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New decade, New approaches to AECOPD

New decade, New approaches to AECOPD. Prof. Nadeem Rizvi Head of Chest Medicine Jinnah Postgraduate Medical Center, Karachi. Definition of COPD Exacerbations. An event in the natural course “of the disease characterized by a

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New decade, New approaches to AECOPD

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  1. New decade, New approaches to AECOPD Prof. Nadeem Rizvi Head of Chest Medicine Jinnah Postgraduate Medical Center, Karachi

  2. Definition of COPD Exacerbations An event in the natural course “of the disease characterized by a change in the patient’s baseline dyspnea, cough, and/or sputum that is beyond normal day-to-day variations, is acute in onset, and may warrant a change in regular medication in a patient with underlying COPD.” From the Global Strategy for the Diagnosis, Management, and Prevention of Chronic Obstructive Pulmonary Disease, Global Initiative for Chronic Obstructive Lung Disease (GOLD) 2008. Available from: http://www.goldcopd.org. 2

  3. What Does an Exacerbation Mean to a Patient? Decline in lung function Increased symptoms (I.e. breathlessness) Greater anxiety Worsening quality of life Social withdrawal More exacerbations Garcia-Aymerich J et al. 2001 Donaldson D et al. 2002 Gore JM et al. 2000 Seemungal T et al. 1998 Pauwels Pet al. 2001 Seemungal T et al. 2000 Garcia-Aymerich J et al. 2003 Anto JM et al. 2001 Increased risk of hospitalisation Increased risk of mortality

  4. Causes of AECB Infection Bacterial Viral Allergy AECB Pollution Cigarette smoke Industrial dusts Weather Fall in temperature Ball. CHEST 1995; 108: 43S–52S; Miravitlles & Niederman. Lectures in Respiratory Tract Infections. Science Press Communications, 2004; Donaldson et al. Eur Respir J 1999; 13: 844–9

  5. Epidemiology of Exacerbations: Frequency Increases with Declining FEV1 3.0 2.5 2.0 Exacerbations per Year 1.5 1.0 0.5 0 < 1.25 1.25 – 1.54 > 1.54 2.40 2.50 FEV1 (1) Donaldson GC, Wedzicha JA. Thorax. 2006;61:164-168. 5

  6. Impact of Exacerbations in COPD Patients with Frequent Exacerbations Greater AirwayInflammation Faster Declinein Lung Function Higher Mortality Poorer Qualityof Life Wedzicha JA, Seemungal TA. Lancet. 2007;370:786-796. 6

  7. More Rapid Decline in FEV1 With Higher Exacerbation Frequency 0.95 Infrequent Exacerbators Frequent Exacerbators 0.90 Percent Change from Baseline in FEV1 0.85 0.80 0.75 0 1 2 3 4 Years Donaldson GC, et al. Thorax. 2002;57:847-852. 7

  8. Frequent Exacerbations Are Associated With More Rapid Decline in Pulmonary Function FEV1 (mL) PEF (L/minute) ** Annual Change * P<0.05 versus infrequent exacerbators; ** P<0.001 versus infrequent exacerbators * Donaldson GC, et al. Thorax. 2002;57:847-852. 8

  9. Mortality Following Emergency Department Visit for COPD Exacerbation Kim S, et al. COPD. 2006;3:75-81. 10

  10. Exacerbation Frequency and SeverityBoth Increase Mortality Risk 1.0 1.0 0.8 0.8 (1) A p<0.0002 NS 0.6 0.6 (2) p<0.0001 Probability of surviving Probability of surviving p=0.005 p<0.0 B p=0.069 0.4 0.4 p<0.0001 (3) NS C 0.2 0.2 (4) 0.0 0.0 0 10 20 30 40 50 60 0 10 20 30 40 50 60 Time (months) Time (months) Group (1) no acute exacerbations Group (2) acute exacerbations requiring emergency service visits without admission Group (3) patients with acute exacerbations requiring one hospital admission Group (4) patients with acute exacerbations requiring readmissions Group A patients with no acute exacerbations Group B patients with 1–2 acute exacerbations requiring hospital management Group C patients with >3 acute exacerbations Soler-Cataluña JJ, et al. Thorax. 2005;60:925-931. 11

  11. Cost of Treatment for an Acute Exacerbation of COPD O'Reilly JF, et al. Int J Clin Pract. 2007;61:1112-1120. 123

  12. Exacerbations Negatively Affect Quality of Life * * * * * P<0.05 versus lower exacerbation rate Seemungal TA, et al. Am J Respir Crit Care Med. 2000;161:1608–1613. 14

  13. ISSUE OF ANTIBIOTIC USE IN EXACERBATION

  14. Stratification of AECB patients – the Anthonisen criteria • Increase in: • dyspnea • sputum volume • sputum purulence TYPE I All three present, antibiotic recommended TYPE II Two of three present, antibiotic recommended if includes purulence TYPE III One of three present, antibiotic not recommended Anthonisen et al. Ann Intern Med 1987 [Adapted from Woodhead et al. Eur Respir J 2005]

  15. Using Antibiotics in AECB Prevents Treatment Failure Treatment failure is associated with increased acute exacerbation episodes and disease progression Favours Antibiotics Favours Placebo Elmes et al, 1965 Pines et al, 1968 Anthonisen et al, 1987 Jorgensen et al, 1992 Nouira et al, 2001 Pooled summary(RR, 0.54; 95% CI, 0.32-0.92) 0.1 0.2 0.5 1 2 5 10 Relative Risk (95% Confidence Interval) Quon BS et al. Chest 2008; 133:756-766

  16. Which Antibiotics are Recommended?

  17. Antibiotics for AECOPD: Risk Stratification • MILD • Only 1 of the 3 cardinal symptoms: • Increased dyspnea • Increased sputum volume • Increased sputum purulence • MODERATE OR SEVERE • At least 2 of the 3 cardinal symptoms: • Increased dyspnea • Increased sputum volume • Increased sputum purulence Uncomplicated COPD No risk factors: Age <65 years FEV1 >50% predicted <3 exacerbations/year No cardiac disease Complicated COPD 1 or More risk factors: Age >65 years FEV1 <50% predicted >3 exacerbations/year Cardiac disease • No antibiotics • Increased bronchodilator • Symptomatic therapy • Monitoring symptoms • Advanced macrolide (azythromycin, clarithromycin) • Cephalosporin (cefuroxime, cefpodoxime, cefdinir) • Doxycycline • Trimethoprim–sulfamethoxazole • If recent antibiotic exposure (<3 months), use alternative class • Fluoroquinolone(moxi, gemi, levo) • Amoxicillin-clavulanate • If at risk for Pseudomonas,consider ciprofloxacin andobtain sputum culture • If recent antibiotic exposure (<3 • months), use alternative class Worsening clinical status or inadequate response in 72 hrs A wind of change in AECOPD Reevaluate Consider sputum culture Sethi S, Murphy TF. NEJM 2008;359:2355-65.

  18. Antibiotics for AECOPD: Risk Stratification • MILD • Only 1 of the 3 cardinal symptoms: • Increased dyspnea • Increased sputum volume • Increased sputum purulence • MODERATE OR SEVERE • At least 2 of the 3 cardinal symptoms: • Increased dyspnea • Increased sputum volume • Increased sputum purulence Uncomplicated COPD No risk factors: Age <65 years FEV1 >50% predicted <3 exacerbations/year No cardiac disease Complicated COPD 1 or More risk factors: Age >65 years FEV1 <50% predicted >3 exacerbations/year Cardiac disease • No antibiotics • Increased bronchodilator • Symptomatic therapy • Monitoring symptoms • Advanced macrolide (azythromycin, clarithromycin) • Cephalosporin (cefuroxime, cefpodoxime, cefdinir) • Doxycycline • Trimethoprim–sulfamethoxazole • If recent antibiotic exposure (<3 months), use alternative class • Fluoroquinolone(moxi, gemi, levo) • Amoxicillin-clavulanate • If at risk for Pseudomonas,consider ciprofloxacin andobtain sputum culture • If recent antibiotic exposure (<3 • months), use alternative class Worsening clinical status or inadequate response in 72 hrs A wind of change in AECOPD Reevaluate Consider sputum culture Sethi S, Murphy TF. NEJM 2008;359:2355-65.

  19. Antibiotics for AECOPD: Risk Stratification • MILD • Only 1 of the 3 cardinal symptoms: • Increased dyspnea • Increased sputum volume • Increased sputum purulence • MODERATE OR SEVERE • At least 2 of the 3 cardinal symptoms: • Increased dyspnea • Increased sputum volume • Increased sputum purulence Uncomplicated COPD No risk factors: Age <65 years FEV1 >50% predicted <3 exacerbations/year No cardiac disease Complicated COPD 1 or More risk factors: Age >65 years FEV1 <50% predicted >3 exacerbations/year Cardiac disease • No antibiotics • Increased bronchodilator • Symptomatic therapy • Monitoring symptoms • Advanced macrolide (azythromycin, clarithromycin) • Cephalosporin (cefuroxime, cefpodoxime, cefdinir) • Doxycycline • Trimethoprim–sulfamethoxazole • If recent antibiotic exposure (<3 months), use alternative class • Fluoroquinolone(moxi, gemi, levo) • Amoxicillin-clavulanate • If at risk for Pseudomonas,consider ciprofloxacin andobtain sputum culture • If recent antibiotic exposure (<3 • months), use alternative class Worsening clinical status or inadequate response in 72 hrs A wind of change in AECOPD Reevaluate Consider sputum culture Sethi S, Murphy TF. NEJM 2008;359:2355-65.

  20. New Decade New Approaches to Treat AECB “The MAESTRAL Study”

  21. MAESTRAL (moxifloxacin in acute exacerbations trial) A prospective, multinational, multicentre, randomised, double‑blind, double‑dummy, controlled study comparing the efficacy and safety of moxifloxacin to that of amoxicillin/clavulanic acid for the treatment of subjects with acute exacerbations of chronic bronchitis (AECB)

  22. Current questions in management of AECB 31 Does the choice of antibiotic impact the clinical outcome of AECB? Is there adequate clinical evidence to support current guidelines for the antibiotic management of AECB? Are systemic steroids always beneficial in combination with antibiotics in the out-patient management of AECB ?

  23. MAESTRAL STUDY DESIGN

  24. MAESTRAL: a novel study vs a gold-standard therapy Stratification1 at enrolment per steroid use Randomisation Moxifloxacin 400 mg qd 5 days Amoxicillin/clavulanic acid 875/125 mg bd 7 days PRIMARY ENDPOINT 8 weeks post- therapy (Day 63 ±3) 4 weeks post-therapy (Day 35 ±3) Screening and enrolment EOT (Day 13 ±1) Primary endpoint: clinical failure at 8 weeks post-therapy - patient’s symptoms have not improved or have worsened such that additional or alternate systemic antimicrobial and/or corticosteroid therapy is required any time up to EOT 1Stratum 1: co-administration of systemic steroids for the current AECOPD Stratum 2: no co-administration of systemic corticosteroids for the current AECOPD Wilson R et al., Int J COPD 2011;6:373–83.

  25. MAESTRAL patient selection1 Main inclusion criteria: 60 years and older Moderate-to-severe chronic bronchitis (COPD by definition) FEV1≤60% at enrolment History of ≥2 AECB (treated) in past 12 months At least 20 pack-year cigarette smoking history no fossil fuels, pollution, etc Anthonisen Type 1: exacerbation has increased sputum purulence, volume and dyspnea2 Main exclusion criteria: Prior use of antibiotic and/or a short course of systemic corticosteroids in previous month Exacerbation in previous month 1Wilson R et al., Int J COPD 2011;6:373–83. 2Anthonisen NR et al., Ann Intern Med 1987;106:196–204.

  26. MAESTRAL used a novel primary endpoint • Primary efficacy outcome • Clinical failure rates at the 8-week post-therapy visit • Clinical failure defined as requirement of additional treatment for an exacerbation of respiratory symptoms (within 8 weeks post-therapy): • with systemic antibiotics and/or systemic corticosteroids and/or • hospitalisation with systemic antibiotics and/or systemic corticosteroids Wilson R et al., Int J COPD 2011;6:373–83.

  27. MAESTRAL secondary outcomes • Secondary efficacy outcomes • Clinical failure rates at different time points; clinical failure rates by steroid strata; for patients with positive sputum culture at enrolment, spirometry change; change in dosage/or additional respiratory concomitant medication • Bacteriological outcomes • Bacteriological eradication rates • Questionnaires outcomes • Improvement of quality of life (SGRQ); rates and speed of symptom relief (AECB-SS, a 7-item questionnaire on cough, phlegm consistency and colour, breathing difficulties, sleep disturbances and daily life disturbances) • Healthcare resource utilisation/consumption outcomes • Direct and indirect healthcare costs outcomes • Safety outcomes • Safety and tolerability Wilson R et al., Int J COPD 2011;6:373–83. A wind of change in AECOPD

  28. MAESTRAL: a global study Andorra, Belgium, Croatia, Czech Republic, Germany, Greece, Ireland, Italy, Latvia, Lithuania, Netherlands, Portugal, Spain, Switzerland, United Kingdom China, Hong-Kong, Indonesia, Pakistan, Philippines, Thailand Canada, Mexico Pakistan Argentina, Brazil, Chile, Colombia, Peru Australia South Africa 30 countries 150 sites Wilson R et al., Int J COPD 2011;6:373–83.

  29. Patient disposition: optimal randomisation of a large cohort Enrolled n=1492 Not randomised n=120 Amoxicillin/ clavulanic acid Moxifloxacin Randomised n=686 Randomised n=686 ITT with pathogens n=335 ITT with pathogens n=327 ITT/safety n=677 ITT /safety n=675 PP n=538 PP n=518 PP with pathogens n=260 PP with pathogens n=261 Wilson R et al., Int J COPD 2011;6:373–83.

  30. MAESTRAL:CLINICAL EFFICACY

  31. MAESTRAL met the primary endpoint 42 Per-protocol population

  32. Moxifloxacin was superior in patients with confirmed bacterial exacerbations PP with pathogens ITT with pathogens Clinical failure (% patients) Clinical failure (% patients) P=0.016 P=0.030 Wilson et al., Eur Resp J 2011; in press Bayer Pharma AG; data on file

  33. Clinical failure rates1 at 8 weeks post-therapy by systemic corticosteroid use 95% CI –20.8, 2.1 P=0.110 95% CI –25.8, 0.21 P=0.055 95% CI –13.9, 0.54 P=0.072 95% CI –13.6, 3.2 P=0.266 Clinical failure (% patients) 23/94 27/166 34/126 28/201 40/119 32/93 45/216 36/168 With corticosteroid use Without corticosteroid use 1Failures and relapses are included in the failure rate calculation 95% CI stratified by region Wilson et al., Eur Resp J 2011; in press

  34. MAESTRAL MICROBIOLOGICAL EFFICACY

  35. Causative organisms at enrolment (ITT with pathogens) 662/1352 (49.0%) ITT patients had causative organisms isolated from sputum at baseline Sethi et al. 51st Interscience Conference on Antimicrobial Agents and Chemotherapy. Sept 17–20, 2011, Chicago, USA. Poster L1-269.

  36. MIC distribution by key organism (ITT with pathogens population) 1MIC for S. pneumoniae vs penicillin 1.0 mg/L; range 0.015−2.0 mg/L MIC changes during therapy or up to 8 weeks post-therapy were rare and were not significant in both treatment groups Wilson et al., Eur Resp J 2011; in press

  37. Bacteriological success rates by organism and time-point Haemophilus influenzae (ITT with pathogens population) Sustained advantage for Moxifloxacin against H. influenzae Wilson et al., Eur Resp J 2011; in press

  38. Clinical failure rates in patients with confirmed bacterial exacerbations ITT with pathogens PP with pathogens Clinical failure (% patients) Clinical failure (% patients) P=0.030 P=0.016 Wilson et al., Eur Resp J 2011; in press Bayer Pharma AG; data on file

  39. SAFETY

  40. Overview of treatment-emergent adverse events through week 8 post-therapy (ITT/safety population) P>0.05 for all categories Wilson et al., Eur Resp J 2011; in press Bayer Pharma AG; data on file

  41. MAESTRAL Study Results Summary – 1/2 Moxifloxacin was equivalent to amoxicillin/clavulanic acid in the treatment of acute exacerbations in outpatients with moderate-to-severe COPD. Moxifloxacin was superior to amoxicillin/clavulanic acid in terms of clinical cure at 8 weeks post-therapy for patients with confirmed bacterial exacerbations at baseline. Patients with confirmed bacterial exacerbations who received concomitant steroids generally had more severe disease and had a higher clinical failure rate than those who were not on steroids. In this sicker population of patients with confirmed bacterial exacerbations who received steroids, there was a trend for lower clinical failure rates with Moxifloxacin vs amoxicillin/clavulanic acid.

  42. The overall eradication rate at end-of-therapy was higher with Moxifloxacin than with amoxicillin/clavulanic acid, mainly explained by a better efficacy against H. influenzae. There was a clear correlation between bacteriological response at end-of-therapy and clinical cure at 8 weeks post-therapy – overall and for the Moxifloxacin group. Both treatments were well-tolerated and had similar safety profiles. MAESTRAL Study Results Summary – 2/2 57

  43. THANK YOU!

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