Broncodilatazione ed esercizio fisico Enrico Clini

Mechanisms of exercise limitation in COPD Functional abnormalities Airway obstruction Static and dinamic hyperinflation Skeletal muscle dysfunction Deconditioning Hypoxia, metabolic changes Comorbidities and nutritional status Cardiovascular, metabolic, … Systemic inflammation Cardiovascular effect (?)

Static and dynamic hyperinflation in COPD

Skeletal muscle involvement in COPD Bernard S, et al. AJRCCM 1998

Organized the first multidisciplinary pulmonary rehabilitation program Thomas L. Petty, MD Master FCCP 1932-2009

Poor physical activity and low exercise performance are associated with mortality in COPD patients Garcia-Rio et al. Chest 2012 Celli B, et al. Respir Med 2008

Key question Is there a link between bronchodilation and exercise function or performance in patients with COPD ? 7 7 7

Outline The effect of single BD on exercise performance The effect of combined BDs on exercise performance Optimising bronchodilation during training in a rehabilitation course 8 8 8

Outline The effect of single BD on exercise performance The effect of combined BDs on exercise performance Optimising bronchodilation during training in a rehabilitation course 9 9 9

Liesker JJ et al. Chest 2002; 121: 597-608 EDRA 2014 Ottimizzando la terapia inalatoria con I broncodilatatori è possibile incidere sul miglioramento della ventilazione polmonare Nei soggetti con BPCO i broncodilatatori (sia SA che LA) sono in grado di aumentare la capacità di esercizio Liesker JJ et al. Chest 2002; 121: 597-608 Benchè i farmaci steroidi inalatori vengano impiegati per la cura dei pazienti BPCO gravi con riacutizzazioni ricorrenti, essi NON possiedono di per se favorevoli effetti sulla capacità individuale di esercizio Yang IA et al. Cochrane Database Syst Rev 2007; CD002991

Longer duration of bronchodilation is associated with greater airway calibre stabilization Beeh, Adv Ther 2010

TDI score

Liesker JJ et al. Chest 2002; 121: 597-608 EDRA 2014 Ottimizzando la terapia inalatoria con I broncodilatatori è possibile incidere sul miglioramento della ventilazione polmonare Nei soggetti con BPCO i broncodilatatori (sia SA che LA) sono in grado di aumentare la capacità di esercizio Liesker JJ et al. Chest 2002; 121: 597-608 Benchè i farmaci steroidi inalatori vengano impiegati per la cura dei pazienti BPCO gravi con riacutizzazioni ricorrenti, essi NON possiedono di per se favorevoli effetti sulla capacità individuale di esercizio Yang IA et al. Cochrane Database Syst Rev 2007; CD002991

Bronchodilators (Sal or Ipr) Placebo

Improvers = defined as those with ΔET by at least 25 sec Improvers = defined as those with ΔET by at least 25 sec. (median value of the ΔET between BD-ICS and Placebo)

Improvers = defined as those with ΔET by at least 25 sec Improvers = defined as those with ΔET by at least 25 sec. (median value of the ΔET between BD-ICS and Placebo)

Tiotropium reduces dynamic hyperinflation and improves exercise performance in COPD Placebo Tiotropium O’Donnell D, et al. ERJ 2004

2,25 hr 8 hr 2,25 hr 8 hr

Lung volumes Exercise endurance

Beeh et al, BMC Pulm Med 2015

O’Donnell D, et al. Respir Med 2011 LA-bronchodilators improve exercise response and maintain effect over time TIOTROPIUM INDACATEROL Maltais F, et al. Chest 2005 O’Donnell D, et al. Respir Med 2011

Outline The effect of single BD on exercise performance The effect of combined BDs on exercise performance Optimising bronchodilation during training in a rehabilitation course 24 24 24

New LABA-LAMA combinations Indacaterol-glycopirronium u.i.d. On the market More effective than monocomponents Vilanterol-Umeclidinium u.i.d. Olodaterol-tiotropium u.i.d. Under registration Formoterol-Aclidinium t.i.d

33 randomised-controlled trial included, 1007 pts 50% of the studies showed a significant effect of bronchodilator therapy on exercise capacity High-dose anticholinergic agents have significant and better effects in the majority of studies (steady-state exercise protocols) compared with low-dose SABA (and better than LABA) have favourable effects on exercise capacity in more than 65% of studies Theophyllines have negative effects on exercise capacity Effects of dual bronchodilation on exercise is still to be elucidated

FOR-TIO FOR-Pla

Beeh M, et al. Int J COPD 2012

What is relevant to the patient ? AUMENTO DEI GIORNI “ATTIVI” Inda /glico AUMENTO DEI GIORNI “ATTIVI” (+16 rispetto a TIO) Inda /glico

Outline The effect of single BD on exercise performance The effect of combined BDs on exercise performance Optimising bronchodilation during training in a rehabilitation course 33 33 33

Casaburi R, ZuWallack R. NEJM 2009

Exercise training principles Total training load must reflect the individual’s specific requirements Total training load must exceed loads encountered during daily life to improve aerobic capacity and muscle strength Training load must progress as improvement occurs

Constant work rate exercise tolerance: 6.6  18.2 minutes CHEST 2005; 128:2025–2034 Constant work rate exercise tolerance: 6.6  18.2 minutes

Optimizing medical treatment before exercise training with bronchodilator therapy, long-term oxygen therapy, and treatment of comorbidities may maximize the effectiveness of exercise training intervention

+ 5,35 min + 6,60 min

“ The present study documented improvements in spirometry and a trend towards reduced exacerbations.” “… tiotropium in combination with PR significantly improved dyspnea at the end of the program but did not show any additional benefit in 6MWT compared to PR and placebo. We encountered methodological issues regarding the 6MWT…..”

Bronchodilation and Training (Rehab) Question 1- Effective for all ? Bronchodilator therapy may be especially effective in enhancing exercise performance in individuals with a ventilatory exercise limitation Question 2- Why might increase effectiveness ? With optimal broncodilation the primary locus of exercise limitation may change from dyspnea to leg fatigue…allowing individuals to exercise their peripheral muscles to a greater degree Question 3- So what ? The use of maintenance bronchodilator therapy within the context of a PR program for COPD results in augmentation of exercise tolerance benefits

Summary BDs of different mechanism of action may positively impact on the exercise performance in COPD patients Combining BDs may be feasible and useful but direct effects on exercise performance need to be further elucidated Optimal bronchodilation is recommended during a rehabilitation course and may impact on the individual’s clinical response to exercise