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Treatment decision in exacerbations of COPD

Treatment decision in exacerbations of COPD. Marc Miravitlles Institut Clínic del Tòrax Hospital Clínic Barcelona marcm@clinic.ub.es. Burden of COPD. Cost of COPD. €/year. Miravitlles et al. Chest 2003;123:784-791. Cost of COPD. Drugs. Visits and diagnostic tests. 16. 42.

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Treatment decision in exacerbations of COPD

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  1. Treatment decision in exacerbations of COPD Marc Miravitlles Institut Clínic del Tòrax Hospital Clínic Barcelona marcm@clinic.ub.es

  2. Burden of COPD

  3. Cost of COPD €/year Miravitlles et al. Chest 2003;123:784-791

  4. Cost of COPD Drugs Visits and diagnostic tests 16 42 Costs of hospitalisation 42 Miravitlles et al. Chest 2003;123:784-791

  5. Frequency of E-COPD n FEV1 Miravitlles et al. Respir Med 1999; 93: 173-179

  6. Failure rate of E-COPD Author n Follow-up Relapse (days) (%) MacFarlane, Lancet 93 315 AECB NR 26 Davey, PharmacoEc 94 62 AECB NR 18 Ball, QJMed 95 417 AECB 30 15 Woodhead, ERJ 96 390 AECB NR 14 DeAbate, Chest 98 488 AECB 10 13 Grossman, Chest 98 240 AECB NR 14 Miravitlles, Respir Med 99 1,001 COPD 10 13 Miravitlles, ERJ 2001 2,414 AECB 30 21 Dewan, Chest 2000 107 COPD 30 15 Adams, Chest 2000 173 COPD 14 22

  7. Evolution of E-COPD Relapse 507 (21%) Emergency 161 (33%) Change in AB 152 (31%) Ad. events 14 (3%) Admission 84 (17%) Miravitlles et al. Eur Respir J 2001; 17: 928-933

  8. Distribution of costs of AECB Add-on drugs (18%) Failure (63%) New clinic visit (1%) Initial drugs (14%) Emergency (7%) Clinic visit (5%) Hospitalisation (92%) Miravitlles et al. Chest 2002;121:1449-1455

  9. Risk factors for relapse Increasing number of visits for respiratory problems (>3/yr) Increasing baseline dyspnoea Severity of FEV1 impairment (FEV1<35%) Increasing age (>70 yrs.) Inadequate antibiotic choice Underprescription of oral steroids Use of home oxygen Miravitlles. Clin Pulm Med 2002; 9: 191-197

  10. Clinical efficacy

  11. Analysis of sputum

  12. Characterisation of E-COPD % Stockley et al. Chest 2000;117:1638-1645

  13. 3500 3000 2500 2000 1500 1000 500 0 Etiology of E-COPD and FEV1 FEV1.0 value (ml) H. influenzae P. aeruginosa Otros S. pneumoniae M. catarrhalis Non-PPMs Miravitlles et al. Chest 1999; 116: 40-46

  14. MOSAIC study • A multicentre, multinational, prospective, randomised, double blind study to compare the effectiveness ofMoxifloxacin Oral tablets to Standard oral antibiotic regimen given as first-line therapy in out-patients with Acute Infective exacerbations of Chronic bronchitis. MOSAIC Wilson R et al. Chest 2004; 125: 953-964

  15. MOSAIC study: objectives To investigate whether Moxifloxacin (the antibiotic with superior in vitro activity) gives superior clinical outcomes compared to standard therapy in the treatment of AECB

  16. MOSAIC:inclusion criteria • Age  45 years • History of chronic bronchitis • Smoking exposure  20 packs-year • History of  2 documented AECB episodes in the last 12 months • FEV1 < 85% of predicted value Wilson R et al. Chest 2004; 125: 953-964

  17. MOSAIC: design Moxifloxacin 400mg od 5 days ARM1 • V4 • Next AECB episode • or • Month 9 (at a maximum) Monthly contact from Month 1 (after end of treatment) up to Month 9 Phone contact Day 7 End of treatment V3 7 - 10 days after end of treatment V1 Enrolment V2 STRATIFICATION and RANDOMIZATION ARM2 Screening (up to 12 months) Treatment Post-Treatment and Follow-up (up to 9 months) Choice of comparator left to investigator Amoxicillin 500 mg tid 7 days or Clarithromycin 500 mg bid 7 days or Cefuroxime 250 mg bid 7 days

  18. 88 (23.4%) n=376 174 (46.3%) amoxicillin 500mg tid clarithromycin 500mg bid cefuroxime-axetil 250mg bid 114 (30.3%) Comparator regimen Wilson R et al. Chest 2004; 125: 953-964

  19. Clinical resolution Efficacy end-point 7-10 days post-therapy 70.9% 69.7% 62.8% 62.1% 95% CI 1.4-14.9 95% CI 0.2-15.9 Wilson et al. Chest 2004; 125: 953-964

  20. Post-therapy antibiotic administration Moxifloxacin Comparator 16 14.8 14 14.1 12 10 % 8.8 8 7.6 6 4 2 0 ITT PP p=0.006 p=0.030 Wilson et al. Chest 2004; 125: 953-964

  21. Bacterial eradication

  22. Protected specimen brush cultures in stable and exacerbated COPD (>1000 CFU/ml Monsó et al. AJRCCM 1995; 152: 1316-20

  23. Bronchial colonisation and COPD Bresser et al. Eur Respir J 1997;10:2319-26

  24. Pathogenesis of COPD Production of IL-8 by epithelial cells in response to cigarette smoke extract. Mio et al. AJRCCM 1997; 155: 1770-1776

  25. Colonisation and inflammation IL-8 (nM) Quantitative culture of sputum in 160 COPD patients in stable phase. Hill et al. Am J Med 2000;109:288-295

  26. Bronchial colonisation and COPD Correlation between bronchial colonisation and FEV1 decline R= 0.56; p=0.001 Wilkinson et al. AJRCCM 2003;167:1090-1095

  27. Bronchial colonisation and COPD PPM; FEV1= 40.3% nonPPM; FEV1= 45.2% P<0.03 Banerjee et al. Eur Respir J 2004; 23: 685-691

  28. The “fall & rise” of bacterial AECB Modifying factors Clinical threshold Bacterial load (CFU/ml) AB1 AB2 AB3 Time (days) AE ABCureCureCureStop AB Time to relapse Miravitlles. Eur Respir J 2002;20 (Suppl 36):9-19

  29. Infection-free interval 100 90 80 70 60 50 40 30 20 10 0 Nº AECOPD in the previous 12 months (p < 0.01) Persistent pathogen at the end of treatment (p < 0.01) Patients free of infection (%) 100 200 300 400 Days from end of therapy Chodosh et al. CID 1998; 27:730–738

  30. Bacterial infection and COPD Pooled analysis of 7 studies using PSB samples (1993-2002) Population:70 Healthy individuals181 Stable COPD (FEV1=51%)86 Exacerbated COPD (FEV1=37%) Rosell et al. Arch Intern Med 2005 (April 25th)

  31. 70 64 60 55 5,5 50 40 4,2 30 27 20 2,2 10 0 Healthy subjects Stable COPD Exacerb.COPD Bacterial infection and COPD Bacterial index Culture + Rosell et al. Arch Intern Med 2005 (April 25th)

  32. New strain acquisition and E-COPD Ex Ex Ex 1 month 13 1 2 3 4 5 6 7 8 9 10 11 12 HI HI HI HI HI A A B C C 108 106 106 108107 Sethi et al. N Engl J Med 2002; 347: 465-471

  33. New strains of bacteria and E-COPD % 81 outpatients followed up for 56 months: 374 AECOPD. Sputum samples each month in stable phase and during AECOPD. Percentage of acquisition of new strains RR=2.15 (1.8-2.5); p<0.01 Sethi et al. N Engl J Med 2002;347:465-471

  34. Rotate Antibiotics Same Antibiotic Causes of E-COPD Early relapse: Inadequate host defence Insufficient eradication Same bacterial strain Fall & Rise Late relapse: Lack of specific AB response New bacterial strain

  35. Eradication rate ofH. influenzae in AEBC % 94 % 81 % 74 % DeAbate, ICC 1999

  36. Bacterial eradication % Bacterial eradication with telithromycin in patients with AECB. Aubier et al. Respir Med 2002; 96: 862-871

  37. Bacterial eradication Efficacy end-point 7-10 days post-therapy 91.5% 81% 76.8% 67.5% 95% CI -1.8-20.3 95% CI 0.44-22.0 Wilson et al. Chest 2004; 125: 953-964

  38. Time free from exacerbation ITT population, N=730 *Failure, next AECB or need for further antimicrobial treatment1 Moxifloxacin Comparator 100 90 80 70 Patients not experiencing composite event (%) 60 50 40 30 p=0.032 20 0 1 2 3 4 5 6 7 8 9 10 Time since randomisation (months) Wilson et al. Chest 2004; 125: 953-964

  39. Impact of steroids vs no steroids among comparator group patients Steroids No Yes 100 90 80 70 Patients not experiencing composite event (%) 60 N = 373 p = 0.01 50 40 30 **p = 0.01 20 0 1 2 3 4 5 6 7 8 9 10 Time since randomisation (months) Time free from exacerbation Wilson et al. Chest 2004; 125: 953-964

  40. Impact of steroids vs no steroids among moxifloxacin patients Steroids Yes No 100 90 80 70 Patients not experiencing composite event (%) 60 N = 349 p > 0.05 (log rank test) 50 40 30 20 0 1 2 3 4 5 6 7 8 9 10 Time since randomisation (months) Time free from exacerbation Wilson et al. Chest 2004; 125: 953-964

  41. HRQL and exacerbations • IMPAC study: • 441 patients with moderate-severe COPD followed up for 2 years in 39 hospitals in Spain • Mean age 66 years (SD= 8) • FEV1= 36% (SD=8,8%) • At least 10 pack-years Miravitlles et al. Thorax 2004; 59: 387-395

  42. Impact of exacerbations Miravitlles et al. Thorax 2004; 59: 387-395

  43. Bacterial eradication H.pylori H.influenzae + + + + + + + + + + Persistence Inflammation Recurrent symptoms Long-term effects Diagnosis

  44. Fast recovery

  45. Comparing two drugs for clinical efficacy A B A Curacion Clinica, % B 5 10 Tiempo (días)

  46. Speed of action • IMPAC study: • 441 patients with moderate-severe COPD followed up for 2 years in 39 hospitals in Spain • Mean age 66 years (SD= 8) • FEV1= 36% (SD=8,8%) • At least 10 pack-years Miravitlles et al. Clin Drug Invest 2003; 23: 439-450

  47. Speed of action 614 exacerbations in 2 years p=0.02 Days with symptoms Miravitlles et al. Clin Drug Invest 2003; 23: 439-450

  48. EFEMAP study Design of study: • Observational in primary care centers. • Multicenter, comparative in exacerbations of chronic bronchitis and COPD. • Treatmient options: moxifloxacin, amoxicillin/clavulanic acid or clarithromycin. Miravitlles et al. Clin Drug Invest 2004; 24: 63-72

  49. Days until resolution of symptoms Moxifloxacin Amoxi/clav Clarithro Fever 2.0 (1.6) 2.3 (2.0) 2.4 (2.1) Sputum* 3.7 (1.6) 4.6 (2.1) 4.4 (2.2) Purulence* 3.3 (1.6) 4.1 (2.1) 3.9 (2.0) Dyspnea 3.8 (2.1) 4.6 (2.5) 4.6 (2.4) *p<0.03 Miravitlles et al. Clin Drug Invest 2004; 24: 63-72

  50. Speed of recovery * p< 0.001 % cure * * Miravitlles et al. Clin Drug Invest 2004; 24: 63-72

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