MALATTIE RESPIRATORIE Modena 6-7/8-9 Settembre 2011 Corso di Aggiornamento su MALATTIE RESPIRATORIE Ridefinizione della BPCO e delle riacutizzazioni dei sintomi in pazienti con BPCO

TREATMENT TARGETS IN COPD: CURRENT AND EVOLVING MANAGEMENT OPTIONS COPD and chronic comorbidities Exacerbations in COPD Current and future treatment Treatment of co-morbidities of COPD Futuristic treatments Diabetes Intervention Study (1) L’importanza della glicemia postprandiale come fattore di rischio cardiovascolare è stata dimostrata anche per i pazienti diabetici Tipo 2 in questo studio condotto in 1139 pazienti diabetici di Tipo 2 di nuova diagnosi.

OUTCOME OF COPD EXACERBATIONS Hospital mortality 20%-24% (1 year) In ICU patients In hospitalized patients Hospital mortality 2.5%-10% (5 days) Treatment failure is defined as not responsive to initial treatment(s). Outcomes = health utilizations. This slide shows outcomes of patients with acute exacerbations: 20-24% of patients in the ICU with an exacerbation died; 6-12% of patients in general hospital beds, not ICU beds, died. Of those who visited the ER for an acute exacerbation, 22-32% of those patients had to revisit the emergency room after being discharged. Those who were treated as outpatients 13-33% of those patients did not response to initial treatments and needed further medical intervention. Main point: Acute exacerbations are a serious matter and should be of concern to the health care provider. Relapse (repeat ER visit) 22%-32% (14 days) In ER patients Treatment failure rate 13%-33% (14 days) In outpatients Seneff MG, Wagner DP, Wagner RP, Zimmerman JE, Knaus WA. Hospital and 1-year survival of patients admitted to intensive care units with acute exacerbation of chronic obstructive pulmonary disease. JAMA. 1995;274:1852-857. Murata GH, Gorby MS, Chick TW, Halperin AK. Treatment of decompensated chronic obstructive pulmonary disease in the emergency department—correlation between clinical features and prognosis. Ann Emerg Med. 1991;20:125-129. Adams SG, Melo J, Luther M, Anzueto A. Antibiotics are associated with lower relapse rates in outpatients with acute exacerbations of COPD. Chest. 2000;117:1345-1352. Patil SP, Krishnan JA, Lechtzin N, Diette GB. In-hospital mortality following acute exacerbations of chronic obstructive pulmonary disease. Arch Int Med. 2003; 160:1180-1186. Seneff et al. JAMA. 1995; 274:1852-1857; Murata et al. Ann Emerg Med. 1991;20:125-129; Adams et al. Chest. 2000; 117:1345-1352; Patil et al. Arch Int Med. 2003; 163:1180-1186.

Goal of COPD Management Overall COPD Control achieving reducing Current Control Future Risk defined by defined by Symptoms Reliever use Exacerbations Mortality Activity Lung function Progression of the disease Medication adverse effects ????? GOLD 2011 www.goldcopd.org

COPD COPD exacerbations Chronic disease Exacerbations progressive nature lung function symptoms comorbidities typically 1 - 3 per year frequency proportional to COPD severity the frequent exacerbator chronic decline resulting in poorer prognosis   HRQL   hospitalizations   mortality Vestbo J. What is an exacerbation of COPD? European Respiratory Review 2004;13:6–13 Synopsis: This review explores the different ways in which exacerbations of COPD are defined and examines the aetiology of these events and the burden they impose on patients and society in terms of morbidity, mortality, HRQL and costs. The impact of ICS and ICS/LABA combinations, including Symbicort, on exacerbations and related outcomes are discussed. Published abstract: Patients with chronic obstructive pulmonary disease (COPD) experience acute exacerbations that increase in frequency with disease severity. Exacerbations may be defined in various ways, depending on the needs of researchers, clinicians, patients or healthcare payers. At present, action-based definitions (based on the need for treatment with oral corticosteroids, antibiotics, or both, and/or hospitalisation due to respiratory symptoms) are the best available for the purposes of comparing medical treatments that may reduce or prevent exacerbations. Further research is required to elucidate the mechanisms underlying COPD exacerbations, including the possible role of eosinophils. Exacerbations of COPD accelerate lung function decline, increase the risk of hospitalisation and death, cause sustained impairment of health status, and generate substantial socio-economic costs. Combination therapy with inhaled corticosteroids and long-acting β2-agonists reduces the frequency of exacerbations, in addition to improving lung function, symptoms and health status and, possibly, lowering the risk of mortality. In summary, a greater awareness of the pathogenesis of exacerbations and their impact is necessary to encourage optimal treatment. Interventions that effectively prevent or treat exacerbations, such as inhaled corticosteroids/long-acting β2-agonists combination therapy, have the potential to significantly reduce the impact of chronic obstructive pulmonary disease on patients and society. This material has been supplied by AstraZeneca to you under licence from the copyright owner, and may not be recopied or redistributed outside AstraZeneca without permission from the copyright owner. Tashkin D. N Engl J Med 2010; 363: 1184 Hurst et al, N Engl J Med 2010; 363: 1128-38 5

Hurst J.R. et al., N Engl J Med 2010; 363: 1128-38 ASSOCIATION OF DISEASE SEVERITY WITH THE FREQUENCY AND SEVERITY OF EXACERBATIONS DURING THE FIRST YEAR OF FOLLOW-UP IN PATIENTS WITH COPD % of patients (N=945) (N=900) (N=293) Hurst J.R. et al., N Engl J Med 2010; 363: 1128-38

STABILITY OF THE FREQUENT-EXACERBATION PHENOTYPE IN THE 1679 PATIENTS WITH CHRONIC OBSTRUCTIVE PULMONARY DISEASE WHO COMPLETED THE STUDY 20 40 60 80 100 Percent Year 1 Year 2 Year 3 23% 6% 2% 3% 1% 5% 4% 12% Patients with no exacerbation Patients with 1 exacerbation Patients with ≥ 2 exacerbations Hurst J.R. et al., N Engl J Med 2010; 363: 1128-38

Breast Cancer Diseases - 2015 All Breast Cancers PI3Kmut 10% ER+ 65-75% HER3+ IGFR1+ HER2+ 15-20% p95+ 4% P53mut 30-40 % FGFR1 Ampl 8% Triple negative 15% PTENloss 30-50% BRCAMut 8%

BAC EGFR mut+: Response to TKI 12-02 12-00

INTACT 1: Lack of benefit in combination with chemotherapy Median survival, months 1-year survival rate, % Log rank vs placebo 9.92 43 0.7759 (p=0.4377) 9.86 41 1.0290 (p=0.3034) 11.07 45 Proportion event free 1.0 WE DIDN’T KNOW ABOUT EGFR MUTATION 0.8 Gefitinib 500 mg/day Gefitinib 250 mg/day Placebo 0.6 0.4 At neither dose did ZD1839 improve survival when added to gemcitabine plus cisplatin vs gemcitabine plus cisplatin alone. Median survival ranged from 9.9 to 11.1 months, with no significant difference between the three treatment groups. 0.2 0.0 4 8 12 16 20 24 Survival time (months) At risk 1093 898 641 463 152 11 Population: intention to treat 10

K Kobayashi et al, P ASCO 2009 11

CAUSES OF EXACERBATION OF RESPIRATORY SYMPTOMS IN CHRONIC PATIENTS PNEUMONIA THROMBOEMBOLISM ACUTE HEART FAILURE METABOLIC ACIDOSIS ANEMIA Diabetes Intervention Study (1) L’importanza della glicemia postprandiale come fattore di rischio cardiovascolare è stata dimostrata anche per i pazienti diabetici Tipo 2 in questo studio condotto in 1139 pazienti diabetici di Tipo 2 di nuova diagnosi.

Biochemical Markers of Cardiac Dysfunction Predict Mortality in Acute Exacerbations of COPD Elevated levels of NT-proBNP and troponin T are strong predictors of early mortality among patients admitted to hospital with acute exacerbations of COPD independently of other known prognostic indicators The pathophysiological basis for this is unknown, but indicates that cardiac involvement in exacerbations of COPD may be an important determinant of prognosis Chang CL et al, Thorax in press

CHF and COPD frequently coexist UNRECOGNIZED VENTRICULAR DYSFUNCTION IN CHRONIC OBSTRUCTIVE PULMONARY DISEASE CHF and COPD frequently coexist Ventricular dysfunction worsens survival in patients with COPD Considering the high prevalence and the prognostic implications of ventricular dysfunction, routine assessment with either BNP or echocardiogram should be considered in COPD patients Macchia A et al, ERJ Express - June 23, 2011

Iversen KK et al, Eur J Heart Fail. 2010 Jul;12(7):685-91. The prognostic importance of lung function in patients admitted with heart failure Prognostic importance for all-cause mortality of lung function variables obtained by spirometry in an unselected group of patients admitted with heart failure (HF) Iversen KK et al, Eur J Heart Fail. 2010 Jul;12(7):685-91.

TARGETING THE LUNG ATTACKS FitzGerald JM, Thorax May 2011 Vol 66 No 5 Current management strategiesfor acute asthma and AECOPD within and subsequent to discharge from hospital are suboptimal We suggest that the term ‘lung attack’ may resonate more with patients and the broader community FitzGerald JM, Thorax May 2011 Vol 66 No 5

 Aggiornamento concetti generali sulla componente respiratoria della BPCO Leonardo M. Fabbri DEFINIZIONE Chronic Obstructive Pulmonary Disease (COPD) is a common preventable and treatable disease. It is characterized by chronic respiratory symptoms, particularly dyspnea and persistent airflow limitation that is usually progressive and associated with an enhanced chronic inflammatory response of the airways and the lung to cigarette smoke and/or other noxious particles or gases. Exacerbations and significant concomitant disorders contribute to the overall severity in individual patients.

5-yrs mortality The present study analysed data from 20,296 subjects aged >45 yrs at baseline in the Atherosclerosis Risk in Communities Study (ARIC) and the Cardiovascular Health Study (CHS).

COPD and chronic comorbidities Exacerbations in COPD CORSO DI AGGIORNAMENTO SU MALATTIE RESPIRATORIE Modena 20-21 Luglio 2011 INTRODUZIONE E LINEE GUIDA PER LA BPCO Leonardo M. Fabbri COPD and chronic comorbidities Exacerbations in COPD Current and future treatment Treatment of co-morbidities of COPD Futuristic treatments Diabetes Intervention Study (1) L’importanza della glicemia postprandiale come fattore di rischio cardiovascolare è stata dimostrata anche per i pazienti diabetici Tipo 2 in questo studio condotto in 1139 pazienti diabetici di Tipo 2 di nuova diagnosi.

SYSTEMIC EFFECTS AND COMORBIDITIES OF CHRONIC OBSTRUCTIVE PULMONARY DISEASE Barnes PJ et al., Eur Respir J 2009;33:1165–1185

Severity of airflow limitation Frequency and severity of exacerbations Comorbidities

MALATTIE RESPIRATORIE Modena 20-21 Luglio 2011 Corso di Aggiornamento su MALATTIE RESPIRATORIE Ridefinizione della BPCO e delle riacutizzazioni dei sintomi in pazienti con BPCO