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Exacerbations The burden of COPD. 2 GOLD 2014 definition of exacerbations  GOLD defines an exacerbation as an acute event characterized by worsening.

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Presentation on theme: "Exacerbations The burden of COPD. 2 GOLD 2014 definition of exacerbations  GOLD defines an exacerbation as an acute event characterized by worsening."— Presentation transcript:

1 Exacerbations The burden of COPD

2 2 GOLD 2014 definition of exacerbations  GOLD defines an exacerbation as an acute event characterized by worsening of respiratory symptoms Worsening must be beyond normal day-to-day variations Worsening must lead to a change in medication  Diagnosis relies on patient presentation  An important goal of COPD treatment is to minimize impact of current exacerbation and prevent development of subsequent exacerbations COPD = chronic obstructive pulmonary disease; GOLD = Global Initiative for Chronic Obstructive Lung Disease GOLD 2014 (http://www.goldcopd.org/)http://www.goldcopd.org/

3 3 Epidemiology of COPD exacerbations  On average, 0.85–3.00 exacerbations are reported per patient per year 1  The average number of days with an exacerbation(s) was 12–14 per patient per year 2  60%–70% of patients have an exacerbation over 2–4 years 2,3  On average, 3 days are spent in hospital per patient per year 2  ‘Frequent exacerbator’ COPD phenotype 4 Is prone to frequent exacerbations Uses considerable healthcare resources Experiences higher morbidity and mortality 1. Seemungal TA. Int J Chron Obstruct Pulmon Dis 2009;4:203–23 2. Tashkin DP. N Engl J Med 2008;359:1543–54 3. Wedzicha JA. Am J Respir Crit Care Med 2008;177:19–26 4. Soler-Cataluña JJ and Rodriguez-Roisin R. COPD 2010;7:276–84 COPD, chronic obstructive pulmonary disease.

4 4 Seasonality of COPD exacerbations  COPD exacerbations are more frequent in winter months than in summer months Month Patients reporting an exacerbation (%) JanFebMarAprMayJunJulAugSepOctNovDec Northern* and Southern † regionsTropics ‡ Month JanFebMarAprMayJunJulAugSepOctNovDec Patients reporting an exacerbation (%) NorthernSouthernTropics *Canada, China, eastern/western Europe and USA; † Argentina, Australia, Brazil, Chile, New Zealand and South Africa; ‡ Hong Kong, Malaysia, Mexico, Philippines, Singapore, Taiwan and Thailand COPD = chronic obstructive pulmonary disease 1.Jenkins CR et al. Eur Respir J 2012;39:38-45

5 5 Exacerbation triggers and effects Systemic inflammation Bronchoconstriction edema, mucus Cardiovascular comorbidity Exacerbation symptoms Inflamed COPD airways Greater airway inflammation Viruses Bacteria Pollutants Effects Triggers Expiratory flow limitation Dynamic hyperinflation COPD = chronic obstructive pulmonary disease Wedzicha JA, Seemungal TA. Lancet 2007;370:786–96

6 6 Risk factors for an exacerbation  COPD severity (GOLD stage) 1  Older age 2  Degree of FEV 1 impairment 2  Chronic bronchial mucus hypersecretion 2  Frequent past exacerbations 2  Daily cough and wheeze  Persistent symptoms of chronic bronchitis 2 Proportion of COPD patients reporting exacerbation by GOLD severity stage 1 Exacerbation requiring hospitalization within past yr Exacerbation requiring doctor visit within past yr Exacerbation within past yr Proportion of subjects (%) GOLD Stage 4 GOLD Stage 3 GOLD Stage 2 GOLD Stage 1 Ever had exacerbation Ever had an exacerbation, p<0.0001; Exacerbation within past year, p=0.0002; Exacerbation requiring doctor visit, p= Exacerbation requiring hospitalization, p= COPD = chronic obstructive pulmonary disease; GOLD = Global Initiative for Chronic Obstructive Lung Disease; FEV 1 = forced expiratory volume in 1 s 1.De Oca MM, et al. Chest 2009;136:71–78; 2.Anzueto A, et al. Proc Am Thorac Soc 2007;4:554–64

7 7 The best predictor of future exacerbations is a history of previous exacerbations  Exacerbations during previous year OR [95% CI] (≥2 versus 0 exacerbations): 5.72 [4.47, 7.31], p<0.001  100 mL decrease in FEV 1 OR: 1.11 [1.08, 1.14], p<0.001  4-point increase in SGRQ-C OR: 1.07 [1.04, 1.10], p<0.001  History of reflux/heartburn OR: 2.07 [1.58, 2.72], p<0.001  1x10 9 increase in white blood cell count OR: 1.08 [1.03, 1.14], p=0.007 FEV 1 = forced expiratory volume in 1 s; OR = odds ratio; SGRQ-C = St George’s Respiratory Questionnaire for COPD patients Hurst J, et al. N Engl J Med 2010:363:1128–38

8 8 ‘Frequent exacerbator’ and ‘non exacerbator’ are stable phenotypes  71% of frequent exacerbators in Years 1 and 2 were frequent exacerbators in Year 3  74% of patients with no exacerbations in Years 1 and 2 had no exacerbations in Year 3 Year ≥2≥2 Percentage Exacerbations/year Year 2 Year 3 Percentage Data are for 1679 patients with COPD who completed the study 1 0 ≥2≥2 1 0 ≥2≥2 1 0 ≥2≥2 1 0 ≥2≥ COPD = chronic obstructive pulmonary disease Hurst J, et al. N Engl J Med 2010:363:1128–38

9 9 Importance of accurate recognition and prompt reporting of exacerbations  There are limitations to the GOLD 2014 criteria Exacerbations do not always fulfil these criteria  Furthermore, exacerbations are not always recognized or reported by patients 1–3  Under-recognition, under-reporting and delayed treatment can impact negatively on outcomes Slower recovery 1 Increased hospitalization risk 1 Worse HRQoL 1,2 COPD = chronic obstructive pulmonary disease; GOLD = Global Initiative for Chronic Obstructive Lung Disease; HRQoL, health-related quality of life 1.Wilkinson TM et al. Am J Respir Crit Care Med 2004;169:1298–303 2.Xu W et al. Eur Respir J 2010;35:1022–30 3.Langsetmo L et al. Am J Respir Crit Care Med 2008;177:396–401

10 10 COPD exacerbations have a significant impact on clinical outcomes Patients with frequent exacerbations Higher mortality Greater airway inflammation Poorer quality of life Faster decline in lung function More hospital admissions COPD = chronic obstructive pulmonary disease 1.Wedzicha JA, Seemungal TA. Lancet. 2007;370:786–96

11 11 COPD exacerbations worsen airflow obstruction, cause hyperinflation and contribute to inactivity Disability Disease progressionDeath Air trapping Expiratory flow limitation Hyperinflation DeconditioningInactivity Reduced exercise capacity Exacerbations COPD Shortness of breath Quality of life Exercise COPD = chronic obstructive pulmonary disease; HRQoL = health-related quality of life 1.Cooper CB. Respir Med 2009;103:325–34

12 12 COPD exacerbations have a significant impact on personal well being Due to flare-ups Lost energy/interest of doing what I had planned Intimacy with my partner was impossible I was very frustrated with myself Was frightened of the onset of winter I was very scared Results from 1,100 patient interviews, in five European countries and the USA. Had to cancel public outings Wanted to be alone/with few close friends/family I was bed-ridden/hospitalized COPD = chronic obstructive pulmonary disease 1.Miravitlles M et al. Respir Med 2007;101:453–60

13 13 Implications of exacerbations for prognosis of COPD  Hospitalization (3–16% of patients) 1  Death (8–14% of hospitalized patients) 2–4  Pulmonary embolism, myocardial infarction, stroke 5–7  Worsening lung function 8  Impaired quality of life 9,10 Frequent exacerbations Worsening lung function COPD = chronic obstructive pulmonary disease 1. MacIntyre N, Huang YC. Proc Am Thorac Soc. 2008;5:530–535; 2. Fuso L, et al. Am J Med. 1995;98:272–77; 3. Connors AF Jr, et al. Am J Respir Crit Care Med. 1996;154:959–67; 4. Gunen H, et al. Eur Respir J. 2005;26:234–21; 5. Gunen H, et al. Eur Respir J 2010;35:1243–8; 6. Rizkallah J, et al. Chest. 2009;135:786–93; 7. Donaldson GC, et al. Chest. 2010;137:1091–97; 8. Donaldson GC, et al. Thorax. 2002;57:847–52; 9. Llor C, et al. Int J Clin Pract. 2008;62:585–92; 10. Spencer S, et al. Eur Respir J. 2004;23:698–702

14 14 COPD exacerbations increase mortality risk Time (months) p< p< A B C p= Survival probability Group A: no exacerbations Group B: 1–2 exacerbations Group C: ≥3 exacerbations COPD = chronic obstructive pulmonary disease 1.Soler-Cataluña JJ et al. Thorax 2005;60:925–31

15 15 Treatment challenges of COPD exacerbations  Identifying the frequent exacerbator Especially in early-stage disease  Treating exacerbations Patients need to report promptly to ensure rapid recovery  Detecting exacerbations Exacerbations may cluster, be seasonal and be relatively uncommon  Control of symptoms, especially dyspnea, is key to reducing exacerbations and their severity COPD = chronic obstructive pulmonary disease

16 16  In the INSPIRE study, rates of ‘All exacerbations’ at 2 years were similar between tiotropium and salmeterol/fluticasone treatment groups Tiotropium 18 μg o.d. (n=665) Salmeterol/fluticasone 50/500 μg b.i.d. (n=658) p=ns p=0.028 p= All exacerbationsExacerbations requiring antibiotics Exacerbations requiring systemic corticosteroids Rate per year Limited evidence for reduction in exacerbation rate with salmeterol/fluticasone vs tiotropium b.i.d. = twice daily; ICS = inhaled corticosteroid; LABA = long-acting β 2 -agonist; LAMA = long-acting muscarinic antagonist; o.d. = once daily Wedzicha JA et al. Am J Respir Crit Care Med 2008;177:19–26

17 17 LAMAs have demonstrated ability to reduce the risk of exacerbation vs placebo  Both glycopyrronium and tiotropium significantly reduced the risk of exacerbation (in terms of time to first moderate-to-severe exacerbation) vs placebo (p=0.001) 100 Patients exacerbation-free (%) Time to first exacerbation (weeks) Glycopyrronium 50 μg o.d. Tiotropium Placebo  Glycopyrronium significantly reduced the rate of moderate-to-severe COPD exacerbations vs placebo CI = confidence interval; COPD = chronic obstructive pulmonary disease; HR = hazard ratio; RR, rate ratio. Kerwin E et al. Eur Respir J 2012;40:1106–14 Glycopyrronium vs placebo: HR 0.66 (95% CI 0.520–0.850); p=0.001 Tiotropium vs placebo: HR 0.61 (95% CI, 0.456–0.821); p=0.001

18 18 Conclusions  Exacerbations are characterized by worsening of respiratory symptoms beyond normal day-to-day variation and requiring a change in medication 1  60–70% of patients with COPD will have an exacerbation over 2–4 years 2,3  Risk factors for exacerbations include: COPD severity (GOLD stage) 4 Older age 5 Degree of FEV 1 impairment 5 Frequent past exacerbations (the best predictor of future exacerbations) 5,6  ‘Frequent exacerbators’ and ‘non-exacerbators’ are stable phenotypes 6 Patients with frequent exacerbations have poorer clinical outcomes 7  Failure to identify and treat exacerbations promptly can adversely affect outcomes 8,9  COPD exacerbations significantly affect clinical outcomes 7 and personal well being, 10 result in an increased mortality risk, 11 and lead to hyperinflation and inactivity 12  There is limited evidence that LABA/ICS therapy reduces exacerbation rates compared with a LAMA 3  LAMAs have been shown to reduce the risk of exacerbations vs placebo 13 COPD = chronic obstructive pulmonary disease; GOLD = Global Initiative for Chronic Obstructive Lung Disease; ICS= inhaled corticosteroid; LABA = long-acting β 2 agonist; LAMA = long-acting muscarinic antagonist 1. GOLD 2014 (http://www.goldcopd.org/); 2. Tashkin DP, et al. N Engl J Med 2008;359:,1543–54; 3. Wedzicha JA,et al. Am J Respir Crit Care Med 2008;177:19–26; 4. De Oca MM, et al. Chest 2009;136:71–78; 5. Anzueto A, et al. Proc Am Thorac Soc 2007;4:554–64; 6. Hurst J, et al. N Engl J Med 2010:363:1128–38; 7. Wedzicha JA, Seemungal TA. Lancet. 2007;370:786–96; 8. Wilkinson TM et al. Am J Respir Crit Care Med 2004;169:1298–303; 9. Xu W et al. Eur Respir J 2010;35:1022–30; 10. Miravitlles M et al. Respir Med 2007;101:453–60; 11. Soler-Cataluña JJ et al. Thorax 2005;60:925–31;http://www.goldcopd.org/ 12. Cooper CB. Respir Med 2009;103:325–34; 13. Kerwin E et al. Eur Respir J 2012;40:1106–14


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