary bicycle. In some of the tests, exercise intensity is externally controlled either by imposing a walking speed or by the work rate on a bicycle. Patients are asked to exercise until limited by exhaustion; the outcome variables are the endurance time and symptoms that can be measured at the same exercise intensity and duration each time they undertake the test (“isotime”). Summaries of some of the more commonly used tests and the proposed minimal clinically important difference for each outcome measure can be found in Table 2. Options to evaluate patient endurance include the constant work rate cycle ergometry (CWRCE; cycling conducted at a set resistance for as long as patients can continue or until they are limited by their symptoms) and the endurance shuttle walk test (ESWT; patients walk back and forth between two cones placed 10 m apart at a predefined and constant speed until they are impeded by symptoms) (Table 2) [31, 32]. The 6-min walk test (6MWT; during which patients are asked to walk as far as they can back and forth between two cones placed 100 feet apart in 6 min) is another commonly used exercise test [33]. However, its design differs from the two preceding tests because the walking speed is self-controlled and may vary from one test to another. As such, it is not possible to measure symptoms at the same work intensity with this test. Rather, the outcome variable with the 6MWT is walking distance. In addition, as 6MWT is self-paced, it provides a measure of exercise performance rather than being a maximal test; it is therefore not as responsive to bronchodilator therapy as CWRCE and ESWT [34, 35].

Monitoring exercise capacity in a laboratory setting allows accurate physiological evaluation in a controlled environment. Treatment with tiotropium/olodaterol has been found to improve exercise capacity during walking and cycling tests. Two 6-week, replicate, incomplete-crossover studies, each in approximately 300 patients, found a 20.9% and 13.4% increase in geometric mean exercise endurance time during CWRCE in MORACTO 1 and MORACTO 2, respectively (both P < 0.0001) in patients with COPD treated with tiotropium/olodaterol compared with placebo (Table 3) [28]. More recently, data from TORRACTO demonstrated, in approximately 400 patients, that tiotropium/olodaterol 5/5 µg improved exercise endurance time by 13.8% versus placebo (geometric mean ± SE, tiotropium/olodaterol 5/5 µg: 527.5 ± 20.2 s; placebo: 463.6 ± 18.8 s; P = 0.02 for tiotropium/olodaterol versus placebo) during CWRCE after 12 weeks (Table 3) [29]. This study also included an ESWT outcome in a subset of patients. After 12 weeks of treatment with tiotropium/olodaterol 5/5 µg, walking endurance time increased by 20.9% compared with placebo (geometric mean ± SE, tiotropium/olodaterol 5/5 µg: 376.4 ± 25.0 s; placebo: 311.4 ± 22.5 s; descriptive statistics, nominal P = 0.055 for tiotropium/olodaterol versus placebo) (Table 3) [29].

Additional insight comes from our meta-analysis/pooled analysis that we performed to evaluate the effect of tiotropium/olodaterol on endurance time during CWRCE in MORACTO 1 and 2 and TORRACTO (see Box 1 for details).

Improving breathlessness and physical activity are important goals in the treatment of COPD, and considered a valuable component of COPD assessment, particularly in response to treatment [16]. Exercise studies have demonstrated that bronchodilator treatment improves activity-related breathlessness in patients with COPD [28, 29, 37]. The 1-year, replicate, parallel-group, multicentre TONADO trials demonstrated that dual bronchodilation with tiotropium in combination with olodaterol in patients with moderate to very severe COPD improves lung function and reduces breathlessness compared with the monocomponents [20].

It is important to understand how reducing hyperinflation with tiotropium/olodaterol treatment can help to decrease activity-related breathlessness. Measuring patient perception of symptoms is very informative in understanding how the information arising from the exercising locomotor and respiratory muscles is integrated by the central nervous system [38]. One approach used is to ask patients to rate their breathlessness during controlled in-clinic exercise tests using a scale such as the modified Borg scale (Table 2) [38, 39]. This scale is a simple numerical list from which patients are asked to rate their symptoms during exertion [40].

Treatment with tiotropium/olodaterol has consistently been found to decrease breathing discomfort, measured using the Borg dyspnoea scale during CWRCE. In the 6-week replicate MORACTO trials, tiotropium/olodaterol reduced breathing discomfort at isotime during CWRCE by 0.693 Borg units (P = 0.0001) compared with placebo [28]. The 12-week TORRACTO clinical trial found that treatment with tiotropium/olodaterol decreased breathing discomfort versus placebo at isotime during the CWRCE at week 6 (− 0.600 Borg units; 95% CI − 1.180, − 0.019; P = 0.0429) and a trend for decreased breathing discomfort at week 12 (− 0.348 Borg units; 95% CI − 0.936, 0.239; P = 0.2451) [29].

The 3-min constant speed shuttle test is an exercise test specifically designed to measure the effect of interventions on breathlessness during activity. Patients are asked to score their perception of breathlessness before, after and at prespecified time points during the shuttle test using the Borg scale [41, 42]. In contrast to the 6MWT, the walking speed is fixed, allowing breathlessness perception at the same exercise intensity to be compared before and after treatment. In a recent two-period crossover study, 6 weeks of treatment with tiotropium/olodaterol and tiotropium alone reduced the intensity of breathlessness at the end of the 3-min constant speed shuttle test (mean improvement − 1.325 units [95% CI − 1.594, − 1.056] and − 0.968 units [95% CI − 1.238, − 0.698], respectively) compared with baseline [30]. In this trial, a statistically significantly greater reduction in the intensity of breathlessness was observed with tiotropium/olodaterol versus tiotropium (treatment difference − 0.357 units; 95% CI − 0.661, − 0.053; P = 0.0217) [30]. Despite the between-treatment difference in dyspnoea score being relatively small, it was calculated that a number needed to treat (NNT) of 7 was necessary to achieve a clinically relevant improvement in activity-related breathlessness (at least a 1-point improvement in the modified Borg dyspnoea score) for tiotropium/olodaterol compared with tiotropium in one patient [30]. Considering the favourable safety profile of tiotropium/olodaterol, this NNT was felt to be clinically relevant [43].

Another approach to measure activity-related breathlessness is to use questionnaires that require patients to recall their symptoms during daily life [17]. The PHYSACTO trial utilised the Chronic Respiratory Questionnaire (CRQ), modified Medical Research Council (mMRC) questionnaire and Functional Performance Inventory Short Form questionnaire to assess the impact of interventions on breathlessness or their effect on daily activities. In this study, all patients were enrolled in a self-management behaviour modification programme and treated once daily with tiotropium/olodaterol (either alone or in combination with exercise training), placebo or tiotropium alone (Fig. 2) [44]. Treatment with tiotropium/olodaterol, with or without exercise training, reduced physical activity-related breathlessness, and patients reported less difficulty while performing physical activity of daily living compared with placebo [17].

As shown by improvements in the dyspnoea domain of the CRQ (CRQ-SAS dysp), tiotropium/olodaterol reduced breathlessness during activity versus baseline after 12 weeks, with adjusted mean changes ± SE in CRQ-SAS dysp of 0.71 ± 0.10 or 0.59 ± 0.10 either with or without exercise training, respectively (both P < 0.05 versus baseline) [17]. This was confirmed by an improvement in mMRC score observed at 12 weeks with tiotropium/olodaterol with or without exercise training (adjusted mean change ± SE versus placebo – 0.44 ± 0.13 [P = 0.001] and – 0.36 ± 0.13 [P = 0.007], respectively) [17]. Improving patients’ overall experience of physical activity by decreasing breathlessness and perceived difficulty of activity could be an important contributor to long-term adherence to an active lifestyle for patients with COPD, resulting in an improved quality of life [45].

COPD is a complex disease with multiple effects beyond the respiratory system. It is becoming apparent that increasing physical activity and reducing discomfort during physical activity requires a more holistic approach than solely providing adequate bronchodilation. Treatment should consider all aspects of the disease, including mental, physical and emotional health. Pulmonary rehabilitation and exercise programmes can improve patients’ physiology [46, 47], while counselling or psychological programmes support the change in behaviour that is needed for patients to be more active [48]. Increasing and maintaining physical activity has been demonstrated to have a positive impact not only on breathlessness but also on poor outcomes in patients with COPD, including risk of exacerbations, hospitalisation and mortality [11, 13‐15].

Improving lung function and limb muscle function is expected to result in increased capacity to perform exercise and, potentially, in increased physical activity as measured by steps per day, average daily walking time and walking intensity [17]. Pulmonary rehabilitation, defined by the American Thoracic Society/European Respiratory Society as ‘a comprehensive intervention based on a thorough patient assessment followed by patient-tailored therapies’ [46] plays an important role in the management of patients with COPD. The core of pulmonary rehabilitation includes exercise training, education and behaviour change, which are designed to improve the physical and psychological condition of people with chronic respiratory disease and to promote the long-term adherence to health-enhancing behaviours [46]. Rehabilitation programs help to decrease breathlessness, improve health-related quality of life and reduce healthcare utilisation [16, 49, 50]. However, although rehabilitation has been shown to enhance exercise tolerance in patients with COPD [51], this does not always guarantee the adoption of a more active lifestyle, particularly in the long term.

Pulmonary rehabilitation has been shown to be more effective when given in combination with bronchodilator therapy. In combination with tiotropium, pulmonary rehabilitation improved treadmill walking endurance time compared with pulmonary rehabilitation alone, and these improvements lasted up to 3 months after completion of the pulmonary rehabilitation programme [52]. Patient-reported involvement in physical activities was also significantly improved in patients taking tiotropium and participating in pulmonary rehabilitation compared with those taking placebo and pulmonary rehabilitation [53]. Pulmonary rehabilitation does have some limitations, one of which is that the effects diminish over time if the exercise training component of the intervention is not maintained. Long-term maintenance of the benefits of pulmonary rehabilitation require changes in patient health behaviour, taking into account personal needs, preferences and personal goals [16].

Behaviour-change interventions such as self-management behaviour modification programmes are designed to train and support patients, in collaboration with physicians and other healthcare professionals, via increased patient engagement and maintenance of exercise and physical activity [54]. The PHYSACTO study was the first COPD trial in which all patients received a self-management behaviour modification programme to examine the effect of bronchodilator therapy and exercise training on exercise capacity and physical activity (Fig. 2) [17]. In this study, tiotropium/olodaterol 5/5 µg significantly improved endurance time during an ESWT after 8 weeks of treatment compared with placebo, either with exercise training (treatment ratio versus placebo 1.46; 95% CI 1.20, 1.78; P = 0.0002) or without exercise training (treatment ratio versus placebo 1.29; 95% CI 1.06, 1.57; P = 0.0109) (Table 3) [17]. Tiotropium/olodaterol 5/5 µg also significantly improved IC compared with placebo, either with or without exercise training (Table 1) [17]. Furthermore, patients in this study showed significant improvement in adjusted mean distance walked ± SE during the 6MWT when treated with tiotropium/olodaterol 5/5 µg, with or without exercise training, after 8 weeks compared with placebo (27.33 ± 10.06 m [P = 0.007] and 21.03 ± 9.89 m [P = 0.034], respectively) [17]. After 12 weeks, self-management behaviour modification alone resulted in a clinically meaningful increase in physical activity, both in terms of steps per day (adjusted mean change from baseline ± SE, 1098 ± 325 steps per day, representing a 20% increase from baseline) and daily walking time (adjusted mean change from baseline ± SE, 10.86 ± 3.53 min/day, representing a 16% increase from baseline). These observed improvements in physical activity were not further increased with additional interventions [17]. Importantly, patients also perceived less breathing discomfort during physical activities of daily living when bronchodilation with tiotropium/olodaterol and exercise training were added to self-management behaviour modification [17]. This study highlights the need for combining behavioural interventions with optimal bronchodilation and pulmonary rehabilitation while improving and maintaining comfort during physical activities, with the hope of affecting long-term change.

The combination of self-management behaviour modification, exercise training and tiotropium/olodaterol demonstrated the largest effect on physical activity experience (assessed using the amount and difficulty domains of the daily version of the PROactive Physical Activity in COPD instrument) and breathlessness during daily life in patients with COPD [17]. This supports the concept that improving airflow, symptoms and the experience of physical activity, providing physical reconditioning with exercise training and addressing psychological factors are all important components to provide patients with the best chance of increasing and maintaining their physical activity.

Several clinical trials have consistently demonstrated that treatment with tiotropium/olodaterol can make it easier for people with COPD to stay active by reducing symptoms and the difficulties related to physical activity [20, 22, 28, 29, 37]. However, data from clinical trials can be difficult to extrapolate to the general population because of the stringent inclusion criteria used to select participants for clinical trials. Real-world data complement evidence from clinical trials and help us to understand the effects of therapies in everyday clinical practice. With physical activity becoming more and more important in the management of patients with COPD, seeking to understand the best way to address this in everyday clinical practice has resulted in many observational studies. For example, an observational study carried out in a very large population from practices spread throughout Germany, including both urban and rural areas, investigated the effect of tiotropium/olodaterol on physical functioning using the 10-item Physical Functioning Questionnaire, which provides a measure of physical activity in daily living [55]. This study found that tiotropium/olodaterol improved physical function and health-related quality of life within 6 weeks of treatment over a broad range of disease severities in patients with COPD [55]. In a similar observational study evaluating tiotropium in a large German population, the observed improvements in physical function with tiotropium also had a positive effect on patients’ general condition, a physician-assessed measure of a patient’s overall clinical condition evaluated using the Physician’s Global Evaluation score [56]. More recently, patients receiving tiotropium/olodaterol in the OTIVACTO observational studies have, across several European countries, reported improvements in their general condition and ability to better manage their daily routines [57, 58]. These tiotropium/olodaterol observational studies complement the existing body of long-acting bronchodilator clinical trial data on which to base the choice of therapy to help improve quality of life for patients with COPD.