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Aggiornamento Linee Guida GINA 2003 1/4/2004 Sala Congressi Hotel Michelangelo Sassuolo

ATTUALITA’ ED EVOLUZIONE NELLA GESTIONE CLINICA DELL’ASMA. Aggiornamento Linee Guida GINA 2003 1/4/2004 Sala Congressi Hotel Michelangelo Sassuolo Prof. Leonardo M. Fabbri Clinica di Malattie dell’Apparato Respiratorio Università degli Studi di Modena e Reggio Emilia, Modena. G lobal

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Aggiornamento Linee Guida GINA 2003 1/4/2004 Sala Congressi Hotel Michelangelo Sassuolo

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  1. ATTUALITA’ ED EVOLUZIONE NELLA GESTIONE CLINICA DELL’ASMA Aggiornamento Linee Guida GINA 2003 1/4/2004 Sala Congressi Hotel Michelangelo Sassuolo Prof. Leonardo M. Fabbri Clinica di Malattie dell’Apparato Respiratorio Università degli Studi di Modena e Reggio Emilia, Modena

  2. Global INitiative for Asthma 2003 www.ginasthma.com

  3. Executive CommitteeChair: Paul O’Byrne, MD GINA Structure Dissemination Committee Chair: Tan Wan-Cheng, MD Science Committee Chair: Eric Bateman, MD GINA reports prepared during workshops conducted in cooperation with the U.S. National Heart, Lung, and Blood Institute, NIH and the World Health Organization.

  4. G lobal Initiative for Chronic O bstructive L ung D isease www.goldcopd.com

  5. S.Buist, US P.Calverley, UK B.Celli, US L.Fabbri, Italy Y.Fukuchi, Japan L.Grouse, US S.Hurd, US C.Jenkins, Australia C.Lenfant, US J.Luna, Guatemala W.McNee, UK E.Nizankowska-Mogilnicka, Poland K.Rabe, NL R.Rodriguez Roisin, E P.Van Der Molen, NL N.Zhong, China Global Initiative on Obstructive Lung DiseaseEXECUTIVE COMMITTEEChair: Romain Pauwels

  6. P. Barnes, UK S. Buist, US P. Calverley, UK Y. Fukuchi, Giappone W. McNee, UK R. Pauwels, Belgium K. Rabe, Germany Roberto Rodrigues Roisin, Spain N. Zielinski, Poland Global Initiative on Obstructive Lung DiseaseSCIENTIFIC COMMITTEEChair: Leonardo M. Fabbri

  7. Third Quarter, 2000: Publication Date from 2000/07/01 to 2000/09/30 Search COPD NOT ASTHMA: All Fields. Limits: All Adult: 19+ years, only items with abstracts, English, Clinical Trial, Human Sort by: Authors (20 citations) No star = Clinical Trial, One * = Randomized Clinical Trials (15 citations) Two ** = Randomized Clinical Trials and Core Clinical Journals (7 citations)  ASSIGNMENTS, REVIEWER,PUBLICATION NUMBER Peter Barnes, 8 Sonia Buist, 16, 17 Leo Fabbri, 14, 20, 10, 19 Yoshi Fukuchi, 5, 7, 10, 12, 19, 20 Bill MacNee, 1, 5, 8, 15 Romain Pauwels, 16, 17 Klaus Rabe, 2, 3, 4, 11, 14 Roberto Rodriguez-Roisin, 2, 3, 4, 11, 13, 18 Jan Zielinski, 1, 7, 10, 15, 19

  8. ORIGINAL TEXT …. tract inflammation57-61. It is likely that indoor air pollution derived from the burning of biomass fuels will prove to have similar effects. SUGGESTED REVISION …. tract inflammation57-61. It is likely that indoor air pollution derived from the burning of biomass fuels will prove to have similar effects.Also bacterial colonization contributes to the airway inflammation in patients with stable COPD. The degree of inflammation also relating to the bacterial load and to the bacterial species (Hill at et al, 2000). Consequences of such colonization and enhanced inflammation on morbidity and lung function is not clear GOLD REPORT – Section 4Page 32, left column, end of para 2, Hill AT, Campbell EJ, Hill SL, Bayley DL, Stockley RA. Association between airway bacterial load and markers of airway inflammation in patients with stable chronic bronchitis. Am J Med 2000 Sep;109(4):288-95

  9. PATIENTS AT HIGH RISK OF DEATH AFTER LUNG-VOLUME–REDUCTION SURGERY National Emphysema Treatment Trial Research Group N Engl J Med 2001; 345: to be published on October 11

  10. Patients at High Risk of Death after Lung-Volume-Reduction Surgery NATIONAL EMPHISEMA TREATMENT TRIAL RESEARCH GROUP P < 0.001 Surgery Probability of death Medical therapy Months since Randomization New Engl J Med 2001; to be published next Oct 11

  11. Levels of evidence

  12. INSTITUTE OF SCIENTIFIC INFORMATION (ISI) ISI JOURNAL CITATION REPORTS http://jcrweb.com/ Impact Factor Number of Citations in 2002 Number of articles 2000-2001

  13. IMPACT FACTOR 2002 Medicine, General & Internal: 1) New Engl J Med 31.74 2) JAMA – J Am Med Assoc 16.78 3) Lancet 15.39 4) Ann Intern Med 11.41 5) Annu Rev Med 7.95 6) Brit Med J 7.58 7) Arch Intern Med 6.74 8) Medicine 5.18

  14. IMPACT FACTOR 2002 Respiratory System 1) Am J Resp Crit Care 6.56 2) Am J Resp Cell Mol 4.17 3) Thorax 4.08 4) Am J Physiol-Lung C 3.90 5) Chest 2.97 6) Eur Respir J 2.94 7) J Thorac Cardiov Sur 2.84 8) Sarcoidosis Vasc Dif 2.83

  15. Le linee guida GINA in Italia: passare dalla teoria ai fatti Prof. L.M. Fabbri Processo di aggiornamento delle linee guida Trattamento farmacologico: 2003-2004 Asma grave/BPCO Nuovi farmaci antiasmatici

  16. Le linee guida GINA in Italia: passare dalla teoria ai fatti Prof. L.M. Fabbri Processo di aggiornamento delle linee guida Trattamento farmacologico: 2003-2004 Asma grave/BPCO Nuovi farmaci antiasmatici

  17. Global INitiative for Asthma 2003 www.ginasthma.com

  18. Executive CommitteeChair: Paul O’Byrne, MD GINA Structure Dissemination Committee Chair: Tan Chen Wan, MD Science Committee Chair: Eric Bateman, MD GINA reports prepared during workshops conducted in cooperation with the U.S. National Heart, Lung, and Blood Institute, NIH and the World Health Organization.

  19. E. Bateman, South Africa, Chair P. Barnes, UK S. Holgate, UK J. Bousquet, France J. Kips, Belgium W. Busse, USA P. O’Byrne, Canada J. Drazen, USA K. Ohta, Japan M. FitzGerald, Canada S. Pedersen, Denmark P. Gibson, AustraliaE. von Mutius,Germany Science Committee

  20. Le linee guida GINA in Italia: passare dalla teoria ai fatti Prof. L.M. Fabbri Processo di aggiornamento delle linee guida Trattamento farmacologico: 2003-2004 Asma grave/BPCO Nuovi farmaci antiasmatici

  21. Management of asthma:updating the GINA guidelines Mild Intermittent Avoidance of risk factors, immunotherapy Short-acting beta-2 agonists as needed Mild Persistent Low-dose inhaled steroids Combination of long-acting beta2 agonists with low dose inhaled steroids Moderate Persistent Asthma severity Moderate Persistent (Severe?) Combination with higher doses inhaled corticosteroids, theophylline, antileukotrienes Severe Persistent (Very severe?) Systemic steroids

  22. Stepwise Approach to Asthma Therapy Controlled by inhaled short-acting beta-2 agonists prn Step 1: Mild Intermittent Asthma Controller • Not required Reliever • Inhaled beta2-agonist prn <3-4x a day • Inhaled beta2-agonist or Cromolyn or Leukotriene modifier prior to exerciseor exposure to antigen Avoid or Control Triggers

  23. Part A – Budesonide therapy Adults Budesonide 400 g once daily + usual asthma therapy Part B Children (6–10 yrs) Adults Budesonide 200 g once daily + usual asthma therapy Budesonide 400 g once daily + usual asthma therapy Part A – Reference therapy Children (6–10 yrs) Budesonide 200 g once daily + usual asthma therapy Adults and Children Placebo once daily+ usual asthma therapy START – study outline 0 1 2 3 4 5 Year Visit 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 Pauwels R et a. Lancet 2003; 371: 1071-1076

  24. Long-term, once-daily treatment with low-dose budesonide decreases the risk of severe exacerbations by 44% and improves asthma control compared with placebo in patients with recent onset, mild persistent asthma. START Conclusions Pauwels R et a. Lancet 2003; 371: 1071-1076

  25. Stepwise Approach to Asthma Therapy Controlled by low-dose inhaled steroids Step 2: Mild Persistent Asthma Controller • Daily inhaled cortico- steroid (200-500 mcg) • Cromolyn, Nedocromil, sustained release Theophylline • Consider Leukotriene Modifiers Reliever • Inhaled beta2-agonist prn <3-4x a day • Inhaled beta2-agonist or Cromolyn or Leukotriene modifier prior to exercise or exposure to antigen Avoid or Control Triggers

  26. mast cells 760 720 240 200 160 120 80 40 0 Pre-BD 6 wk Pre-BD 6 wk Pre-BD 6 wk Effects of Inhaled Beclomethasone Dipropionate in Clinical Asthma Bronchial Function Bronchial Submucosa PC20 methacholine (mg/ml) Asthmatic symptoms eosinophils T lymphocytes number of cells/mm2 of submucosa Severity mg/ml Djukanovic et al, Am Rev Respir Dis 1992 Mar;145(3):669-74

  27. LONG-ACTING b2-AGONIST MONOTHERAPY VS CONTINUED THERAPY WITH INHALED CORTICOSTEROIDS IN PATIENTS WITH PERSISTENT ASTHMA A Randomized Controlled Trial Patients with persistent asthma well controlled by low doses of triamcinolone cannot be switched to salmeterol monotherapy without risk of clinically significant loss of asthma control. Lazarus SC et al. JAMA 2001; 285: 2583-2593

  28. Low-dose Fluticasone is More Effective of Montelukast in Mild Persistent Asthma * * * * * * * * Mean % change from baseline in FEV1 Baseline Endpoint Treatment week Busse W et al., J Allergy Clin Immunol 2001; 107: 461-468

  29. Low Dose Inhaled Budesonide and Formoterol in Mild Persistent Asthma . The OPTIMA Randomized Trial Paul M. O‘Byrne, Peter J. Barnes, Roberto Rodriguez-roisin, Eva Runnerstrom,Thomas Sandstrom, Klas Svensson, and Anne Tattersfield O’Byrne et al. Am. J. Respir. Crit. Care Med. 2001;164 1392-1397

  30. Time to first severe exacerbation Budesonide 200 34/226 Proportion 44/227 Budesonide 200 + Formoterol Placebo 79/237 Days O’Byrne et al. Am. J. Respir. Crit. Care Med. 2001;164 1392-1397

  31. Rate for poorly controlled days 0.144 0.15 0.10 0.083 0.073 Rate 0.05 0.00 Placebo Budesonide 200 Budesonide + Formoterol O’Byrne et al. Am. J. Respir. Crit. Care Med. 2001;164 1392-1397

  32. Mometasone furoate administered once daily is as effective as twice-daily administration for treatment of mild-to-moderate persistent asthma _________________________________________________ This is the first study demonstrating that a total daily dose of 400 g of mometasone furoate (MF) administered by dry powder inhaler is an effective treatment for patients with mild-to-moderate persistent asthma previously taking only 2-agonists • Kemp et al, J Allergy Clin Immunol. 2000 Sep;106(3):485-92

  33. Stepwise Approach to Asthma Therapy Controlled by inhaled steroids plus long-acting bronchodilators Step 3: Moderate Persistent Asthma Controller • Add long acting broncho- dilators to low dose inhaled steroids • Increase the dose of inhaled corticosteroids 800-2,000g • Add leukotriene modifiers if control is not achieved Reliever • Inhaled beta2-agonist prn <3-4x a day • Inhaled beta2-agonist or Cromolyn or Leukotriene modifier prior to exercise or exposure to antigen Avoid or Control Triggers

  34. Addition of salmeterol to inhaled BDP is superior to increased dose of BDP in persistent asthma *p<0.05, **p<0.01, ***p<0.001 vs BDP 35 Salmeterol 50 g bid+ BDP 200 g bid 30 ** *** ** 25 * ** 20 Mean change from baseline in morning PEF (L/min) *** 15 10 BDP 500 g bid 5 0 0 3 6 9 12 15 18 21 Time (weeks) BDP, beclomethasone dipropionate; ICS, inhaled corticosteroid PEF, peak expiratory flow Greening et al. Lancet 1994

  35. Addition of salmeterol to inhaled BDP is superior to increased dose of BDP in moderate/severe asthma 10 9 ** * * 8 Salmeterol 50 g bid+ BDP 500 g bid ** 7 6 *p<0.001, **p<0.05 Change in FEV1 (% predicted) 5 4 3 BDP 1000 g bid 2 1 0 0 2 8 16 24 Weeks of treatment Woolcock et al. Am J Respir Crit Care Med 1996 Adapted with permission BDP, beclomethasone dipropionate

  36. Changes in FEV1 during the study 90 85 FEV1 (% of predicted) 80 75 Higher-dose budesonide plus formoterol Lower-dose budesonide plus formoterol Higher-dose budesonide Lower-dose budesonide -1 0 1 2 3 6 9 12 Month Pauwels RA et al., N Engl J Med 1997 FACET

  37. Estimates of severe exacerbation rates BUD200 h=0.91 BUD800 h=0.46 BUD200+F h=0.67 BUD800+F h=0.34 BUDH: - 49% (p<0.001) p=0.031 FORM: - 26% (p=0.014) Pauwels RA et al., N Engl J Med 1997

  38. Estimates of mild exacerbation rates BUD200 h=35.4 BUD800 h=22.3 BUD200+F h=21.3 BUD800+F h=13.4 BUDH: - 37% (p<0.001) p=0.76 FORM: - 40% (p=0.001) Pauwels RA et al., N Engl J Med 1997 FACET

  39. CLASSIFY SEVERITY Clinical Features Before Treatment Symptoms NighttimeSymptoms PEF Continuous Limited physical activity Frequent ≤60% predicted Variability >30% STEP 4 Severe Persistent Daily Use 2-agonist daily Attacks limit activity >1 time week 60-80% predicted Variability >30% STEP 3 Moderate Persistent ≥80% predicted Variability 20-30% >2times a months STEP 2 Mild Persistent ≥1 time a week but <1 time a day ≤2 times a month <1 time a week Asymptomatic and normal PEF between attacks STEP 1 Intermittent ≥80% predicted Variability <20% One of the features of severity is sufficient to place a patient in that category Classification of Asthma Severity Treatment Intensity of treatment

  40. Management of Asthma Oral steroids Long-acting bronchodilators and/or LTRA Inhaled steroids Short-acting 2 agonists prn Severity of asthma IMMUNOTHERAPY ? PREVENTION

  41. Treatment Options for Patients Not Controlled on Inhaled Steroids Patients not controlled on inhaled steroids Add leukotriene receptor antagonists Increase the dose of inhaled steroid Add theophylline Add long-acting beta2-agonists

  42. Montelukast + Budesonide vs higher-dose budesonide 440 Montelukast + budesonide 800 µg (n=433) 430 Budesonide 1600 µg (n=425) 420 AM PEF (L/min) 410 p=0.367 between groups during the last 10 weeks of the 12-week treatment period 400 390 Days relative to start of trial -14 -7 0 7 14 21 28 35 42 48 56 63 70 77 84 Run-in Price et al., Thorax 2003

  43. COMPARISON OF INHALED SALMETEROL AND ORAL ZAFIRLUKAST IN PATIENTS WITH ASTHMA In patients with persistent asthma, most of whom currently using inhaled corticosteroids, treatment with inhaled salmeterol provided significantly greater improvement that oral zafirlukast in overall clinical control over the 4-week treatment period Busse WW et al. J Allergy Clin Immunol 1999; 103: 1075-80

  44. A ONE-YEAR COMPARATIVE TRIAL OF MONTELUKAST AND FLUTICASONE VS SALMETEROL AND FLUTICASONE IN PROTECTING AGAINST ASTHMA ATTACKS The study demonstrates the equal clinical benefit of including montelukast or salmeterol in asthma therapy for protection against asthma exacerbations of patients inadequately controlled by inhaled corticosteroids. Biermer L t al. BMJ 2003; in press

  45. ADDITION OF LEUKOTRIENE ANTAGONISTS • TO THERAPY IN CHRONIC PERSISTENT • ASTHMA: A RANDOMISED DOUBLE-BLIND • PLACEBO-CONTROLLED TRIAL • Used as additional therapy in a hospital outpatient clinic setting, • montelukast did not provide such additional benefit in patients • with moderate or severe asthma Robinson DS et al Lancet 2001; 357: 2007-11

  46. Le linee guida GINA in Italia: passare dalla teoria ai fatti Prof. L.M. Fabbri Processo di aggiornamento delle linee guida Trattamento farmacologico: 2003-2004 Asma grave/BPCO Nuovi farmaci antiasmatici

  47. Differences between asthma and COPD ASTHMA Sensitizing agent COPD Noxious agent Asthmatic airway inflammation CD4+ T-lymphocytes Eosinophils COPD airway inflammation CD8+ T-lymphocytes Marcrophages Neutrophils Airflow limitation Completely reversible Completely irreversible Airflow limitation

  48. COPD Asthma B A B D C Fabbri LM et al Am J Respir Crit Care Med 2003;167 418-424

  49. Management of COPD and asthma:GOLD and GINA guidelines ASTHMA COPD Mild Intermittent 2 prn Mild 2 prn Mild persistent iGCS Moderate LABA Moderate persistent Combination Severe Combination LABA+iGCS LABA+iGCS Severe persistent Oral GCS Very Oxygen, Sx severeSurgery

  50. Le linee guida GINA in Italia: passare dalla teoria ai fatti Prof. L.M. Fabbri Processo di aggiornamento delle linee guida Trattamento farmacologico: 2003-2004 Asma grave/BPCO Nuovi farmaci antiasmatici

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