Dr. Fabbri

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Presentación utilizada en el Siposium de Oviedo SEPAR 2011.

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  • 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.
  • 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.
  • 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. 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.
  • 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.
  • 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 β 2 -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 β 2 -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.
  • 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.
  • This provides a summary of the recommended treatment at each stage of COPD.
  • This provides a summary of the recommended treatment at each stage of COPD.
  • Speaker Notes This study of 449 patients with moderate-to-severe COPD was carried out to determine whether combining tiotropium with salmeterol or fluticasone-salmeterol improves clinical outcomes in adults with moderate to severe COPD compared with tiotropium alone. Study results showed that the proportion of patients in the tiotropium plus placebo group (62.8%) who experienced an exacerbation did not differ from that in the tiotropium plus salmeterol group (64.8%) or in the tiotropium plus fluticasone and salmeterol group (60.0%). Reference Aaron SD, Vandemheen KL, et al. Tiotropium in combination with placebo, salmeterol, or fluticasone-salmeterol for treatment of chronic obstructive pulmonary disease: a randomized trial. Ann Intern Med . 2007;146:545-555.
  • An increased reporting rate of pneumonia for subjects treated with SFC and FP was observed in the TORCH study. 1,2 A similar trend has also been observed in previous studies with SFC 50/500, but numbers of reports were too small to make definitive conclusions and these studies were of shorter duration (up to one year) compared to TORCH which is a 3 year study In TORCH, there was no protocol-defined diagnostic criterion for pneumonia - therefore a uniform definition of these events was not available. The adverse event data was based on investigator reporting and was not always backed up with, for example, chest X-ray. It is possible that this increase in cases of pneumonia reporting came to light as a result of such large patient numbers in the TORCH trial, and may not have been apparent in previous studies as they were too small. The increase in pneumonia was consistent across the different regions, suggesting that this is an important signal whose nature is currently unclear. However it should be noted that despite an increase in pneumonia reporting in the SFC group, there was no corresponding increase in mortality with SFC due to pneumonia, although numbers are small. This can be seen both in the fatal SAEs 2 (deaths on treatment where pneumonia was noted on the CRF) and in the CEC adjudicated deaths. 1 CEC adjudicated deaths in the safety population for patients on treatment up to 3 years were 7 on placebo, 9 on SAL, 13 on FP and 8 on SFC. 1,2 It is also important to put this data into context compared with the overall number of exacerbation events – over 13,000 exacerbation events were recorded in the efficacy population alone. Thus, these events did not compromise the overall benefits of SFC treatment, which was associated with fewer exacerbations and hospitalisations, better health status and lung function than placebo and components, and significantly better mortality than with FP treatment. Reference Ferguson GT, Calverley PMA, Anderson JA et al. The TORCH (Towards a Revolution in COPD Health) study: salmeterol/fluticasone propionate (SFC) is well tolerated in patients with COPD over three years. Abstract presented at European Respiratory Society Meeting Munich Sep 2-6 th 2006 GSK Data on File 2006
  • Following a 2-week run-in period, eligible patients were randomised to receive either tiotropium (18 μg once daily by HandiHaler  ) or salmeterol (50 μg twice daily by pressurised metered-dose inhaler) for one year, with a follow-up period of 30 days (refer to supplementary appendix 5). All patients were trained in the use of the HandiHaler ® and pMDI devices at visits 1 (screening) and 2 (randomisation). During run-in, patients receiving tiotropium were required to switch to ipratropium 160 μg total daily dose, which was discontinued at randomisation. Patients previously receiving a LABA were permitted to continue medication use during run-in. Patients receiving fixed-dose combinations of LABAs and ICS were instructed to switch to ICS monotherapy prior to start of randomised treatment. Patients were allowed to continue usual COPD medication during double-blind treatment phase, except for anticholinergics or LABAs. After randomisation, patients attended the clinic at months 2, 4, 8, and 12, and monthly telephone calls were scheduled between visits. Patients completed a daily diary, and records were reviewed at each study visit to assess treatment compliance and whether respiratory symptoms met the definition criteria for exacerbation. During clinic visits and telephone calls, a questionnaire was used for collecting COPD exacerbation-related details. For patients who prematurely discontinued treatment, vital status and primary cause of death were recorded until the end of the study period. Peak flow was measured at home for the first 4 months in patients who had given consent for genotyping. Adverse events (AEs) leading to treatment discontinuation, serious AEs and fatal AEs were recorded at each clinic visit for safety reasons.
  • Tiotropium significantly increased the time to first exacerbation (primary endpoint) compared with salmeterol by 42 days (187 vs 145 days in the first quartile of patients), corresponding to a 17% reduction in risk (HR 0.83; 95% CI 0.77-0.90; P<0.001). Given that less than 50% of patients experienced an exacerbation, it was not possible to calculate the median time to first exacerbation, therefore the time to first exacerbation in the first quartile of patients was calculated instead. Randomized patients taking ≥1 dose of study medication included in analysis. COPD exacerbations with onset during actual treatment. Hazard ratio based on Cox proportional hazards regression model including terms for (pooled) centre and treatment.
  • Randomized patients taking ≥1 dose of study medication included in analysis. COPD exacerbations with onset during actual treatment. Hazard ratio based on Cox proportional hazards regression model including terms for (pooled) centre and treatment.
  • Patients were male or female, age ≥40 years, with moderate-to-severe COPD (FEV 1 <80% and ≥30% predicted; FEV 1 /FVC <70% post-bronchodilator) and a smoking history ≥ 20 pack-years. Following screening, 1,732 patients were randomized to 52 weeks of treatment with indacaterol 300 or 600 μ g once daily , or formoterol 12 μ g twice daily via proprietary single dose dry powder inhalers. The 600 μ g dose was included to provide additional safety data, but results are not included here (registered doses of indacaterol are 150 and 300 μ g via Onbrez ® Breezhaler ® ). The primary objective was to compare the efficacy of indacaterol with that of placebo based on measurement of trough FEV 1 (defined as the average of the 23 hours 10 minutes and the 23 hours 45 minutes post-dose values) at Week 12. N.B. Modified ITT populations were used for the efficacy analysis – these populations do not include centres which were excluded due to Good Clinical Practice non compliance and unreliability of data. INVOLVE (B2334) is a Phase III study. Reference Dahl R et al., on behalf of the INVOLVE (indacaterol: value in COPD pulmonary disease longer term validation of efficacy and safety) study investigators. Efficacy of a new once-daily LABA, indacaterol, versus the twice-daily LABA formoterol, in COPD. Thorax 2010;65:473–9 .
  • The primary efficacy analysis in the INVOLVE study (B2334) showed that treatment with indacaterol 300 µg once daily resulted in significantly higher trough FEV 1 values at Week 12 (1.48 L, p<0.001) than in the placebo group (1.31 L). Further, secondary analyses demonstrated that trough FEV 1 values were significantly higher in indacaterol recipients than in patients receiving formoterol (1.48 vs 1.38 L at 12 weeks, p<0.001 vs indacaterol). Differences versus placebo in trough FEV 1 for indacaterol 300 μ g were greater than those for formoterol after 1 day (140 versus 110 mL; p<0.05 indacaterol versus formoterol), at Week 12 (170 vs 70 mL; p<0.001 for indacaterol versus formoterol) and at Week 52 (160 versus 50 mL; p<0.001 indacaterol versus formoterol). 1 Thus, benefits with indacaterol were apparent as early as Day 2 and were sustained through 52 weeks. INVOLVE (B2334) is a Phase III study . Reference Dahl R et al, on behalf of the INVOLVE (indacaterol: value in COPD pulmonary disease longer term validation of efficacy and safety) study investigators. Efficacy of a new once-daily LABA, indacaterol, versus the twice-daily LABA formoterol, in COPD. Thorax 2010;65:473 – 9.
  • Among patients participating in INDORSE, indacaterol 150 and 300 µg resulted in significant improvements in FEV 1 compared with placebo throughout the 52 weeks of the study (all p<0.001). The differences between indacaterol 300 µg and placebo exceeded the threshold for a clinically important difference (120 mL) at all timepoints from Day 1 to Week 52, while differences between indacaterol 150 µg and placebo exceeded the threshold at all timepoints from Day 15 to Week 52. Reference Chapman KR, Rennard SI, Dogra A, Owen R, Lassen C, Kramer B. Long-term safety and efficacy of indacaterol, a novel long-acting β 2 -agonist, in subjects with COPD: a randomized, placebo-controlled study. Chest 2011 [accepted] .
  • A secondary objective of INTEGRAL (B2340) was to measure inspiratory capacity (IC) at individual time points on Days 1 and 14. For individual time point IC, indacaterol was superior to placebo at all post-baseline time points on both Day 1 and Day 14 (p<0.001; the slide illustrates Day 14 data). In addition, indacaterol IC measurements were statistically superior to salmeterol at many time points (including 15 minutes pre-dose, and 11 hours 45 minutes and 23 hours 45 minutes post-dose on Day 14 – time points that are at the end of salmeterol’s dosing interval). Reference La Force C et al., on behalf of the INTEGRAL* study investigators. Sustained 24-hour efficacy of once-daily indacaterol (300 μg) in patients with chronic obstructive pulmonary disease: a randomized, crossover study. Pulm Pharmacol Ther 2011; 24:162–168.
  • INABLE 1 (B2311) was a randomized, placebo-controlled, double-blind, two-way crossover study with two 3-week treatment periods. The primary objective was to evaluate the effect of indacaterol 300 μ g administered once-daily for 21 days (3 weeks) on exercise endurance. Exercise endurance time was measured through constant-load cycle ergometry testing (at 75% W max ). Additional efficacy assessments included exercise endurance time on Day 1, trough inspiratory capacity (IC) and trough FEV 1 measured at rest (60 minutes pre-dose), peak IC measured at exercise completion after 21 days (3 weeks) of treatment (‘end-exercise IC’), and use of rescue medication (albuterol) throughout the study. Safety and tolerability were also monitored. Patients aged at least 40 years with moderate or severe COPD were randomized to receive indacaterol 300 µ g or placebo once daily via Onbrez ® Breezhaler ® according to a preset treatment sequence. Reference O’Donnell DE et al.. Effect of indacaterol on exercise endurance in patients with moderate-to-severe COPD. Am J Respir Crit Care Med 2010;181:A4431 (+ poster) .
  • In INABLE 1 (B2311), patients receiving indacaterol 300 µg once daily had a significant improvement in exercise endurance (measured during constant-load cycle ergometry testing at 75% W max ), compared with placebo, after the first treatment on Day 1 and Day 21 (Week 3). Exercise endurance was increased by 1.68 minutes (101 s), compared with placebo, on Day 1 and by 1.85 minutes (111 s) on Day 21 (Week 3). Reference O’Donnell DE et al.. Effect of indacaterol on exercise endurance in patients with moderate-to-severe COPD. Am J Respir Crit Care Med 2010;181:A4431 (+ poster) .
  • In INABLE 1 (B2311), patients receiving indacaterol 300 µg once daily had a significant improvement in inspiratory capacity at the end of exercise, compared with placebo, after the first treatment on Day 1 and Day 21 (Week 3). Inspiratory capacity was increased by 190 mL, compared with placebo, on Day 1 and by 280 mL on Day 21 (Week 3). Reference O’Donnell DE et al.. Effect of indacaterol on exercise endurance in patients with moderate-to-severe COPD. Am J Respir Crit Care Med 2010;181:A4431 (+ poster) .
  • INDORSE was the final stage of a three-part adaptive, seamless, randomized, double-blind, parallel-group study. At the end of stage 1 (Week 2), two indacaterol doses were selected for further evaluation in Stage 2, based on efficacy and safety data versus placebo, tiotropium and formoterol. Other indacaterol doses and formoterol were discontinued at Week 2. In Stage 2 (INHANCE, B2335S) the selected doses of indacaterol (150 and 300 μg once-daily), placebo and open-label tiotropium were continued to 26 weeks. In Stage 3 (INDORSE, B2335SE) indacaterol 150 or 300μg or placebo was inhaled once-daily for a further 26 weeks. The purpose of the study was to evaluate long-term safety and efficacy of these two doses of indacaterol compared with placebo. INDORSE (B2335SE) was a Phase III study. Reference Rennard SI et al.. Once-daily indacaterol provides effective bronchodilation over 1 year of treatment in patients with chronic obstructive pulmonary disease (COPD) . Chest 2009;136:4S-f. Chapman KR, Rennard SI, Dogra A, Owen R, Lassen C, Kramer B. Long-term safety and efficacy of indacaterol, a novel long-acting β 2 -agonist, in subjects with COPD: a randomized, placebo-controlled study. Chest 2011 [accepted] .
  • INDORSE was the final stage of a three-part adaptive, seamless, randomized, double-blind, parallel-group study. At the end of stage 1 (Week 2), two indacaterol doses were selected for further evaluation in Stage 2, based on efficacy and safety data versus placebo, tiotropium and formoterol. Other indacaterol doses and formoterol were discontinued at Week 2. In Stage 2 (INHANCE, B2335S) the selected doses of indacaterol (150 and 300 μg once-daily), placebo and open-label tiotropium were continued to 26 weeks. In Stage 3 (INDORSE, B2335SE) indacaterol 150 or 300μg or placebo was inhaled once-daily for a further 26 weeks. The purpose of the study was to evaluate long-term safety and efficacy of these two doses of indacaterol compared with placebo. INDORSE (B2335SE) was a Phase III study. Reference Rennard SI et al.. Once-daily indacaterol provides effective bronchodilation over 1 year of treatment in patients with chronic obstructive pulmonary disease (COPD) . Chest 2009;136:4S-f. Chapman KR, Rennard SI, Dogra A, Owen R, Lassen C, Kramer B. Long-term safety and efficacy of indacaterol, a novel long-acting β 2 -agonist, in subjects with COPD: a randomized, placebo-controlled study. Chest 2011 [accepted] .
  • This provides a summary of the recommended treatment at each stage of COPD.
  • 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).
  • This provides a summary of the recommended treatment at each stage of COPD.
  • 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.
  • A positive aspect of a more comprehensive approach is suggested by a post-hoc analysis of studies. This analysis suggests, in fact, that patients with COPD and significant comorbidities (hypertension or chronic heart failure) treated with statins, angiotensin-converting enzyme (ACE) inhibitors and/or angiotensin receptor blockers (ARBs) may actually, particularly in severe COPD, benefit from this treatment in the COPD aspect of the disease. This treatment seems to reduce mortality, morbidity and hospitalization in these patients. Obviously this data needs to be confirmed by further studies. But it does suggest that if we treat a COPD patient – not only for COPD, but also for chronic comorbidities – we may achieve better outcomes for the patient and provide better treatment overall. Mancini JB et al. Reduction of morbidity and mortality by statins, angiotensin-converting enzyme inhibitors, and angiotensin receptor blockers in patients with chronic obstructive pulmonary disease. J Am Coll Cardiol 2006;47(12):2554-60.
  • 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.
  • 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.
  • Dr. Fabbri

    1. 1. Management of COPD: GOLD guidelines SEPAR 44th National Congress Oviedo, 17 June 2011
    2. 2. <ul><li>COPD and chronic comorbidities </li></ul><ul><li>Exacerbations in COPD </li></ul><ul><li>Current and future treatment </li></ul><ul><li>Treatment of co-morbidities of COPD </li></ul><ul><li>Futuristic treatments </li></ul>MANAGEMENT OF COPD Leonardo M. Fabbri
    3. 3.   Aggiornamento concetti generali sulla componente respiratoria della BPCO Leonardo M. Fabbri <ul><li>DEFINIZIONE </li></ul><ul><li>Chronic Obstructive Pulmonary Disease (COPD) is a common preventable and treatable disease. </li></ul><ul><li>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, significant concomitant disorders contribute to the overall severity in individual patients. </li></ul>Bologna 8 Febbraio 2011
    4. 4.   Courtesy of PW Jones, 2011 CHANGING CONCEPTS IN COPD ASSESSMENT OF SEVERITY AND MANAGEMENT OF COPD
    5. 5. COMPLEX CHRONIC CO-MORBIDITIES OF COPD Fabbri, Beghe, Luppi and Rabe, Eur Respir J 2008;31:204-212
    6. 6. 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). 5-yrs mortality
    7. 7. Clinical practice guidelines (CPGs) and quality of care for older patients with multiple comorbid diseases: implications for pay for performance Boyd C et al JAMA. 2005 Aug 10;294(6):716-24 <ul><li>This review suggests that adhering to current CPGs in caring for an older person with several comorbidities may have undesirable effects </li></ul><ul><li>Basing standards on existing CPGs could lead to inappropriate judgment of the care provided to older individuals with complex comorbidities </li></ul><ul><li>Developing measures of the quality of the care needed by older patients with complex comorbidities is critical to improving their care </li></ul>
    8. 8. <ul><li>COPD and chronic comorbidities </li></ul><ul><li>Exacerbations in COPD </li></ul><ul><li>Current and future treatment </li></ul><ul><li>Treatment of co-morbidities of COPD </li></ul><ul><li>Futuristic treatments </li></ul>Management of COPD: GOLD guidelines Leonardo M. Fabbri
    9. 9. OUTCOME OF COPD EXACERBATIONS 20%-24% (1 year) 2.5%-10% (5 days) 22%-32% (14 days) 13%-33% (14 days) Hospital mortality Hospital mortality Relapse (repeat ER visit) Treatment failure rate 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. In hospitalized patients In ER patients In ICU patients In outpatients
    10. 10. <ul><li>PNEUMONIA </li></ul><ul><li>THROMBOEMBOLISM </li></ul><ul><li>ACUTE HEART FAILURE </li></ul><ul><li>METABOLIC ACIDOSIS </li></ul><ul><li>ANEMIA </li></ul>CAUSES OF EXACERBATION OF RESPIRATORY SYMPTOMS IN CHRONIC PATIENTS
    11. 11. 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.
    12. 12. 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
    13. 13. CARDIOVASCULAR MECHANISMS OF DEATH IN SEVERE COPD EXACERBATION: TIME TO THINK AND ACT BEYOND GUIDELINES Patients hospitalized because of ECOPD should be carefully examined for the relevant biomarkers and for any concomitant abnormality that may call for specific therapy This in line with the recent editorial of FitzGerald20 and comment by the Editors of Thorax who recommends replacing the term ‘exacerbations’ with the term ‘lung attacks’ to emphasise their severity, dramatic consequences, and need for more aggressive, comprehensive and prolonged treatment Fabbri LM, Beghe B and Agusti A, Thorax, June 2011
    14. 14. Goal of COPD Management Overall COPD Control Current Control Future Risk Symptoms Activity Reliever use Lung function Exacerbations Progression of the disease Mortality Medication adverse effects achieving reducing defined by defined by ????? GOLD 2011 www.goldcopd.org
    15. 15. Chronic disease Tashkin D. N Engl J Med 2010; 363: 1184 Hurst et al, N Engl J Med 2010; 363: 1128-38 <ul><li>progressive nature </li></ul><ul><li>lung function </li></ul><ul><li>symptoms </li></ul><ul><li>comorbidities </li></ul>Exacerbations <ul><li>typically 1 - 3 per year </li></ul><ul><li>frequency proportional to COPD severity </li></ul><ul><li>the frequent exacerbator </li></ul><ul><li>chronic decline resulting </li></ul><ul><li>in poorer prognosis </li></ul><ul><li>  HRQL </li></ul><ul><li>  hospitalizations </li></ul><ul><li>  mortality </li></ul>COPD exacerbations COPD
    16. 16. ASSOCIATION OF DISEASE SEVERITY WITH THE FREQUENCY AND SEVERITY OF EXACERBATIONS DURING THE FIRST YEAR OF FOLLOW-UP IN PATIENTS WITH COPD Hurst J.R. et al., N Engl J Med 2010; 363: 1128-38 (N=945) % of patients (N=900) (N=293)
    17. 17. STABILITY OF THE FREQUENT-EXACERBATION PHENOTYPE IN THE 1679 PATIENTS WITH CHRONIC OBSTRUCTIVE PULMONARY DISEASE WHO COMPLETED THE STUDY Hurst J.R. et al., N Engl J Med 2010; 363: 1128-38 0 20 40 60 80 100 Percent 0 20 40 60 80 100 Percent 0 20 40 60 80 100 Percent 0 20 40 60 80 100 Percent 0 20 40 60 80 100 0 20 40 60 80 100 0 20 40 60 80 100 0 20 40 60 80 100 0 20 40 60 80 100 0 20 40 60 80 100 0 20 40 60 80 100 0 20 40 60 80 100 0 20 40 60 80 100 Percent Year 1 Year 2 Year 3 23% 6% 2% 6% 3% 2% 2% 2% 1% 5% 3% 1% 3% 2% 2% 2% 2% 3% 2% 1% 1% 2% 2% 3% 1% 4% 12% Patients with no exacerbation Patients with 1 exacerbation Patients with ≥ 2 exacerbations
    18. 18. Breast Cancer Diseases - 2015 All Breast Cancers ER+ 65-75% HER2+ 15-20% Triple negative 15% HER3+ IGFR1+ p95+ 4% P53 mut 30-40 % FGFR1 Ampl 8% PTEN loss 30-50% PI3K mut 10% BRCA Mut 8%
    19. 19. TARGETED THERAPIES IN A-NSCLC Positive Phase III Studies Monotherapy ComboTherapy Erlotinib BR.21 Bevacizumab ECOG 4599/AVAiL Gefitinib IPASS/INTEREST/NEJG002 EGFR Mut+ 1 st Line A-NSCLC Cetuximab FLEX Not Registered! 2 nd /3 rd Line 2005 2008 2009 2007 EGFR Mut+ All lines
    20. 20. <ul><li>COPD and chronic comorbidities </li></ul><ul><li>Exacerbations in COPD </li></ul><ul><li>Current and future treatment </li></ul><ul><li>Treatment of co-morbidities of COPD </li></ul><ul><li>Futuristic treatments </li></ul>Management of COPD: GOLD guidelines Leonardo M. Fabbri
    21. 21. Add inhaled glucocorticosteroids if repeated exacerbations IV: Very Severe III: Severe II: Moderate I: Mild Therapy at Each Stage of COPD <ul><li>FEV 1 /FVC < 70% </li></ul><ul><li>FEV 1 > 80% predicted </li></ul>Add one or more long-acting bronchodilators (when needed); Add rehabilitation Add long term oxygen if chronic respiratory failure. Consider surgical treatments <ul><li>FEV 1 /FVC < 70% </li></ul><ul><li>50% < FEV 1 < 80% </li></ul><ul><li>predicted </li></ul><ul><li>FEV 1 /FVC < 70% </li></ul><ul><li>30% < FEV 1 < 50% predicted </li></ul><ul><li>FEV 1 /FVC < 70% </li></ul><ul><li>FEV 1 < 30% predicted </li></ul><ul><li>or FEV 1 < 50% predicted plus chronic respiratory failure </li></ul>Active reduction of risk factor(s); influenza vaccination Add short-acting bronchodilator (when needed)
    22. 22. Add inhaled glucocorticosteroids if repeated exacerbations IV: Very Severe III: Severe II: Moderate I: Mild Therapy at Each Stage of COPD <ul><li>FEV 1 /FVC < 70% </li></ul><ul><li>FEV 1 > 80% predicted </li></ul>Add one or more long-acting bronchodilators (when needed); Add rehabilitation Add long term oxygen if chronic respiratory failure. Consider surgical treatments <ul><li>FEV 1 /FVC < 70% </li></ul><ul><li>50% < FEV 1 < 80% </li></ul><ul><li>predicted </li></ul><ul><li>FEV 1 /FVC < 70% </li></ul><ul><li>30% < FEV 1 < 50% predicted </li></ul><ul><li>FEV 1 /FVC < 70% </li></ul><ul><li>FEV 1 < 30% predicted </li></ul><ul><li>or FEV 1 < 50% predicted plus chronic respiratory failure </li></ul>Active reduction of risk factor(s); influenza vaccination Add short-acting bronchodilator (when needed)
    23. 23. Comprehensive Management of COPD
    24. 24. Optimal Pharmacotherapy
    25. 25. CHANGING CONCEPTS IN COPD ASSESSMENT OF SEVERITY AND MANAGEMENT OF COPD Courtesy of PW Jones, 2011
    26. 26. Calverley PMA et al, NEJM 2007; 356:775-78
    27. 27. Rate of Exacerbations Plc SAL FP SFC * p< 0.001 vs Plc, † p=0.002 vs SAL, # p=0.024 vs FP * † # * * 0.85 0.93 0.97 1.13 number/patient/year Calverley PMA et al, N Engl J Med. 356(8): 775-89. 0 0.5 1
    28. 28. THE OPTIMAL STUDY: Effects on Exacerbations Aaron SD, et al. Ann Intern Med. 2007;146:545-555. No significant differences among groups N=449 Assumes all patients lost to follow-up did not have exacerbations (4 for tiotropium, 2 for tiotropium + salmeterol, 2 for tiotropium + salmeterol/fluticasone)
    29. 29. Mean number of severe exacerbations EFFICACY AND TOLERABILITY OF BUDESONIDE/FORMOTEROL ADDED TO TIOTROPIUM IN PATIENTS WITH COPD Welte T, et al. Am J Respir Crit Care Med. 2009 Oct 15;180(8):741-50 0.4 0.3 0.2 0.1 0.0 0 15 30 45 60 75 90 Days since randomisation Exacerbations/patient Bud/form + TIO PBO + TIO
    30. 30. Increased risk of pneumonia in COPD patients treated with ICS Torch Study, 2008 0.0032 0.0042 0.0031 0.0031 Fatal serious AE rate* 0.055 0.052 0.030 0.030 Serious adverse event rate* 0.088 0.084 0.052 0.052 Adverse event rate* SFC (N = 1546) FP (N = 1552) SAL (N = 1542) Placebo (N = 1544) * Rate per treatment year
    31. 31. POET-COPD ® : A Double-Blind, Double-Dummy Study Treatment period 12 months Run in 2 weeks Follow-up SAEs 30 days Salmeterol 50 µg MDI twice daily + Placebo Handihaler ® once daily Tiotropium 18 µg Handihaler ® once daily + Placebo MDI twice daily Screening Day 1 Randomization 4 months 8 months 12 months End of trial All previously prescribed COPD medications permitted ( except anticholinergics and beta-agonists, but salbutamol) 2 months Exacerbations at Clinic Visits/Vital Status MDI=metered-dose inhaler; SAE=serious adverse event. Vogelmeier C et al N Engl J Med 2011, 24 March 2011
    32. 32. Tiotropium Significantly Delayed Time to First Exacerbation Probability of COPD exacerbation (%) Time to event (days) 0 50 0 30 60 90 120 150 180 210 240 270 300 330 360 Hazard ratio = 0.83* (95% CI, 0.77, 0.90) P <0.001 (log-rank test) No. of patients at risk: 45 40 35 30 25 20 15 10 5 *Cox regression adjusted for (pooled) centre and treatment. 17% Risk difference Vogelmeier C et al N Engl J Med 2011, 24 March 2011 Tiotropium 3707 3369 3136 2955 2787 2647 2561 2455 2343 2242 2169 2107 1869 Salmeterol 3669 3328 3028 2802 2605 2457 2351 2251 2137 2050 1982 1915 1657 Tiotropium Salmeterol
    33. 33. Hazard ratio = 0.88* (95% CI, 0.78, 0.98) P =0.02 (log-rank test) No. of patients at risk: Reduced Risk of Premature Discontinuation with Tiotropium *Cox regression adjusted for (pooled) centre and treatment. 12% Risk difference Vogelmeier C et al N Engl J Med 2011, 24 March 2011 Probability of premature discontinuation of trial medication (%) Time to event (days) 0 0 5 10 15 20 30 60 90 120 150 180 210 240 270 300 330 360 Tiotropium 3707 3592 3501 3429 3382 3330 3299 3268 3225 3186 3158 3138 2841 Salmeterol 3669 3541 3436 3337 3291 3209 3181 3151 3111 3074 3054 3037 2703 Tiotropium Salmeterol
    34. 34. INSPIRE: Study Endpoints (I) <ul><li>Primary Objective </li></ul><ul><ul><li>To study the effect of SALMETEROL/FLUTICASONE combination vs TIOTROPIUM in reducing the rate of healthcare utilisation COPD exacerbations over 104 weeks in subjects with severe COPD. </li></ul></ul><ul><li>Main Secondary Endpoints </li></ul><ul><ul><li>Rate of symptom-defined exacerbations </li></ul></ul><ul><ul><li>Time to withdrawal </li></ul></ul><ul><ul><li>Post-dose FEV 1 </li></ul></ul><ul><li>Main Other Endpoints Health Outcomes Safety </li></ul><ul><li>Total exacerbation rate SGRQ Adverse events </li></ul><ul><li>Other lung function parameters AEs of special interest </li></ul><ul><li>TDI, All-cause Mortality All-cause Mortality </li></ul>
    35. 35. INSPIRE: Study Design Run-in Treatment Follow-up Prednisolone 30mg/day + salmeterol 50mcg bd tiotropium bromide 18mcg od SFC combination 50/500mcg bd via DISKUS Any COPD therapy 0 2 4 8 20 32 44 56 68 80 92 104 106 2 weeks
    36. 36. Exacerbation rates SFC (n=641) Tio (n=650) Rate Ratio (CI) P value Rate of all HCU exacerbations 1.28 1.32 0.976 ( 0.836,1.119) 0.651 HCU exacerbations using OCS 0.69 0.85 0.814 (0.670,0.990) 0.039 HCU exacerbations (ab) 0.97 0.82 1.186 (1.019,1.381) 0.028 Symptom defined exacerbations 3.04 3.02 1.006 (0.901,1.123) 0.913 Total exacerbatoins 3.37 3.37 1.000 (0.904,1.107) 0.995
    37. 37. Time to Withdrawal Cox Hazard Ratio 95% CI p-value SFC vs TIO 0.776 (0.651,0.926) 0.005 Probability of wd prior to wk 104 SFC 34.5% TIO 41.7%
    38. 38. Time to Withdrawal due to an Exacerbation Probability of wd prior to wk 104 SFC 9.5% TIO 12.8% Cox Hazard Ratio 95% CI p-value SFC vs TIO 0.736 (0.518,1.046) 0.088
    39. 39. INVOLVE: 52-week efficacy and safety 52 weeks 2 weeks Indacaterol 300 μ g o.d. (n=437) Indacaterol 600 μ g o.d. (n=428) Placebo (n=432) Formoterol 12 μ g b.i.d. (n=435) Double-blind, randomized, placebo-controlled, parallel-group study Baseline Screening period N.B. Indacaterol 150 μ g and 300 μ g once-daily are registered doses The recommended dose strength is 150 μ g once-daily, to be increased only on medical advice Dahl et al. Thorax 2010
    40. 40. Indacaterol 300 µg provided significant improvement in trough FEV 1 over 52 weeks, superior to formoterol 1.38 *p<0.05, ***p<0.001 vs placebo; † p<0.05, ††† p<0.001 vs formoterol Data are LSM in the modified intent-to-treat population Trough = average of 23 h 10 min and 23 h 45 min post-dose values *** 1.43 1.45 1.31 1.32 1.28 1.48 1.31 1.38 1.55 1.50 1.45 1.40 1.35 1.30 1.25 1.20 1.15 Trough FEV 1 (L) *** *** * 1.43 Day 2 Week 12 Week 52 Primary endpoint † Dahl et al. Thorax 2010 *** ††† *** †††
    41. 41. Improvements in trough FEV 1 were sustained over 52 weeks of treatment ***p<0.001 vs placebo. Data are LSM with 95% confidence intervals. The study was powered to detect an indacaterol-placebo difference of 120 mL (dotted line) FEV 1 (mL): differences between indacaterol and placebo Chapman et al. Chest 2011 After 1 day Day 15 Week 12 Week 26 Week 52 Indacaterol 150 µg Indacaterol 300 µg 250 200 150 100 50 *** *** *** *** *** *** *** *** *** ***
    42. 42. Symptom summary: Indacaterol vs twice a day beta agonists <ul><li>Indacaterol is superior to salmeterol and formoterol for </li></ul><ul><ul><li>Dyspnoea score </li></ul></ul><ul><ul><li>Quality of life </li></ul></ul><ul><li>The improvements in lung function translate into clinically meaningful changes </li></ul>
    43. 43. Summary: comparison with beta agonists <ul><li>Indacaterol </li></ul><ul><ul><ul><li>significantly improved lung function compared with salmeterol and formoterol </li></ul></ul></ul><ul><li>I mproved clinical outcomes for patients: </li></ul><ul><ul><li>breathlessness </li></ul></ul><ul><ul><ul><li>significant improvements compared with formoterol (300 µg) and salmeterol (150 µg) </li></ul></ul></ul><ul><ul><li>health related quality of life </li></ul></ul><ul><ul><ul><li>Significant improvements compared with placebo </li></ul></ul></ul><ul><ul><ul><li>significant improvements compared with salmeterol and numerical improvements vs formoterol </li></ul></ul></ul><ul><ul><li>reduction in need for rescue medication compared with salmeterol, formoterol and placebo </li></ul></ul>
    44. 44. Markers of hyperinflation and exercise endurance
    45. 45. Indacaterol improved inspiratory capacity which is sustained over 24 hours LaForce et al. Pulm Pharmacol Ther 2011 Indacaterol Salmeterol (1 st dose) Salmeterol (2 nd dose) – 2 0 2 4 6 8 10 12 14 16 18 20 22 24 2.2 2.1 2.0 1.9 1.8 1.7 1.6 Inspiratory capacity (L) Time post-dose *p<0.05 indacaterol vs salmeterol; p≤0.015 for indacaterol vs placebo at all time points; p<0.05 for salmeterol vs placebo at all time points except –50 minutes, 3 hours, 8 hours, 10 hours, 11 hours 10 minutes and 23 hours 45 minutes. Data are LSM±SE Placebo Indacaterol 300 µg o.d. Open-label Salmeterol 50 µg b.i.d. * * * * * * * * * *
    46. 46. INABLE 1: 21-day exercise endurance study n=90 Indacaterol 300 µg o.d. Indacaterol 300 µg o.d. Placebo Placebo Screening Treatment 1 Washout Treatment 2 21 days 21 days 21 days O’Donnell et al. Respir Med 2011 (accepted)
    47. 47. Indacaterol improved exercise endurance time on Days 1 and 21, compared with placebo 5 8 10 11 12 Day 1 Day 21 *p=0.011, ***p<0.001 Data are LSM and SE Exercise endurance time (mins) 8.07 9.75 1.68 *** 7.92 9.77 1.85 * 9 7 6 Placebo Indacaterol 300 µg o.d. O’Donnell et al. Respir Med 2011 (accepted)
    48. 48. Indacaterol improved inspiratory capacity at the end of exercise 1.5 2.1 2.5 Day 1 Day 21 *p=0.04, **p=0.002 Data are LSM and SE End-exercise inspiratory capacity (L) 1.98 2.17 190 mL * 1.94 2.22 280 mL ** 2.3 1.9 1.7 Placebo Indacaterol 300 µg o.d. O’Donnell et al. Respir Med 2011 (accepted)
    49. 49. INDORSE: 52-week safety and efficacy Stage I Indacaterol 75 µg o.d. Indacaterol 150 µg o.d. Indacaterol 300 µg o.d. Indacaterol 600 µg o.d. Placebo Formoterol 12 μ g b.i.d. Tiotropium* 18 μ g o.d. Indacaterol 150 µg Indacaterol 300 µg Placebo Tiotropium* 18 μ g Stage II Dose selection *Open-label All drugs were delivered via proprietary SDDPIs Stage III extension Indacaterol 150 µg Indacaterol 300 µg Placebo Stage I: ≥2 weeks, seven treatment arms Stage II: 26 weeks, four treatment arms (efficacy and safety) Stage III: 52 weeks, three treatment arms (safety and efficacy) Rennard et al. ACCP 2009; Chapman et al. Chest 2011
    50. 50. BLINDED 12 WEEK COMPARISON OF ONCE DAILY INDACATEROL AND TIOTROPIUM IN COPD Buhl R et al, Eur Respir J 2011, 24 May 2011 Both bronchodilators demonstrated spirometric efficacy The two treatments were well tolerated with similar adverse event profiles Compared with tiotropium, indacaterol provided significantly greater improvements in clinical outcomes
    51. 51. ONCE-DAILY BRONCHODILATORS FOR CHRONIC OBSTRUCTIVE PULMONARY DISEASE: indacaterol versus tiotropium Donohue JF et al, Am J Respir Crit Care Med Vol 182. pp 155–162, 2010 Indacaterol was an effective once-daily bronchodilator As effective as tiotropium in improving clinical outcomes for patients with COPD
    52. 52. Summary: comparison with tiotropium <ul><ul><ul><li>Improved lung function at least as effectively as tiotropium </li></ul></ul></ul><ul><li>I mproved clinical outcomes for patients for patients treated with indacaterol compared to tiotropium: </li></ul><ul><ul><li>breathlessness </li></ul></ul><ul><ul><li>health related quality of life </li></ul></ul><ul><ul><li>reduction in need for rescue medication </li></ul></ul><ul><li>Indacaterol has faster onset of action </li></ul>
    53. 53. INDORSE: 52-week safety and efficacy Stage I Indacaterol 75 µg o.d. Indacaterol 150 µg o.d. Indacaterol 300 µg o.d. Indacaterol 600 µg o.d. Placebo Formoterol 12 μ g b.i.d. Tiotropium* 18 μ g o.d. Indacaterol 150 µg Indacaterol 300 µg Placebo Tiotropium* 18 μ g Stage II Dose selection *Open-label All drugs were delivered via proprietary SDDPIs Stage III extension Indacaterol 150 µg Indacaterol 300 µg Placebo Rennard et al. ACCP 2009; Chapman et al. Chest 2011 (accepted) INDORSE
    54. 54. Chapman et et al, Chest 24 february 2011 During 1 year of treatment: indacaterol was well tolerated provided significant and well-maintained bronchodilation that was accompanied by improved clinical outcomes LONG-TERM SAFETY AND EFFICACY OF INDACATEROL, A NOVEL LONG-ACTING Β2-AGONIST, IN SUBJECTS WITH COPD: A RANDOMIZED, PLACEBO-CONTROLLED STUDY
    55. 55. BRONCHODILATORS ARE ASSOCIATED WITH INCREASED MORTALITY CHARM trial: patients with HF receiving bronchodilators (n=674 of 7599) Hawkins NM et al Eur J Heart Fail 2010;12:557-65 0.7 0.8 0.9 1.0 Survival Rate 0 0.5 1.0 1.5 2.0 2.5 3.0 3.5 Time (years) No bronchodilator and beta-blocker No bronchodilator and no beta-blocker Bronchodilator and beta-blocker Bronchodilator and no beta-blocker
    56. 56. HEART FAILURE AND CHRONIC OBSTRUCTIVE PULMONARY DISEASE: THE QUANDARY OF BETA-BLOCKERS AND BETA-AGONISTS β-agonists are associated with incident heart failure in patients with pulmonary disease, and with increased mortality and hospitalization in those with existing heart failure. These purported adverse effects require further investigation In the meantime, clinicians should consider carefully the etiology of dyspnea and obtain objective evidence of airflow obstruction before prescribing β-agonists to patients with heart failure. Hawkins N et al, Am J Coll Cardiologist, 2011, in press
    57. 57. MORTALITY ASSOCIATED WITH TIOTROPIUM MIST INHALER IN PATIENTS WITH CHRONIC OBSTRUCTIVE PULMONARY DISEASE: SYSTEMATIC REVIEW AND META-ANALYSIS OF RANDOMISED CONTROLLED TRIALS <ul><li>Our meta-analysis suggests an increased risk of mortality associated with tiotropium mist inhaler in patients with chronic obstructive pulmonary disease </li></ul><ul><li>Clinicians should inform patients about the possibility of this increased risk and exercise caution when prescribing tiotropium mist inhaler, particularly in patients with possible underlying cardiac disease </li></ul>Singh S, et al, BMJ 2011, 342:d3215
    58. 58. Add inhaled glucocorticosteroids if repeated exacerbations IV: Very Severe III: Severe II: Moderate I: Mild Therapy at Each Stage of COPD <ul><li>FEV 1 /FVC < 70% </li></ul><ul><li>FEV 1 > 80% predicted </li></ul>Add one or more long-acting bronchodilators (when needed); Add rehabilitation Add long term oxygen if chronic respiratory failure. Consider surgical treatments <ul><li>FEV 1 /FVC < 70% </li></ul><ul><li>50% < FEV 1 < 80% </li></ul><ul><li>predicted </li></ul><ul><li>FEV 1 /FVC < 70% </li></ul><ul><li>30% < FEV 1 < 50% predicted </li></ul><ul><li>FEV 1 /FVC < 70% </li></ul><ul><li>FEV 1 < 30% predicted </li></ul><ul><li>or FEV 1 < 50% predicted plus chronic respiratory failure </li></ul>Active reduction of risk factor(s); influenza vaccination Add short-acting bronchodilator (when needed)
    59. 59. <ul><li>Roflumilast is an anti-inflammatory drug and not a bronchodilator </li></ul><ul><li>In patients with severe COPD with chronic bronchitis  prevention of exacerbations  improvement of lung function </li></ul><ul><li>Add-on to bronchodilator maintenance treatment with additive effects </li></ul><ul><li>Specific safety profile </li></ul>ROFLUMILAST IN CLINICAL PRACTICE PDE4 inhibition Clinical benefits Calverley PMA et al, Lancet 2009;374:685-694. Fabbri LM et al, Lancet 2009;374:695-703.
    60. 60. Add ICS OR/AND ROFLUMILAST in “exacerbators” IV: Very Severe III: Severe II: Moderate I: Mild Therapy at Each Stage of COPD <ul><li>FEV 1 /FVC < 70% </li></ul><ul><li>FEV 1 > 80% predicted </li></ul>Add one or more long-acting bronchodilators (when needed); Add rehabilitation Add long term oxygen if chronic respiratory failure. Consider surgical treatments Add ROFLUMILAST <ul><li>FEV 1 /FVC < 70% </li></ul><ul><li>50% < FEV 1 < 80% </li></ul><ul><li>predicted </li></ul><ul><li>FEV 1 /FVC < 70% </li></ul><ul><li>30% < FEV 1 < 50% predicted </li></ul><ul><li>FEV 1 /FVC < 70% </li></ul><ul><li>FEV 1 < 30% predicted </li></ul><ul><li>or FEV 1 < 50% predicted plus chronic respiratory failure </li></ul>Active reduction of risk factor(s); influenza vaccination Add short-acting bronchodilator (when needed)
    61. 61. <ul><li>COPD and chronic comorbidities </li></ul><ul><li>Exacerbations in COPD </li></ul><ul><li>Current and future treatment </li></ul><ul><li>Treatment of co-morbidities of COPD </li></ul><ul><li>Futuristic treatments </li></ul>Management of COPD: GOLD guidelines Leonardo M. Fabbri
    62. 62. Barnes PJ et al., Eur Respir J 2009;33:1165–1185 SYSTEMIC EFFECTS AND COMORBIDITIES OF CHRONIC OBSTRUCTIVE PULMONARY DISEASE
    63. 63. REDUCTION OF MORBIDITY AND MORTALITY BY STATINS, ACE INHIBITORS, AND ARBS IN PATIENTS WITH COPD These agents may have dual cardiopulmonary protective properties, thereby substantially altering prognosis of patients with COPD. These findings need confirmation in randomized clinical trials. Mancini JB et al. J Am Coll Cardiol 2006;47(12):2554-60
    64. 64. EFFECT OF Β BLOCKERS IN TREATMENT OF CHRONIC OBSTRUCTIVE PULMONARY DISEASE: A RETROSPECTIVE COHORT STUDY <ul><li>β blockers (predominantly cardioselective) may confer reductions in mortality, exacerbations, and hospital admissions in patients with COPD, in addition to the benefits attributable to addressing cardiovascular risk </li></ul><ul><li>These additive benefits were seen on top of inhaled therapy, including inhaled corticosteroids and did not result in any worsening of pulmonary function </li></ul>Philip M Short et Al BMJ 2011;342:d2549
    65. 65. <ul><li>COPD and chronic comorbidities </li></ul><ul><li>Exacerbations in COPD </li></ul><ul><li>Current and future treatment </li></ul><ul><li>Treatment of co-morbidities of COPD </li></ul><ul><li>Futuristic treatments </li></ul>Management of COPD: GOLD guidelines Leonardo M. Fabbri
    66. 66. EMERGING PHARMACOTHERAPIES FOR COPD Barnes PJ. Chest 2008; 134:1278-1286
    67. 67. <ul><li>COPD and chronic comorbidities </li></ul><ul><li>Exacerbations in COPD </li></ul><ul><li>Current and future treatment </li></ul><ul><li>Treatment of co-morbidities of COPD </li></ul><ul><li>Futuristic treatments </li></ul>Management of COPD: GOLD guidelines Leonardo M. Fabbri
    68. 68. Management of COPD: GOLD guidelines SEPAR 44th National Congress Oviedo 17 June 2011
    69. 69. VIZI E VIRTU’ Giotto, Cappella degli Scrovegni, Padova <ul><li>Obaji A, Sethi S. Drugs and Aging 2001;18:1-11. </li></ul>
    70. 70. INVIDIA Giotto, Padova, Scrovegni <ul><li>Obaji A, Sethi S. Drugs and Aging 2001;18:1-11. </li></ul>

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