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 2007-1,800,000 ED visits in 2007-689,432 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
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
Hypothesis Chronic administration of a macrolide antibiotic to patients with an risk of AECOPDs will decrease the frequency of these exacerbations MACRO Study 3
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 1 2 3 4 5 6 7 8 9 10 11 12 13 Study Month 4
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 2005 - Within the last year > Received systemic steroids > Were hospitalized > Visited an ED - On supplemental O 2 5
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
Patient Flow (1) (Enrollment: March, 2006 May, 2009) : 570 Screened: 1577 Randomized: 1142 : 572 Exclusions: - Cardiac: 102 - Spirometry 106 - 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
Pack Years Participants (N) Years Patients (N) Age, Gender, Race/Ethnicity 80 70 60 500 400 82% 80% 50 40 30 300 200 41% 41% 20 10 100 13% 15% 2% 3% Age Female White African American Hispanic Smoking Status and GOLD Class on Entry 100 250 40% 41% 80 200 34% 33% 60 150 21% 23% 26% 27% 40 100 20 50 Smoking History Current Smokers 2 3 GOLD Class 4 8
Liters % Predicted Ratio Spirometry on Entry 1.8 60 60 1.5 50 50 1.2 40 40 0.9 30 30 0.6 20 20 0.3 10 10 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 < 0.001 9
AECOPD (N) AECOPD (N/patient-yr) Participants (N) Treatment on Entry 450 76% 73% 72% 73% 375 64% 62% 300 49% 46% 225 150 75 13% 15% 28% 32% 10% 8% LABA ICS LAMA 1 Med 2 Meds 3 Meds None Number and Rates of AECOPD P < 0.001 (Chi-Square) P < 0.01 (Neg Binomial) 900 900 2.0 1.83 800 700 741 1.6 1.48 600 500 1.2 400 300 0.8 200 100 0.4 Number Rate 10
Rates/Patient-yr Participants (N) Rates of AECOPD/Patient-Year 250 200 150 P = 0.001 by Poisson P = 0.004 by Negative Binomial 100 50 0 0.01-1.50 1.51-3.00 3.01-4.50 4.51-6.00 6.01-7.50 > 7.50 Rates of AECOPD/patient-year Secondary Endpoints 0.70 0.60 0.50 0.40 0.30 0.20 0.10 P = 0.13 P = 0.14 P = 0.47 P = 0.048 322 316 246 140 237 249 175 110 P = 0.23 16 11 Hospitalized (all cause) Hospitalized (COPD-related) ED/Urgent Care Visits Unscheduled Office Visits Intubations 11
Patients (N) D SGRQ Score (units) Patients with 4 unit D (%) SGRQ (Entry to 12 M) P < 0.006-2.8 16 0.6 0.5 P < 0.034 42.6% 8 0.4 35.8% 0 0.3-8 0.2-16 0.1 D Score % with 4 unit D Serious Adverse Events (Non-Fatal) 120 100 107 107 80 P = 0.11 60 40 20 41 26 6 8 15 21 1 2 29 33 12
Patients (N) Patients (N) Serious Adverse Events (Fatal) 20 P = 0.87 20 18 16 12 8 4 P = 0.48 P = 1.0 P = 0.09 P = 0.50 P = 0.77 10 7 5 6 5 1 1 1 0 2 Adverse Events Leading to Drug Discontinuation (1) 12 10 8 6 4 3 P = 0.23 11 6 6 4 4 4 5 8 4 3 2 0 13
Patients (%) Patients (N) Adverse Events Leading to Drug Discontinuation (2) 150 142 (25%) 125 100 75 50 P = 0.04 110 (20%) Mean D in Hearing (db) P value 0 to 3 rd M -0.7-0.0 0.01 0 to 12 th M -1.2-0.9 0.25 25 Hearing Decrement Audiometry May Overestimate Hearing Decrement mycin (N = 80) (N = 45) 90 75 61 (76%) 90 75 37 (82%) 60 45 30 21/61 (34%) 19 (24%) 6/19 (32%) 60 45 30 14/37 (38%) 8 (18%) 2/8 (25%) 15 15 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
Participants with Macrolide- Resistant Pathogens (%) Participants with Selected Respiratory Pathogens (N) Colonization with Selected Respiratory Pathogens P < 0.001 180 31% 150 120 90 P = 0.81 14% 15% 12% Cultures from 85% and 84% of clinic visits 60 30 79 83 66 172 On Enrollment During Study Colonization with Macrolide- Resistant Pathogens 100 80 60 40 P = 0.64 52% 57% P < 0.0001 81%* 41% Sensitivities from 56% and 59% of pts with pathogens 20 23 28 36 49 On Enrollment During Study 15
mycin and Sudden Death mycin and Sudden Death No Antibiotics Amoxicillin mcyin N 1,391,180 1,348,672 347,795 Cardiac deaths 41 42 29 % 0.00003 0.00003 0.00008 N/million courses 29.8 31.5 85.2 HR 1 0.95 0.55, 1.63 P = 0.85 2.88 1.79, 4.63 P < 0.001 NEJM 2012 16
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 ECG @ 1 month 17
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 = 0.014 0.2 0.4 0.6 0.8 1.0 1.2 1.4 1.6 Favors mycin Favors Hazard Ratio Post Hoc Analyses (2) Ex-smokers (870) Smokers (246) P = 0.012 GOLD 2 (292) GOLD 3 (451) GOLD 4 (370) Chronic bronchitis (625) No chronic bronchitis (498) 0.2 0.4 0.6 0.8 1.0 1.2 1.4 1.6 Favors mycin Favors Hazard Ratio 18
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) 0.2 0.4 0.6 0.8 1.0 1.2 1.4 1.6 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
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