B. Beghé, A. Verduri, M. Bortolotti, P. Roversi

1. Meeting del Dipartimento ad Attività Integrata di Oncologia, Ematologia e Patologie dell’Apparato Respiratorio Villa Pineta, 16 Luglio 2011 Progetto ALICE Airflow Limitation Inpatients with Cardiovascular Events B. Beghé, A. Verduri, M. Bortolotti, P. Roversi

2. Progetto ALICE • This is a cross-sectional study, investigating the prevalence of Airflow Limitation in current or former smokers with established ischemic heart disease • The study will recruit 3000 patients across Europe attending cardiology clinics

3. Background • Airflow Limitation is a functional feature of COPD • Middle-aged and older smokers develop COPD • COPD is associated with co-morbidities • Cardiovascular are more frequent • COPD is often underdiagnosed and undertreated

4. Prevention of exacerbations of chronic obstructive pulmonary diseases with tiotropium, a once-daily inhaled anticholinergic bronchodilator: a randomized trial. • Co-morbilità • Vascolari (compresa l’ipertensione) 64% • Cardiache 38% • Gastrointestinali 48% • Metaboliche o nutrizionali 47% • Muscolo scheletriche o connettivali 46% • Genito-urinarie 27% • Neurologiche 22% Niewoehner et al, Ann Intern Med 2005;143:317-326

5. Role of co-morbidities in a cohort of patients with COPD undergoing pulmonary rehabilitation • 51% of the patients reported at least one chronic • comorbidity added to COPD. • Metabolic (systemic hypertension, diabetes and/or • dyslipidaemia) and heart diseases (chronic heart • failure and/or coronary heart disease) were the most • frequently reported co-morbid combinations (61% and • 24%, respectively) Crisafulli E, et al.,Thorax 2008;63: 487-492.

6. What do COPD Patients Die From? Mannino et al, ERJ, 2007

7. Cardiovascular mortality in COPD For every 10% decrease in FEV1, cardiovascular mortality increases by approximately 28% and non-fatal coronary event increases by approximately 20% in mild to moderate COPD Anthonisen et al, Am J Respir Crit Care Med 2002

8. Risk Factors for chronic complex disease Nutrition Infections Socio-economic status Aging Populations

9. Risk Factors for chronic complex disease

10. Noxious particles and gases Host factors Lung inflammation Anti-proteinases Anti-oxidants Proteinases Oxidative stress Repair mechanisms COPD pathology Alveolar wall destruction (emphysema) Mucus hypersecretion (chronic bronchitis)

11. From the lung to the systemic inflammation

12. Dentener Eid Mannino Mendall Yasuda Pooled summary Greater in controls Greater in COPD Association between chronic obstructive pulmonary disease and systemic inflammation: a systematic review and a meta-analysis Standardised mean difference of CRP Gan WQ et al. Thorax 2004; 59: 574-80

13. Cigarette smoking represents an independent risk factor for cardiovascular disease • Systemic oxidative stress • Inflammatory mechanisms • Haemostatic disturbances • Lipid abnormalities • Vascular endothelial dysfunction Yanbaeva DG et al. Chest 2007;131:1557-66 Wannamethee SG et al. Eur Heart J 2005;26:1765-73

14. Primary outcome To establish the point prevalence of Airflow Limitation (AL) compatible with COPD in current/former smokers with established cardiac diseases, in Europe.

15. Secondary Outcomes • To establish the overall burden of AL in patients with cardiac diseases, stratified by cardiac disease type; • To compare health status and healthcare resource utilisation in patients with cardiac diseases with and without AL, and with or without prior COPD diagnosis; • To explore the relationship between cardiac disease and risk factors with AL: • To explore whether the type of cardiac disease diagnosis (IHD only, co-morbid CHF, or co-morbid with other CV disease (other than CHF)) is related to thepresence and severity of AL, after adjustment for other risk factors of AL (e.g. smoking), • To explore whether the presence of AL is related to the severity of cardiac disease; • To explore overlapping genetic markers of COPD and cardiac diseases, in those patients where genetic samples are collected.

16. Study population • 3.000 former or current smoker, over the age of 40, attending outpatient cardiac clinics for a routine visit for the CV disease. • 220 patients / unit • Tempi • - start : 15 October 2011 • - end: 10 April 2012012 ~ 22 weeks ~ 10 pts/week

17. Inclusion criteria • Subjects aged ≥40 years; • Current or former smokers with ≥10 pack years; • Subjects attending outpatient cardiac clinic (or equivalent) fulfilling any of the following criteria: • Documented history of an Ischemic event, • Current diagnosis of stable IHD (including history of acute Myocardial Infarction (MI) and angina pectoris) as diagnosed in accordance with ESC guidelines (see Appendix 2), • Receiving regular therapy for IHD for >1yr, • Subjects meeting these criteria will be eligible for the study, even if they have other cardiac diseases or other co-morbidities; • Subjects willing and able to sign study consent form.

18. Exclusion criteria • Subjects for whom spirometry is contraindicated • Subjects with recent surgery or MI (within 1 month); lower respiratory tract infection or pneumothorax (within 2 months); or stroke (within 12 months); • Subjects with a pre-existing condition which, in the opinion of the investigator, would compromise the safety of the subject in this study.

19. StudyProcedures Where available, results from the most recent test will be collected Including total cholesterol, HDL-C, LDL-C, glucose (HbA1c), hs-CRP, Pro-BNP and fibrinogen, to be assessed locally Optional: Blood samples will be collected for future exploratory genetic analyses

20. Progetto ALICE The study aims to determine, and raise awareness of, the burden of AL disease in these patients and on healthcare resource utilisation. We hypothesise that patients with cardiac disease with and without AL will differ in a number of characteristics, with patients with comorbid AL reporting higher disease burden and healthcare resource utilisation, especially in those patients with undiagnosed and untreated AL.

21. Meeting del Dipartimento ad Attività Integrata di Oncologia, Ematologia e Patologie dell’Apparato Respiratorio Villa Pineta, 16 Luglio 2011 Grazie dell’attenzione Buone vacanze!