Airway Vista Background

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1 Airway Vista 2013 Chronic Obstructive Airway Diseases Symposium Asan Medical Center, Seoul, South Korea When Should Macrolide Antibiotics be Prescribed to Prevent COPD Exacerbations in Usual Clinical Practice? Richard K. Albert, M.D. Chief of Medicine Denver Health Professor of Medicine University of Colorado Background Acute Exacerbations of COPD (AECOPDs) High health care utilization - 8,000,000 MD office visits in ,800,000 ED visits in ,432 hospitalizations in 2009 (2 nd most common) - Numerous days lost from work High cost of care ($10-$60 B in 2011) High morbidity - More rapid in lung function - Worse quality of life High mortality - 140,000 deaths (2009) 1

2 Rationale for Macrolides in COPD Antimicrobial effects Anti-inflammatory effects In-vivo outcomes Animal Human Macrolide Antibiotics In-vivo Outcomes Human studies Panbronchiolitis Non-CF Bronchiectasis Post-Xplant OB Asthma Chronic rhinosinusitis Cystic fibrosis AECOPDs - 7 studies - Mixed results (2 5 +) - Largest = 109 pts - All with design issues 2

3 Hypothesis Chronic administration of a macrolide antibiotic to patients with an risk of AECOPDs will decrease the frequency of these exacerbations MACRO Study 3

4 COPD Clinical Research Network UCSF S. Lazarus Minnesota D. Niewoehner Minneapolis J. Connett (DCC) Brigham & Women s G. Washko Harbor-UCLA R. Casaburi Denver R. Albert Alabama M. Dransfield Maryland S. Scharf Study Design RCT, Double blind, 1:1 allocation Pts with COPD Usual Rx + (250 mg daily) Usual Rx + Enroll Clinic Phone Clinic Clinic Clinic Clinic Clinic Phone Phone Phone Phone Phone Wash out Start Study Month 4

5 Patient Selection (1) Inclusion Criteria > 40 years old At least moderate COPD - Post-BD FEV 1 /FVC <70% - Post-BD FEV 1 < 80% predicted 10 pack/yr smoking hx - May be active smokers Patient Selection (2) Inclusion Criteria (2) Patients likely to experience AECOPDs Niewoehner et al, AIM Within the last year > Received systemic steroids > Were hospitalized > Visited an ED - On supplemental O 2 5

6 Patient Selection (3) Exclusion criteria < 4 wks from AECOPD Asthma (ATS/ERS guidelines) Clinical dx of bronchiectasis Chronic renal or hepatic insufficiency < 3-year life expectancy Women at risk of pregnancy HR > 100, QTc prolongation, meds that QTc Age-adjusted hearing loss < 95 th percentile Definition of AECOPD Niewoehner et al, AIM 2005 Acute or new onset of: - Cough - Sputum - Wheezing - Dyspnea - Chest tightness Duration: 3 days Treated with systemic steroids and/or abx 6

7 Patient Flow (1) (Enrollment: March, 2006 May, 2009) : 570 Screened: 1577 Randomized: 1142 : 572 Exclusions: - Cardiac: Spirometry Hearing: 27 - No consent: 60 - Other: 140 Total excluded: 435 (28%) No f/u: 12 No f/u: 12 : 558 : 559 Patient Flow (2) : 558 : 559 Self-withdrawal 32 (6%) Lost to follow-up 13 (2%) Died 18 (3%) Self-withdrawal 28 (5%) Lost to follow-up 9 (2%) Died 20 (4%) Completed final or w/o visit: 495 (89%) Completed final or w/o visit: 502 (90%) 7

8 Pack Years Participants (N) Years Patients (N) Age, Gender, Race/Ethnicity % 80% % 41% % 15% 2% 3% Age Female White African American Hispanic Smoking Status and GOLD Class on Entry % 41% % 33% % 23% 26% 27% Smoking History Current Smokers 2 3 GOLD Class 4 8

9 Liters % Predicted Ratio Spirometry on Entry FEV 1 (L) FEV 1 (% pred) FEV 1 /FVC Time to First AECOPD Median = 266 days Median = 174 days HR = 0.73 (0.63, 0.84), P <

10 AECOPD (N) AECOPD (N/patient-yr) Participants (N) Treatment on Entry % 73% 72% 73% % 62% % 46% % 15% 28% 32% 10% 8% LABA ICS LAMA 1 Med 2 Meds 3 Meds None Number and Rates of AECOPD P < (Chi-Square) P < 0.01 (Neg Binomial) Number Rate 10

11 Rates/Patient-yr Participants (N) Rates of AECOPD/Patient-Year P = by Poisson P = by Negative Binomial > 7.50 Rates of AECOPD/patient-year Secondary Endpoints P = 0.13 P = 0.14 P = 0.47 P = P = Hospitalized (all cause) Hospitalized (COPD-related) ED/Urgent Care Visits Unscheduled Office Visits Intubations 11

12 Patients (N) D SGRQ Score (units) Patients with 4 unit D (%) SGRQ (Entry to 12 M) P < P < % % D Score % with 4 unit D Serious Adverse Events (Non-Fatal) P =

13 Patients (N) Patients (N) Serious Adverse Events (Fatal) 20 P = P = 0.48 P = 1.0 P = 0.09 P = 0.50 P = Adverse Events Leading to Drug Discontinuation (1) P =

14 Patients (%) Patients (N) Adverse Events Leading to Drug Discontinuation (2) (25%) P = (20%) Mean D in Hearing (db) P value 0 to 3 rd M to 12 th M Hearing Decrement Audiometry May Overestimate Hearing Decrement mycin (N = 80) (N = 45) (76%) (82%) /61 (34%) 19 (24%) 6/19 (32%) /37 (38%) 8 (18%) 2/8 (25%) Drug d/c d Hearing Returned Drug not d/c d Hearing Returned Drug d/c d Hearing Returned Drug d/c d Hearing Returned 14

15 Participants with Macrolide- Resistant Pathogens (%) Participants with Selected Respiratory Pathogens (N) Colonization with Selected Respiratory Pathogens P < % P = % 15% 12% Cultures from 85% and 84% of clinic visits On Enrollment During Study Colonization with Macrolide- Resistant Pathogens P = % 57% P < %* 41% Sensitivities from 56% and 59% of pts with pathogens On Enrollment During Study 15

16 mycin and Sudden Death mycin and Sudden Death No Antibiotics Amoxicillin mcyin N 1,391,180 1,348, ,795 Cardiac deaths % N/million courses HR , 1.63 P = , 4.63 P < NEJM

17 mycin and Sudden Death mycin Study Exclusions QTc prolongation Medications known to QTc Resting HR > 100 History of: - CHF - Hypokalemia Family hx of prolonged QTc QTc prolongation on 1 month 17

18 Post Hoc Analyses (1) Unadjusted (1117) Adjusted (1117) Women (456) Men (661) Age < 65 (528) Age > 65 (589) On O 2 (662) Not on O 2 (455) P = Favors mycin Favors Hazard Ratio Post Hoc Analyses (2) Ex-smokers (870) Smokers (246) P = GOLD 2 (292) GOLD 3 (451) GOLD 4 (370) Chronic bronchitis (625) No chronic bronchitis (498) Favors mycin Favors Hazard Ratio 18

19 Post Hoc Analyses (3) No ICS (252) ICS (865) No LABAs (286) LABAs (831) No LAMAs (408) LAMAs (709) No ICS, LAMAs or LABAs (101) ICS + LAMAs + LABAs (528) Favors mycin Favors Hazard Ratio Conclusions Adding azithro (250 mg/day) x 1 year to usual Rx of patients with risk of AECOPDs the frequency of AECOPDs Improves QOL Benefits patients receiving optimal Rx Hearing in a small fraction of patients Provisos: HR < 100, no apparent risk of QTc prolongation Hearing 95 th percentile for age 19

20 When Should Macrolide Antibiotics be Prescribed to Prevent COPD Exacerbations in Usual Clinical Practice? Evidence-based: COPD patients with hx of - Previous exacerbation 1-year), or - Supplemental O 2 Care with regard to QTc prolongation - Hx or FHx of QTc prolongation - Screening ECG - Concurrent medications that prolong the QTc 20