1. Grazie per aver scelto di utilizzare a scopo didattico questo materiale delle Guidelines 2011 libra. Le ricordiamo che questo materiale è di proprietà dell’autore e fornito come supporto didattico per uso personale.

2. PHARMACOLOGICAL MANAGEMENT OF COPD IN PATIENTS WITH CHRONIC CO-MORBIDITIES Professor Peter Calverley University Hospital Aintree Liverpool UK

3. A RUMSFELD MOMENT!  Does having COPD influence the choice of therapy for a co-morbidity?  Does taking a treatment for a co-morbidity improve the outcome in COPD?  Does taking a treatment for COPD affect the co- morbidity?

4. BETA –BLOCKERS AND COPD  Good data for the benefits of selective beta- blockade in congestive heart failure, rate control of AF  Longstanding worry that beta-blockade might precipitate bronchospasm  So most people avoided beta-blockers in COPD  Now we have evidence for safety and a reason why this is the case

5. BETA-BLOCKERS, COPD AND VASCULAR SURGERY  1205 COPD patients, 462 receiving therapy with BB pre- surgery Van Gestel et al AJRCCM 2008

6. Why COPD is not asthma –bronchodilator testing is not helpful Change in FEV 1 (L), Post-bronchodilator Subject Group Percent Smoker Controls Percent Non-smoker Contr Percent COPD Subjects 35 30 25 20 15 10 5 0 35 30 25 20 15 10 5 0 35 30 25 20 15 10 5 0 0.150.05-0.65-0.55-0.25-0.050.250.350.450.550.650.750.850.951.051.151.251.35-0.45-0.35-0.15

7. THE STATIN STORY

8. STATINS AND COPD OUTCOMES IN LOW RISK PATIENTS Mancini et al JACC 2006

9. STATINS AND EXACERBATIONS Mortenson E et al Respir Res 2009

10. Systemic Effects of COPD: Target Organs Lung Infections Lung Cancer Weight loss Muscle weakness Osteoporosis Angina Acute coronary syndromes Depression Diabetes Metabolic syndrome Systemic Inflammation Oxidatitive Stress Depression Peptic ulceration/reflux Depression From W MacNee

11. TREATMENT AND COMPLICATIONS  Depression –common, often associated with fatigue. Interaction with therapy more likely with systemic treatment. Corticosteroids possibly – roflumilast unproven  Reflux – GI issues with theophyllines and PDEIV inhibitors  Metabolism and diabetes –ocs associated with hyperglycaemia but this is a feature of acute exacerbations. More data from roflumilast  Muscles

12. COPD safety pool placebo (N=5,491) (%) rof500 (N=5,766) (%) Most frequently reported AEs All AEs 62.867.2 COPD exacerbations 23.119.8 Diarrhoea2.610.1 Weight decreased 1.86.8 Nasopharyngitis6.36.3 Nausea1.45.2 Headache2.04.6 Upper respiratory tract infection 4.33.8 Bronchitis3.53.1 Back pain 2.13.1 Insomnia0.92.6 Influenza2.42.5 Dizziness1.22.4 Decreased appetite 0.42.2 Pneumonia2.01.8

13. ET=number of patient-years of exposure PHARMACOLOGICALLY PREDICTABLE EFFECTS DiarrhoeaNausea <1 week≥1 week to <4 weeks ≥4 weeks to <13 weeks ≥13 weeks to <26 weeks ≥26 weeks<1 week≥1 week to <4 weeks ≥4 weeks to <13 weeks ≥13 weeks to <26 weeks ≥26 weeks placebo (n=5491) rof 500 mcg (n=5766 Events in the category (%) Events in the category

14. Weight loss  Noted as a self-reported finding more often with roflumilast  Not just confined to patients reporting GI intolerance  Monitored with regular weight measurement in pivotal one year trials  In one 6 month study bioimpedance data were available

15. Body weight over time in the studies with available data -4 -2 0 2 4 081624324048 Body Weight [kg] placebo roflumilast 500µg  = -2.17 kg (CI –2.4;-1.9) p < 0.0001 Timecourse: Mean change in kg Between Treatment Differences least-squares means from ANCOVA Weeks

16. Weight change by BMI N = 127134605572462475316317 UnderweightNormalOverweightObese Mean Change (%) Placebo Rof500 Percent weight change from baseline to end of treatment by BMI at baseline: pivotal COPD studies pool (SAF)

17. Mass indices [kg/m 2 ] 0 04812162024 Weeks Tiotropium + placebo (FFMI) Tiotropium + Daxas ® (FFMI) Tiotropium + placebo (BMI) Tiotropium + Daxas ® (BMI) Wouters EFM, Teichmann P, Brose M, et al. Am J Respir Crit Care Med 2010;181:A4473. Weight loss associated with roflumilast was primarily fat mass -0.5 FFMI: Fat Free Mass Index; BMI: Body Mass Index

18. MUSCLES  Loss of muscle bulk vs weakness  A marker for more health care expense and mortality but the thresholds may vary  A clear relationship of weakness to ocs use long term –not seen with ics  Anabolic steroids reverse this process but only in people taking oral corticosteroids ( Kreutzberg E et al)

19. BONES AND INHALED CORTICSTEROIDS  Database associations but confounded by disease severity

20. TORCH - Time to First Fracture Safety Population SFC N=1546 Non-Traumatic20 (1.3%)29 (1.9%)21 (1.4%) 39 (2.5%)37 (2.4%)45 (2.9%)58 (3.8%) FP N=1552 SAL N=1542 Plc N=1544 Traumatic SFC vs Placebo1.22(0.87, 1.72)0.248 SFC vs SAL 1.23(0.88, 1.72)0.229 SFC vs FP 1.16(0.83, 1.61)0.382 SAL vs Placebo 1.00(0.69, 1.43)0.977 FP vs Placebo1.06(0.74, 1.51)0.765 p95% CI Hazard Ratio 5.1% 5.4%6.3% KM Prob at 3 years

21. Prevalence of Osteoporosis & Osteopenia at Baseline 0 10 20 30 40 50 Placebo SALM 50 FP 500 SFC 50/500 T score -2.5 for hip or spine: osteopaenia T score < -2.5 for hip or spine: osteoporosis % patients

22. SFC US Safety sub-study : percent change in total hip BMD Vertical bars are standard errors 161 162 158 162 87 105 112 118 Number of subjects 72 82 80 95 52 78 65 82 048108158 PlaceboSALFP –5 –4 –3 –2 –1 0 1 Adjusted mean change BMD hip Time (weeks) Ferguson et al Chest 2009

23. Time to First Pneumonia AE Probability of event prior to wk 104 SFC 9.9%TIO 5.5% Cox Hazard Ratio95% CIp-value SFC vs TIO1.94(1.19, 3.17)0.008 Number at Risk 013263952657891104 0 1 2 3 4 5 6 7 8 11 12 Probability of Event (%) Time to Event (Weeks) Treatment 656550511491470451426415150SFC 50/500 6645434974684242426405387136TIO 18 9 10 TIO 18 SFC 50/500

24. TIME TO FIRST PNEUMONIA AE OR SAE Sin et al Lancet 2009

25. Cardiovascular Events with Tiotropium PlaceboTiotropiumRate Ratio 1 (95 % CI) nRate 2 n UPLIFT Composite endpoint2462.892082.250.78 (0.65, 0.94) Fatal composite1241.42981.040.73 (0.56, 0.95) 1 rate ratio tio vs. placebo; 2 per 100 person-years of time at risk to tiotropium or placebo *SOC cardiac (fatal), SOC vascular (fatal), MI (fatal+nonfatal), stroke (fatal+nonfatal), sudden death, sudden cardiac death Composite Endpoint* Used by Singh et al applied to UPLIFT

26. SALM FP All-cause mortality at 3 years Vertical bars are standard errors 18 16 14 12 10 8 6 4 2 0 Time to death (weeks) Probability of death (%) 1524 1533 1521 1534 1464 1487 1481 1487 1399 1426 1417 1409 1293 1339 1316 1288 Placebo SFC Number alive 01224364860728496108120132144156 Calverley et al. NEJM 2007

27. CARDIOVASCULAR EVENTS AND THERAPY Calverley et al Thorax 2010

28. CVS TREATED COPD AND THERAPY Calverley et al Thorax 2010

29. Time to onset of first major adverse CV event (MACE*) roflumilast 500 mcg, od, p.o. + roflumilast 250 mcg, od p.o. placebo, od, p.o. Probability of event 0.00 0.02 0.04 0306090120150180210240270300330360390 Days post-randomisation 0.01 0.03 MACE : CV death, non-fatal MI, non-fatal stroke

30. CONCLUSIONS  Beta–blockers and other cardiac drugs are safe in COPD  Statins may improve COPD outcomes but proper trial data are needed  Oral therapies produce more GI upset, oral corticosteroids long term are hazardous  Inhaled corticosteroids do not seem to accelerate osteoporosis but some may induce pneumonia  LAMA and LABA treatment is safe in COPD – anti- inflammatory therapy may improve cardiac outcomes  On balance our treatments are more friend than foe