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- 1. UPDATE ON ASTHMA MANAGEMENT Lunch Hour Talk 12th July, 2005 Rashidi Ahmad Lecturer/Emergentist Department of Emergency Medicine
- 2. Outline • Global Burden of asthma – good @ bad news? • Definition of asthma, what is new? • Pathogenesis of asthma, what is new? • What is persistent asthma? • Scientific rationale of LABA + CS and LABACS inhaler • Formoterol/Budesonide as AMD & single inhaler therapy
- 3. Global Burden of Asthma • Asthma prevalence 2 - 7% internationally (ECRHS studies) • Asthma prevalence on the rise for > 20 year (Vollmer 1998), 74% increase 1980 - 96 (Mannino 1998) & may be stabilizing (Braun-Fahrlander ERS 2004) • 50% of male cases Dx by 3 y.o, 50% of female cases Dx by 8 y.o (Yunginger et al ARRD 1992) • Factors for persistent & relapsed asthma: atopic exposure, bronchial hyperreactivity, female sex, smoking, early age at onset (Sears et al NEJM 2003) • Highest absence rate from school (Weiss et al NEJM 1992) • Costly: 12.6 billion /year direct med costs (Weiss JACI 2000)
- 4. Asthma Exacerbations • In the relatively undertreated 1999 U.S. asthma population (N= 10,488,000 persons) – School absence: 14.0 million days – Work absence: 14.5 million days – Asthma ER visits: 2 million – Asthma Hospitalizations: 478,000 – Asthma Deaths: 4657 MMWR Surveillance Summaries March 29, 2002 / 51(SS01);1-13
- 5. Frequency Adverse Event is Likely to Occur.. - Absenteeism: At least once in every asthmatic (Average: 3.7 days/year) - ER visit: Once in every 5 asthmatics - Hospital visit: Once in every 26 asthmatics - Death: Once in every 2252 asthmatics MMWR Surveillance Summaries March 29, 2002 / 51(SS01);1-13
- 6. Asthma Definition • Chronic Airway Inflammatory Disease • Occurs only in Susceptible Individuals • Recurrent Episodes of Symptoms • Variable and Reversible Airflow Obstruction • Increased Bronchial Hyperreactivity NHLBI 1997
- 7. Asthma Definition – NHLBI 2002 • Chronic Airway Inflammatory Disease • Occurs only in Susceptible Individuals • Recurrent Episodes of Symptoms • Variable and Reversible Airflow Obstruction • Increased Bronchial Hyperreactivity • May have an incomplete response to therapy • May coexist with chronic bronchitis
- 8. Pathogenesis of Asthma Holgate ST. The cellular and mediator basis of asthma in relation to natural history. Lancet 1997;350(suppl 2):5-9.
- 9. Asthma Pathology - Modern view Allergen Macrophage/ dendritic cell Mast cell Th2 cell Neutrophil Eosinophil Mucus plug Epithelial shedding Nerve activation Subepithelial fibrosis Plasma leak Sensory nerve Oedema activation Vasodilatation Cholinergic Mucus reflex New vessels hypersecretion Hyperplasia Bronchoconstriction Hypertrophy/hyperplasia Barnes PJ (1999:2000)
- 11. Bronchial morphology • Inflammation • Eosinophils • Gland hyperplasia • Mucous plug in lumen • Hypertrophy of muscle layer
- 12. Normal bronchial mucosa Goblet-cell hyperplasia in the epithelial-cell lining Sub-basement membrane: thickened, collagen deposition in the submucosal area, cellular infiltrattion Busse et al NEJM 2001
- 13. Cellular Mechanisms Involved in Airway Inflammation
- 14. Mediators of Airflow Obstruction • Bronchoconstriction (histamine, PAF, PGD2, LTC4, LTD4) • Edema (as above plus bradykinin) • Increased mucus secretion (cysteinyl leukotrienes) • Airway remodeling (toxic eosinophil eosinophil, TNF-alpha)
- 15. What is Persistent Asthma? Asthma severity Classified by: 4 Severe Persistent • Symptoms • Activity levels 3 Moderate Persistent • Exacerbations 2 • FEV1/PEFR Mild Persistent • PEFR variability 1 Mild Intermittent “Severity is classified before therapy begins” Global INitiative for Asthma (1998)Asthma Management and Prevention Report, NHLBI and World Health Organization (WHO)
- 16. Mild Intermittent Clinical features before Rx • Symptoms < 2x per week • Brief exacerbations • Night time symptoms < 2x per month • Asymptomatic with normal lung function between exacerbations 1 Mild Intermittent • FEV1 and PEF > 80% predicted • PEF variability < 20%
- 17. Mild Persistent Clinical features before Rx • Sx > 2x/week but <1x/day • Exacerbations may affect activity • Night time asthma Sx > 2x/month 2 • FEV1 and PEF > 80% predicted • PEF variability 20 - 30% Mild Persistent
- 18. Moderate Persistent Clinical features before Rx • Daily symptoms • Exacerbations > 2x/week 3 affect activity • Night time asthma sx > 1x/week Moderate • Daily use of short-acting ß agonist Persistent • FEV1 and PEF > 60% and < 80% predicted • PEF variability > 30%
- 19. Severe Persistent Severe 4 Persistent Clinical features before Rx • Continuous symptoms • Frequent exacerbations • Frequent night time symptoms • Limited activity • FEV1 and PEF < 60% predicted • PEF variability > 30%
- 20. Principles of Asthma MX Acute Chronic Airway Inflammation Inflammation Remodelling Bronchoconstriction Cell recruitment Cellular proliferation Oedema Epithelial damage Extra-cellular matrix Secretions Early structural increase Cough changes
- 21. Asthma Continuum ) dose 00 µg aily 20 (d µg id 0 stero 100 + Prednisone tico β2-agonist cocor 00 µg CS d glu 5 le (mainstay of asthma MX) Inha g 0µ Additional therapy Short-acting β2-agonist on demand Environmental control and education Severity of asthma Very mild Mild Moderate Moderately Severe severe Symptom characteristics Subclinical Intermittent Persistent Canadian Consensus on Asthma 1999
- 22. Questions to be answer? • How CS works in asthma? • What is the maximum effective dose? • How β2-agonist works in asthma? • What are the effects of combination therapy between LABA and CS? • What is the rationale of LABACS in asthma management?
- 23. Steroid Effects in Asthma Enhanced innate immunity Barnes PJ Am J Resp Crit Care Med 1998; 157: S1-S53
- 24. Therapeutic response to CS Laitinen et al JACI 1992; 90: 32-42
- 25. What is the maximum dose? • Those asthmatics who were not controlled on a low dose of ICS (beclomethasone dipropionate 400 µg daily), had little improvement in asthma control even the dose was increased (1000 µg daily) Greening AP et al. Lancet 1994;344:219–224 • Dose/response studies have demonstrated that in patients with moderate asthma there is a relatively flat dose/response curve, with most of the benefit obtained at the lowest doses Holt S et al. Dose-response relation of inhaled fluticasone propionate in adolescents and adults with asthma: meta-analysis. BMJ 2001;323:253–256
- 26. Beclomethasone dipropionate 400 µg daily Optimum dosage
- 27. Revolution in Asthma MX • Landmark study (Lancet 1994) • To examine the benefits of adding salmeterol compared with increasing dose of inhaled corticosteroids. • Systematic review of randomised, double blind clinical trials • 3685 symptomatic patients aged >/= 12 y.o • Results and conclusions (compared with response to increased steroids) • In patients receiving salmeterol morning PEFR was greater at 3 months (difference 22.4 (95% confidence interval 15.0 to 30.0) L/min, P<0.001) and 6 months (27.7 (19.0 to 36.4) L/min, P<0.001).
- 28. Cont… • FEV1 was also increased at 3/12 (0.10 L/min (0.04 to 0.16), P<0.001) and 6/12 (0.08 L/min (0.02 to 0.14), P<0.01), • Mean percentage of days and nights without symptoms (3 months: days 12% (9% to 15%), nights 5% (3% to 7%); 6 months: days 15% (12% to 18%), nights 5% (3% to 7%); all P<0.001) • Mean percentage of days and nights without need for rescue treatment (3 months: days 17% (14% to 20%), nights 9% (7% to 11%); 6 months: days 20% (17 to 23%), nights 8% (6% to 11%); all P<0.001). • Fewer patients experienced any exacerbation with salmeterol (difference 2.73% (0.43% to 5.04%), P=0.02) • The proportion of patients with moderate or severe exacerbations was also lower (2.42% (0.24% to 4.60%), P=0.03). Greening AP, Ind PW, Northfield M, Shaw G. Added salmeterol versus higher-dose corticosteroid in asthma patients with symptoms on existing inhaled corticosteroid. Lancet 1994;344:219–224
- 29. Kips JC, O'Connor BJ, Inman MD, Svensson K, Pauwels RA, O'Byrne PM. A long-term study of the antiinflammatory effect of low-dose budesonide plus formoterol versus high- dose budesonide in asthma. Am J Respir Crit Care Med 2000;161:996–1001
- 30. Kips JC, O'Connor BJ, Inman MD, Svensson K, Pauwels RA, O'Byrne PM. A long-term study of the antiinflammatory effect of low-dose budesonide plus formoterol versus high-dose budesonide in asthma. Am J Respir Crit Care Med 2000;161:996–1001
- 31. Formoterol minimises systemic burden arbitrary units Oxis Turbuhaler® Short-acting β2-agonist Effects in the lung after inhaled administration 0 6 12 hours Systemically derived effects 1. Löfdahl & Svedmyr, Allergy 1989 2. Palmqvist et al, Eur Respir J 1997 3. Borgström et al, AJRCCM 1996 4. Tötterman et al, Eur Respir J 1998 5. Lötvall et al, Eur Respir J 1997
- 32. Questions • Why CS have ceiling effects in inflammation process? I don’t have the answer. ?saturated • How LABA improve the symptoms & lung function beside no inflammatory properties? • Can LABA causes intolerance or mask the exacerbations?
- 34. Non-bronchodilatory effects of β2-agonists • Inhibit mediator release from mast cells • inhibit plasma exudation by preventing separation of endothelial cells in postcapillary venules • inhibit excitatory non-adrenergic non-cholinergic (NANC) bronchoconstrictor responses in guinea-pig bronchi in vitro
- 35. Formoterol does not mask exacerbations % Pulmicort Turbuhaler® 100 mg bid fall in mPEF before, during Pulmicort Turbuhaler® 100 mg bid + Oxis Turbuhaler® 9 mg bid 10 Pulmicort Turbuhaler® 400 mg bid and after severe Pulmicort Turbuhaler® 400 mg bid + Oxis Turbuhaler® 9 mg bid exacerbation 0 -10 -20 -30 -15 -10 -5 0 5 10 15 Days Tattersfield et al, AJRCCM 1999
- 36. No tolerance with long term use of formoterol Pulmicort® 100 mg bid Pulmicort® 100 mg bid + Oxis® 9 mg bid Pulmicort® 400 mg bid Pulmicort® 400 mg bid + Oxis® 9 mg bid FEV1 90 (% predicted) 85 80 75 70 -1 0 1 2 3 6 9 12 run-in Months Pauwels R et al, NEJM 1997
- 37. Summary of the effects of LABA & CS
- 38. Interaction between formoterol & budesonide P J Barnes ERJ 2002; 19:182-191
- 39. Desensitization of ß2 receptor Stimulatory G-protein G-protein receptor kinase-2 Uncoupling
- 40. CS - increased the expression of ß2-receptors ↑ transcriptase GRE: Glucocorticoid response elements
- 41. Interaction of ß2-agonists with corticosteroid effects PKA: protein Kinase A MAPK: mitogen-activated protein kinases
- 42. Clinical implications • LABA & CS have different targets • Complementary effects – CS preventing the loss of function of β2-agonists with chronic use & β2-agonists may potentiate the local inflammatory actions of CS • Combination of LABA + CS more superior than high dose CS in overall control of asthma especially moderate to severe persistent asthma
- 43. Stepwise Approach to Therapy for Children ≤5 Years Step 4 Severe Persistent Step 3 High-dose ICS + Moderate Persistent LABA Step 2 Preferred: (+ systemic Mild Persistent Low-dose ICS + LABA corticosteroids or if needed) Medium-dose ICS Step 1 Preferred: (+ LABA if needed) Mild Intermittent Low-dose ICS Alternative: Alternative: No Daily Cromolyn Low- to Med-dose ICS Medication or + LTRA or LTRA Theophylline NIH/NHLBI Guideline Update. June 2002. NIH Publication No. 02-5075.
- 44. Stepwise Approach to Therapy for Adults and Children > 5 Years Step 4 Severe Persistent Step 3 Moderate Persistent High-dose ICS + LABA Preferred: Step 2 Low- to Medium-dose Mild Persistent (+ systemic ICS + LABA corticosteroids Preferred: (↑ to med-dose ICS+ if needed) Step 1 Low-dose ICS LABA if needed) Mild Intermittent Alternative: Alternative: ↑ ICS With No LABA No Daily Cromolyn, LTM, or Low- to Med-dose Medication Nedocromil, or ICS + LTM or SR Theophylline Theophylline NIH/NHLBI Guideline Update. June 2002. NIH Publication No. 02-5075.
- 45. The Rationale of Inhaler combination therapy (LABACS) • ß2-agonists & CS interact in a beneficial way (CS preventing the loss of function of ß2-agonists with chronic use, whereas ß2-agonists may potentiate the local anti-inflammatory actions of CS) • Therefore it is a powerful scientific rationale for combining ß2-agonists and CS in a single inhaler (LABACS), as most patients with asthma will need both treatments • LABACS inhalers – better overall control of asthma • LABACS inhalers – new “gold standard” of therapy
- 46. Patients with asthma control day (%) Symbicort® improves asthma control* days Additional two 60 months per year 55 of asthma 50 control 45 p<0.001 40 Symbicort® 160/4.5 μg 35 30 Pulmicort® 200 μg + Oxis® 4.5 μg 25 Pulmicort® 200 μg 20 15 -10 0 10 20 30 40 50 60 70 80 90 Treatment Days *Asthma control day = no day/night symptoms, no rescue bronchodilator, no night awakenings Zetterström et al, WCLH/ERS 2000b
- 47. Symbicort® improves morning PEF Symbicort® 160/4.5 μg Pulmicort® 200 μg + Oxis® 4.5 μg Pulmicort® 200 μg 400 390 (L / min) 380 370 p<0.001 360 350 -10 0 10 20 30 40 50 60 70 80 90 Treatment Days Zetterström et al, WCLH/ERS 2000a
- 48. Symbicort® is more effective than a higher dose of ICS in Moderate Asthma 30 Change in morning PEF (L/min) 25 20 15 p<0.001 10 5 0 -5 -10 0 10 20 30 40 50 60 70 80 90 Treatment days Symbicort® 160/4.5 µg bid fluticasone DPI 250 µg bid Bateman et al, Am J Respir Crit Care Med 2001
- 49. Combination inhaler therapy (LABACS) • Symbicort (standard dose (160/4.5µg) and low-dose (80/4.5µg) • Seretide (50 µg of salmeterol (as salmeterol xinafoate) and 100, 250 or 500 µg of fluticasone propionate)
- 50. SABA versus LABA. Anderson et al Eur Respir J 1994; 7: 569-578
- 51. Revolution in single inhaler LABACS • Fixed dosing • Adjustment maintenance dosing • Single inhaler (controller + reliever)
- 52. Aiming for earlier and simpler adjustment in controller treatment to prevent attacks Asthma Worsening Exacerbation Reliever use prior to and after 425 exacerbations (data from FACET) Symbicort -15 -10 -5 0 5 10 15 Days before and after severe exacerbation Adapted from Tattersfield et al: AJRCCM 1999
- 53. Symbicort Ajustable Maintenance Dosing (AMD) compared to fixed-dosing (Canadian, Swedish and SUND Studies) Patients with Patients with Number of exacerbations exacerbation (%) exacerbation (%) 10 10 60 8 8 p<0.05 45 vs p<0.05 Seretide 6 6 P<0.01 30 4 4 2 2 15 0 0 Symbicort Symbicort Symbicort Symbicort Seretide Symbicort Symbicort Fixed AMD Fixed AMD Fixed Fixed AMD Fitzgerald M, et al (2003) Ställberg B, et al (2003) Aalbers R, et al (2004) N=995 N=1034 N=658
- 54. STAY: Study Design 4 x Budesonide + SABA n=926 Run-in Budesonide 320 μg bid a + terbutaline 0.4 mg as needed Previous regular ICS + Symbicort® Fixed Dose + SABA n=909 SABA as R needed Symbicort 80/4.5 μg bid a + terbutaline 0.4 mg as needed Symbicort® Single inhaler Therapy n=925 Symbicort 80/4.5 μg bid a + as needed Visit: 1 2 3 4 5 6 7 Month: -0.5 0 1 3 6 9 12 a Children <12 years received half the daily maintenance dose with a once daily regimen O’Byrne ATS 2004
- 55. Patient Characteristics 4 x BUD Symbicort Symbicort Characteristic + SABA + SABA SiT N=926 N=909 N=925 Males, n (%) 416 (45) 394 (43) 421 (46) Mean age, years (range) 36 (4–79) 36 (4–79) 35 (4–77) Mean FEV1, % predicted 73 73 73 Mean ICS at entry, μg/day 620 598 619 Long-acting β2-agonists (%) 27 28 27 Mean reliever inhalations/24 hours (no.) 2.4 2.4 2.5 Mean total asthma symptom 1.5 1.4 1.5 score (0–6) O’Byrne ATS 2004
- 56. Severe Exacerbations Total exacerbations p<0.001 Exacerbation 600 subtypes 564 553 500 PEF falls Steroid courses Hospitalisations/ ER treatment 400 350 350 40 303 300 250 250 30 200 150 150 20 100 50 50 10 0 4 x BUD + SABA Symbicort + SABA Symbicort SiT O’Byrne ATS 2004
- 57. Total Asthma Exacerbations 280 4 x BUD + SABA 200 Individual patients with exacerbations = 294 events 120 40 requiring intervention 0 3 6 9 12 15 19 23 27 31 35 39 43 47 51 55 280 Symbicort + SABA 200 = 330 events 120 40 0 3 6 9 12 15 19 23 27 31 35 39 43 47 51 55 280 Symbicort SiT # rate reduction 46 to 53% vs both 200 = 160 events # groups; p<0.001 120 40 0 3 6 9 12 15 19 23 27 31 35 39 43 47 51 55 Weeks since randomisation O’Byrne ATS 2004
- 58. Sustained improvements in lung function Morning PEF (L/min) Mean change am p<0.001 PEF (L/min) 370 Symbicort SiT 29.9 Symbicort + SABA 30 p<0.001 4 x BUD + SABA 360 22.0 350 20 13.0 340 10 330 320 0 0 40 80 120 160 200 240 280 320 360 4 x BUD Symbicort Symbicort + SABA + SABA SiT Days since randomisation O’Byrne ATS 2004
- 59. As-needed Medication Use Change from run-in Mean daily inhalations of as (inhalations/day) needed medication per group 0.4 4 x BUD + SABA 1.6 1.45 Symbicort + SABA -0 1.20 Symbicort SiT 1.2 1.0 -0.4 *** both groups p<0.001 0.8 -0.8 -1.2 0.4 *** -1.6 0 0 40 80 120 160 200 240 280 320 360 4 x BUD + Symbicort Symbicort SABA + SABA SiT Days since randomisation O’Byrne ATS 2004
- 60. Night-time awakenings Increase in % of nights undisturbed by asthma 14 *** 12.7 12 *** p<0.001 vs both groups 10 8.8 8.4 difference of at least 8 14 extra nights undisturbed per year 6 4 2 0 4 x BUD + Symbicort Symbicort SiT SABA + SABA O’Byrne ATS 2004
- 61. Steroid load during 1 year of treatment Days with systemic steroid Mean daily ICS μg/day 3500 700 600 2500 500 400 1500 300 200 500 100 0 4 x BUD Symbicort Symbicort 4 x BUD Symbicort Symbicort + SABA SiT + SABA SiT O’Byrne ATS 2004
- 62. Rate of severe exacerbations requiring medical intervention Events/patient/year 2–4 x BUD + SABA Symbicort + SABA 0.6 Symbicort SiT 0.5 0.40 0.4 0.35 0.3 0.2 0.19 *** 0.1 0 STAY moderate *** p<0.001 vs both Symbicort + SABA and 2 to 4x BUD + SABA
- 63. Numbers needed to treat (NNT) to prevent one severe exacerbation per year Comparison NNT Exacerbation reduction /100 patients per year Symbicort SiT vs BUD + SABA STAY (vs 4x BUD) 6.1 16 Symbicort SiT vs Symbicort + SABA STAY 4.7 21 NNT to prevent one severe exacerbation requiring medical intervention
- 64. Incidence of high as-needed use and association with emergency treatment (hospitalisation/ER visit) for asthma No. of patients with high No. of patients with high as-needed use * as-needed use * and at least one hospitalisation/ER visit 150 25 120 20 90 15 60 10 30 5 0 0 4x BUD Symbicort Symbicort 4x BUD Symbicort Symbicort + SABA + SABA SiT + SABA + SABA SiT *>8 as-needed doses/day on any day in the year (STAY study only)
- 65. Incidence of high as-needed use and exacerbation treatment in the STAY study (paediatric data) No. of children with No. of children with high as-needed use* high as-needed use * and at least one exacerbation requiring medical intervention 25 25 20 20 15 15 10 10 5 5 0 0 4 xBUD Symbicort Symbicort 4 xBUD Symbicort Symbicort +SABA + SABA SIT +SABA + SABA SIT * >7 as-needed doses on any day in the year (STAY paediatric data)
- 66. Other add on therapies • Low dose theophylline • Antileukotrienes (Montelukast) • Few trials documented above drugs do have some benefit when added to low doses of ICS • However, it is less effective as an add-on therapy than salmeterol
- 67. Summary • It is unlikely that bronchodilators more effective than ß2-agonists can be discovered, and new classes of bronchodilator have had major problems with vasodilator side effects • Most of the new treatments are more specific inhibitors of the inflammatory process than corticosteroids and are therefore less likely to be as effective, at least in a broad range of asthmatic patients
- 68. Conclusions • LABACS inhalers have shown tremendous results in asthma management (moderate to severe persistent asthma) especially symbicort (AMD + single inhaler therapy) • LABACS inhalers are likely to remain the most effective treatment for asthma over at least the next 10 years (it takes 15 years to bring a novel drug to the market)
- 69. PREVENTERS CONTROLLERS RELIEVERS Anti-inflammatory action to Sustained bronchodilator For quick relief of symptoms prevent asthma attacks action but weak or unproven and use in acute attacks as PRN anti-inflammatory effect dosage only Inhaled corticosteroids∗ Long-acting β2 agonists∗ Short-acting β2 agonists∗ 1. beclomethasone 1. salmeterol 1. salbutamol 2. budenoside 2. formoterol 2. fenoterol 3. fluticasone 3. terbutaline 4. flunisolide 4. hexoprenaline 5. triamcinolone 5. orciprenaline Sustained release theophylline tablets | Anti-cholinergics aminophylline Oral corticosteroids ipratropium bromide 1.prednisone 2.prednisolone Leukotriene antagonists∗∗ Short-acting theophyllines 3.methylprednisone 1. montelukast several preparations 4.methylprednisolone 2. zafirlukast