Roflumilast: dalle linee guida alla pratica clinica 1

Global Strategy for Diagnosis, Management and Prevention of COPD Valutazione della BPCO: obiettivi Determine the severity of the disease, its impact on the patient’s health status and the risk of future events (for example exacerbations) to guide therapy. Consider the following aspects of the disease separately:  current level of patient’s symptoms severity of the spirometric abnormality frequency of exacerbations presence of comorbidities. 2

Assess degree of airflow limitation using spirometry Global Strategy for Diagnosis, Management and Prevention of COPD Valutazione del paziente con BPCO Assess symptoms Assess degree of airflow limitation using spirometry Assess risk of exacerbations Assess comorbidities 3

Use the COPD Assessment Test (CAT) or mMRC Breathlessness scale Global Strategy for Diagnosis, Management and Prevention of COPD Valutazione del paziente con BPCO Assess symptoms Assess degree of airflow limitation using spirometry Assess risk of exacerbations Assess comorbidities Use the COPD Assessment Test (CAT) or mMRC Breathlessness scale 4

Global Strategy for Diagnosis, Management and Prevention of COPD Valutazione del paziente con BPCO Assess symptoms Assess degree of airflow limitation using spirometry Assess risk of exacerbations Assess comorbidities Use spirometry for grading severity according to spirometry, using four grades split at 80%, 50% and 30% of predicted value 5

Use history of exacerbations and spirometry. Global Strategy for Diagnosis, Management and Prevention of COPD Valutazione del paziente con BPCO Assess symptoms Assess degree of airflow limitation using spirometry Assess risk of exacerbations Assess comorbidities Use history of exacerbations and spirometry. Two exacerbations or more within the last year or an FEV1 < 50 % of predicted value are indicators of high risk 6

Assess degree of airflow limitation using spirometry Global Strategy for Diagnosis, Management and Prevention of COPD Valutazione del paziente con BPCO Assess symptoms Assess degree of airflow limitation using spirometry Assess risk of exacerbations Combine these assessments for the purpose of improving management of COPD 7

COPD patients are at increased risk for: Global Strategy for Diagnosis, Management and Prevention of COPD Valutazione delle comorbilità COPD patients are at increased risk for: Cardiovascular diseases Osteoporosis Respiratory infections Anxiety and Depression Diabetes Lung cancer These comorbid conditions may influence mortality and hospitalizations and should be looked for routinely, and treated appropriately. 8

Global Strategy for Diagnosis, Management and Prevention of COPD Il trattamento della BPCO Appropriate pharmacologic therapy can reduce COPD symptoms, reduce the frequency and severity of exacerbations, and improve health status and exercise tolerance. None of the existing medications for COPD has been shown conclusively to modify the long-term decline in lung function. Influenza and pneumococcal vaccination should be offered depending on local guidelines. 9

Global Strategy for Diagnosis, Management and Prevention of COPD Opzioni terapeutiche per la BPCO Beta2-agonists Short-acting beta2-agonists Long-acting beta2-agonists Anticholinergics Short-acting anticholinergics Long-acting anticholinergics Combination short-acting beta2-agonists + anticholinergic in one inhaler Methylxanthines Inhaled corticosteroids Combination long-acting beta2-agonists + corticosteroids in one inhaler Systemic corticosteroids Phosphodiesterase-4 inhibitors 10

Global Strategy for Diagnosis, Management and Prevention of COPD Opzioni terapeutiche: broncodilatatori Bronchodilator medications are central to the symptomatic management of COPD. Bronchodilators are prescribed on an as-needed or on a regular basis to prevent or reduce symptoms. The principal bronchodilator treatments are beta2-agonists, anticholinergics, theophylline or combination therapy. The choice of treatment depends on the availability of medications and each patient’s individual response in terms of symptom relief and side effects. 11

Global Strategy for Diagnosis, Management and Prevention of COPD Opzioni terapeutiche: broncodilatatori Long-acting inhaled bronchodilators are convenient and more effective for symptom relief than short-acting bronchodilators. Long-acting inhaled bronchodilators reduce exacerbations and related hospitalizations and improve symptoms and health status. Combining bronchodilators of different pharmacological classes may improve efficacy and decrease the risk of side effects compared to increasing the dose of a single bronchodilator. 12

Global Strategy for Diagnosis, Management and Prevention of COPD Opzioni terapeutiche: corticosteroidi inalatori Regular treatment with inhaled corticosteroids (ICS) improves symptoms, lung function and quality of life and reduces frequency of exacerbations for COPD patients with an FEV1 < 60% predicted. Inhaled corticosteroid therapy is associated with an increased risk of pneumonia. Withdrawal from treatment with inhaled corticosteroids may lead to exacerbations in some patients. 13

Combination therapy is associated with an increased risk of pneumonia. Global Strategy for Diagnosis, Management and Prevention of COPD Opzioni terapeutiche: terapie di combinazione An inhaled corticosteroid combined with a long-acting beta2-agonist is more effective than the individual components in improving lung function and health status and reducing exacerbations in moderate to very severe COPD. Combination therapy is associated with an increased risk of pneumonia. Addition of a long-acting beta2-agonist/inhaled glucorticosteroid combination to an anticholinergic (tiotropium) appears to provide additional benefits. 14

Global Strategy for Diagnosis, Management and Prevention of COPD Opzioni terapeutiche: corticosteroidi sistemici Chronic treatment with systemic corticosteroids should be avoided because of an unfavorable benefit-to-risk ratio. 15

Global Strategy for Diagnosis, Management and Prevention of COPD Opzioni terapeutiche: inibitori della fosfodiesterasi 4 In patients with severe and very severe COPD (GOLD 3 and 4) and a history of exacerbations and chronic bronchitis, the phospodiesterase-4 inhibitor (PDE-4), roflumilast, reduces exacerbations treated with oral glucocorticosteroids. 16

Global Strategy for Diagnosis, Management and Prevention of COPD Gestione della BPCO in fase stabile Long-acting formulations of beta2-agonists and anticholinergics are preferred over short-acting formulations. Based on efficacy and side effects, inhaled bronchodilators are preferred over oral bronchodilators. Long-term treatment with inhaled corticosteroids added to long-acting bronchodilators is recommended for patients with high risk of exacerbations. 17

Global Strategy for Diagnosis, Management and Prevention of COPD Gestione della BPCO in fase stabile Long-term monotherapy with oral or inhaled corticosteroids is not recommended in COPD. The phospodiesterase-4 inhibitor roflumilast may be useful to reduce exacerbations for patients with FEV1 < 50% of predicted, chronic bronchitis, and frequent exacerbations. 18

Reduce symptoms Reduce risk Relieve symptoms Global Strategy for Diagnosis, Management and Prevention of COPD BPCO: obiettivi terapeutici Relieve symptoms Improve exercise tolerance Improve health status Prevent disease progression Prevent and treat exacerbations Reduce mortality Reduce symptoms Reduce risk 19

Il trattamento farmacologico in funzione alla progressione di malattia Speaker notes Until the 2010 update to the GOLD guidelines, none of the pharmacological agents recommended by GOLD targeted the systemic inflammation underlying COPD. Now, GOLD recommends the use of PDE4 inhibitors, namely roflumilast, to reduce the inflammatory component of COPD, in a specific patient population that has been proven to respond to roflumilast treatment. Reference Global Initiative for Chronic Obstructive Lung Disease. Global strategy for the diagnosis, management, and prevention of COPD. 2010. www.goldcopd.org Global Strategy for the Diagnosis, Management, and Prevention of Chronic Obstructive Pulmonary Disease, Global Initiative for Chronic Obstructive Lung Disease (GOLD) 2010 Available from www.goldcopd.org 20

Studio ECLIPSE: tutti i pazienti con BPCO possono essere frequenti riacutizzatori GOLD stage % Patients on long-acting bronchodilators inhaled corticosteroids Exacerbation rate in year 1 (number/ patient) % of patients who were ‘Frequent exacerbators’ II 67 60 0.85 22 III 83 80 1.34 33 IV 86 2.00 47 Base-line therapy Speaker notes The ECLIPSE (Evaluation of COPD Longitudinally to Identify Predictive Surrogate Endpoints) study is a non-interventional, observational, multicentre, three-year study in 2138 patients with COPD. Data from the ECLIPSE cohort illustrated that exacerbations become more frequent and more severe with increasing severity of COPD. Patients with two or more exacerbations during the year were considered to have frequent exacerbations. Exacerbation rates in the first year of follow-up were 0.85 per person for patients with GOLD stage II COPD, 1.34 for patients with GOLD stage III, and 2.00 for patients with GOLD stage IV. Overall, 22% of patients with stage II disease, 33% with stage III, and 47% with stage IV had frequent exacerbations in the first year of follow-up – despite the fact that the majority were treated with both a long-acting bronchodilator and an inhaled corticosteroid. The single best predictor of exacerbations, across all GOLD stages, was a history of exacerbations in previous year. The frequent-exacerbation phenotype appeared to be relatively stable over a period of 3 years and could be predicted on the basis of patients’ recall of previous treated events. The ECLIPSE data suggests that the ‘frequent exacerbator’ is a distinct sub-group of patients who may be easily identified (based on patient recall) and targeted with specific exacerbation prevention strategies. Reference Hurst JR, Vestbo J, Anzueto A, et al. Susceptibility to exacerbation in Chronic Obstructive Pulmonary Disease. N Engl J Med 2010;363:1128-38. Frequent exacerbations are of concern to all COPD patients, not only those in the very severe stage Adapted from Hurst JR, Vestbo J, Anzueto A et al. N Engl J Med 2010;363:1128-1138. 21

Numero di pazienti da trattare per prevenire una riacutizzazione Treatment % reduction NNT* ICS/LABA vs LABA(TORCH)1 12 (p=0.002) 8.3 Roflumilast/LABA vs placebo/LABA(M2-124/125)2,3 20.7 (p=0.001) 3.1 Dia 2961 COPD is a chronic inflammatory condition leading to physiological changes in the lungs that cause the typical signs and symptoms of the disease. The precise causes of inflammation in COPD are not clearly defined but it is thought that cigarette smoke and other inhaled irritants may initiate the inflammatory response in susceptible individuals. In COPD, there is debate as to whether the airflow obstruction is primarily due to obstruction of the lumen of the small airways, as a result of chronic inflammation of the bronchioles (chronic bronchitis), or whether it is due to loss of elasticity and closure of the small airways as a result of enzymatic destruction of the alveolar walls (emphysema). *Number of patients needed to treat to avoid one exacerbation per patient per year, calcutated from the inverse value of the absolute risk reduction (ARR)2 1. Calverley PMA, Anderson JA, Celli B et al. NEJM 2007;356:775-789. 2. Calverley PMA, Rabe KF, Goehring UM et al. Lancet 2009;374:685-694. 3. Fabbri LM, calverley PMA, Izquierdo-Alonso JL et al. Lancet 2009;374:695-703. 22

Un nuovo paradigma per la ‘cura ottimale’ del paziente con BPCO PATIENT CHARACTERISTICS MANAGEMENT PLAN FUTURE RISK REDUCTION BEST CURRENT CONTROL Exacerbations Speaker notes Very recently a new paradigm for the management of COPD has been proposed. This is based on the concept that ‘here-and-now’ goals to minimise current impact on an individual patient should be integrated with goals to achieve better long-term outcomes and reduce future risks. The terminologies introduced in this concept paper are – ‘optimal COPD care’, ‘best current control’, and ‘future risk reduction’ reflecting the concept that , to a COPD patient, prevention of future risk is of equal importance to the immediate impact of treating symptoms. The impact an intervention may have on long-term disease progression is sometimes independent of any effect it may have on current symptoms. Clinicians already apply this broader approach to risk factors such as hypertension and hypercholesterolaemia. Treatments that reduce high blood pressure and serum cholesterol are nowadays prescribed independently of any acute effects on current symptoms. It has now been suggested that this approach should also be considered in COPD. Exacerbations can be used as an example of the link between best current control and future risk reduction. Exacerbation frequency has been linked to increased disease progression in COPD. Recent studies suggest that future exacerbation risk is related to previous exacerbation history. Current therapies are known to decrease the frequency of these future exacerbation events. Thus, treatment reducing exacerbation-frequency can exemplify why current treatment is warranted independent of its impact on ‘best current control’ and rather as a target for ‘future risk reduction’. Reference Postma D, Anzueto A, Calverley P, et al. A new perspective on optimal care for patients with COPD. Prim Care Respir J 2011; 20:205-209. Postma D, et al. Prim Care Respir J 2011; 20:205-209. 23