COPD EXACERBATIONS AND HOSPITAL ADMISSIONS HOW CAN WE PREVENT THEM? Wisia Wedzicha National Heart and Lung Institute, Imperial College London, UK

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1 COPD EXACERBATIONS AND HOSPITAL ADMISSIONS HOW CAN WE PREVENT THEM? Wisia Wedzicha National Heart and Lung Institute, Imperial College London, UK

2 Presenter Disclosures Wisia Wedzicha All disclosures prior to Jan 2015 from Jan 2015, I am not accepting any honoraria from industry Lecture Fees: Novartis, GSK, Boehringer, Pfizer, AstraZeneca Advisory Boards: Novartis, Boehringer, Takeda, Pfizer, Astra Zeneca Industry sponsored grants - Glaxo Smith Kline, Takeda, Johnson & Johnson, Vifor Pharma

3 COPD - Statistics 3,000,000 estimated UK COPD patients (1,000,000 diagnosed) 24 million working days lost each year 800m direct healthcare costs double the cost of asthma COPD accounts for 10% of all hospital admissions 30% of COPD admissions readmitted within 3 months 10% of COPD patients die within 3 months of being admitted In UK 25,000 30,000 deaths per year Associated co-morbidities

4 Triggers of COPD Exacerbations Triggers Bacteria Viruses Pollutants Effects Inflamed COPD airway Greater airway inflammation Systemic inflammation Bronchoconstriction, edema, mucus t Expiratory flow limitation Cardiovascular comorbidity Exacerbation Dynamic hyperinflation symptoms Wedzicha JA, Seemungal TA. Lancet 2007

5 London December 5th 1952 London 2nd January 1954

6 ALL EXACERBATIONS BY MONTH OF STUDY: Data from East London COPD cohort O N D J F M A M J J A S Y1 Y3 Y5

7 100 ECLIPSE Survival Curves Related to Prior Hospitalization History 95 Survival (%) Year 1 status N (censored) Year 2 survival (95% Cl) No COPD Hosp 1,676 (1590) 94.9% (93.8%, 95.9%) 1 COPD Hosp 289 (247) 85.4% (81.4%, 89.6%) No COPD hospitalization, Year 1 (n=1,676) COPD hospitalization, Year 1 (n=289) Months observed Müllerova H et al. Chest 2015

8 DISTRIBUTION OF EXACERBATIONS IN ECLIPSE (2,138 patients in the ECLIPSE cohort study) Patients (%) % Hospitalized for exacerbation in Year 1 2 exacerbations in Year 1 1 exacerbation in Year 1 22% 39% 18% 52% 33% 33% 47% 62% 0 GOLD Stage 2 GOLD Stage 3 GOLD Stage 4 (moderate) (severe) (very severe) Disease severity 1.Adapted from Hurst JR, Vestbo J, Anzueto A, et al. N Engl J Med 2010;363:

9 Strategies to prevent exacerbations Pharmacological: Bronchodilators (LABA/LAMA) Inhaled corticosteroids Combination of above Dual bronchodilators Macrolide Antibiotics Other antibiotics Roflumilast (PDE4 inhibitor) Non-pharmacological: Smoking cessation Pollution control Pulmonary Rehabilitation Vaccination Anti-viral agents Noninvasive ventilation (NIV) Optimal therapy of acute event

10 Symptoms and COPD exacerbations are closely related 70 Exacerbations with increased dyspnea (%) Days around onset of exacerbation Seemungal TA, et al. Am J Respir Crit Care Med 2000

11 Symptom onset and early start of therapy Patients who receive prompt therapy after symptom onset are likely to recover more rapidly than are patients whose treatment is delayed 24 Symptom recovery time (days) Delay between onset and treatment (days) p<0.001 Wilkinson et al. Am J Respir Crit Care Med 2004

12 Exacerbations Reported and Unreported Number of exacerbations 50% not reported to study team (UNREPORTED EXACERBATIONS) Total Reported Unreported Seemungal TA et al. Am J Respir Crit Care Med 1998

13 RELATION BETWEEN EXACERBATION THERAPY AND HOSPITALISATION P<0.04 Wilkinson et al AJRCCM 2004

14 ACTIVITY AND EXACERBATION REPORTING Al Ahmari et al BMC Pum Med 2014

15 TELEHEALTH STUDY (EDINBURGH TELESCOT) Pinnock et al BMJ 2013

16 Time course of human rhinovirus load changes at COPD exacerbations HRV load log 10 pfu ml Cold No cold ExP Day 3 Day 7 Day 14 Day 35 HRV load log 10 pfu ml Sore throat No sore throat ExP Day 3 Day 7 Day 14 Day 35 George SN, et al. Eur Respir J. 2014;44:87-96.

17 Relationship between viral and bacterial infection during exacerbation recovery HRV load log 10 pfu ml Bacteria HRV ExP Day 3 Day 7Day 14Day Bacterial load log 10 cfu ml -1 HRV load log 10 pfu ml Bacteria HRV ExP Day 3 Day 7Day 14Day Bacterial load log 10 cfu ml -1 NO BACTERIA DETECTED AT EXACERBATION ONSET BACTERIA DETECTED AT EXACERBATION ONSET George SN, et al. Eur Respir J. 2014;44:87-96.

18 Summary of clinical efficacy results at end-of-treatment visit in the intention-to-treat population AMX 500/125 mg n/total (%) PBO n/total (%) p-value Primary outcomes Clinical cure at Days /158 (74.1) 91/152 (59.9) Clinical success at Days /158 (90.5) 123/152 (80.9) Secondary outcomes Clinical cure at Day 20 Clinical success at Day 20 Days until next exacerbation, median (IQR) Change of peak expiratory flow from basal and EOT visits, l/min, mean (SD) 129/158 (81.6) 143/158 (90.5) 233 ( ) 52.8 (61.8) 103/152 (67.8) 122/152 (80.3) 160 (66 365) 38.5 (56.0) AMX = amoxicillin/clavulanate; EOT = end of treatment IQR = interquartile range; PBO = placebo Llor et al. Am J Respir Crit Care Med 2012

19 Kaplan-Meier survival analysis of exacerbation-free interval in patients with clinical success at Days 9 to 11 Patients free of exacerbation (%) Treatment group Placebo Amoxicillin/clavulanate 500/125 mg Placebo-censored Amoxicillin/clavulanate-censored Days after incusion Llor et al. Am J Respir Crit Care Med 2012

20 Oral steroids at COPD exacerbation data from hospital admissions Corticosteroid-treated group (prednisolone 30 mg q.d.) Placebo group AdmissionDay 1 Day 2 Day 3 Day 4 Day 5Discharge Time point of measurement Davies et al. Lancet 1999

21 Short-term vs conventional steroids: REDUCE trial A B Proportion of patients without re-exacerbation Proportion of patients alive Leuppi et al. JAMA 2013

22 COMPARISON OF VILANTEROL/FLUTICASONE FUROATE VERSUS VILANTEROL ON EXACERBATIONS with DIFFERENT COMBINATION DOSAGES Dransfield et al Lancet Resp Med 2014

23 FORWARD STUDY STRATIFICATION BY BLOOD EOSINOPHIL COUNT Siddiqui et al AJRCCM 2015 in press

24 INSPIRE Exacerbation Rates at 2 Years FEV 1 <50% Predicted Exacerbation rates were similar with salmeterol/fluticasone propionate and tiotropium in the INSPIRE study 2.0 p=ns Rate per year All exacerbations Wedzicha JA et al. Am J Respir Crit Care Med 2008;177:19 26

25 QVA149 Significantly Improved Mean Trough FEV 1 vs Glycopyrronium and Tiotropium Over 64 Weeks (Secondary Objective) * * * * * * Trough FEV 1 (l) QVA /50 µg q.d. Glycopyrronium 50 µg q.d. OL tiotropium 18 µg q.d. 0 Baseline *At all time points, p< vs glycopyrronium and OL tiotropium Data are least-squares mean ± SE; OL = open label Time (weeks) Wedzicha JA, et al. Lancet Respir Med 2013

26 Rate of Moderate or Severe COPD Exacerbations Annual rate of moderate or severe COPD exacerbations % reduction, p=0.096 (secondary endpoint) 12% reduction, p=0.038 (primary endpoint) QVA /50 µg q.d. Glycopyrronium 50 µg q.d. OL tiotropium 18 µg q.d. OL = open label Wedzicha JA, et al. Lancet Respir Med 2013

27 QVA149 (ULTIBRO) significantly increased time to first moderate or severe COPD exacerbation vs SFC (Salmeterol/Fluticasone) 40 QVA /50 µg q.d. SFC 500/50 µg b.i.d. Probability of exacerbation (%) Hazard ratio, 0.65 (95% CI 0.44, 0.95) p= Patients with exacerbation (%) Days QVA (3.3) 20 (5.5) 31 (8.6) 43 (12.1) SFC 0 24 (6.6) 38 (10.5) 48 (13.4) 67 (18.9) SFC = salmeterol/fluticasone propionate Zhong N, et al. Int J Chron Obstruct Pulmon Dis 2015

28 NEJM 2014

29 Effect of Azithromycin on the airway immune response of COPD patients Wenzel et al. NEJM 2012

30 MACROLIDES TIME TO 1 ST EXACERBATION Seemungal et al AJRCCM ERYTHROMYCIN P= Cum Survival PLACEBO Time to First Exacerbation (Days) 400

31 Symptom Duration is responsive to Therapy (Macrolide Study) Seemungal et al. AJRCCM 2008

32 MACROLIDE (AZITHROMYCIN) STUDY PROPORTION OF PARTICIPANTS FREE OF ACUTE EXACERBATIONS OF COPD Albert RK et al. N Engl J Med 2011;365:

33 EFFECT OF 3 MONTH THERAPY WITH ANTIBIOTICS ON BACTERIAL RESISTANCE Brill S et al Thorax 2015

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35 Reduction of mortality with noninvasive ventilation in acute hypercapnic respiratory failure Brochardet al NEJM 1995 Bottet al Lancet 1993 Kings, Southampton, London Chest P<0.02 Plant et al Lancet 2000 P<0.05

36 Inpatient mortality acute exacerbations of COPD Data from National Audit Roberts CM et al Thorax 2011

37 Quality of Life Randomised cross over study of long-term non-invasive ventilation with oxygen for Hypercapnic COPD 100 p=0.52 p=0.007 p=0.03 SGRQ Score Mean 0 Run-in O 2 Alone O 2 + NPSV J Meecham Jones et al : Am J Respir Crit Care Med 1995

38 Lancet Resp Med 2014 Thorax 2014

39 ROFLUMILAST AND EXACERBATIONS (FEV1<50% predicted, Chronic bronchitis, exacerbation history) Martinez F et al Lancet 2015

40 ROFLUMILAST AND SEVERE EXACERBATIONS Martinez F et al Lancet 2015

41 Aortic Pulse Wave Velocity at Exacerbation Mean +/ 1SE aortic pulse wave velocity (m/s) Airway infection No airway infection 0.0 Stable state Exacerbation Day 3 Day 7 Day 14 Day 35 Patel AR et al. Am J Respir Crit Care Med 2013

42 Dransfield MT, et al. Thorax 2008;63(4):

43 bb = beta blocker; MI = myocardial infarction Quint JK, et al. BMJ 2013;347:f6650

44 Treatment of Exacerbations from 1878! Catching colds is a far more important cause of bronchitis than pneumonia Next to avoiding a fatal issue, our efforts must be directed to prevent the case going on to chronic bronchitis, especially in those who have had previous attacks THERAPY OF BRONCHITIS For those who can afford it a seasonable change to one of the Mediterranean health resorts, or to Rome or Egypt is highly to be recommended Part 2, Chapter 1, Page 199