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The burden of COPD Exacerbations.

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Presentation on theme: "The burden of COPD Exacerbations."— Presentation transcript:

1 The burden of COPD Exacerbations

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 Reference GOLD Available from: COPD = chronic obstructive pulmonary disease; GOLD = Global Initiative for Chronic Obstructive Lung Disease GOLD 2014 (http://www.goldcopd.org/)

3 Epidemiology of COPD exacerbations
On average, 0.85–3.00 exacerbations are reported per patient per year1 The average number of days with an exacerbation(s) was 12–14 per patient per year2 60%–70% of patients have an exacerbation over 2–4 years2,3 On average, 3 days are spent in hospital per patient per year2 ‘Frequent exacerbator’ COPD phenotype4 Is prone to frequent exacerbations Uses considerable healthcare resources Experiences higher morbidity and mortality References Seemungal TA et al. Int J Chron Obstruct Pulmon Dis. 2009;4:203–23. Tashkin DP et al. N Engl J Med. 2008;359:1543–54. Wedzicha JA et al. Am J Respir Crit Care Med 2008;177:19–26. Soler-Cataluña JJ and Rodriguez-Roisin R. COPD 2010;7:276–84. COPD, chronic obstructive pulmonary disease. 1. Seemungal TA. Int J Chron Obstruct Pulmon Dis 2009;4:203– Tashkin DP. N Engl J Med 2008;359:1543– Wedzicha JA. Am J Respir Crit Care Med 2008;177:19– Soler-Cataluña JJ and Rodriguez-Roisin R. COPD 2010;7:276–84

4 Seasonality of COPD exacerbations
COPD exacerbations are more frequent in winter months than in summer months Northern* and Southern† regions Tropics‡ 14 14 12 12 10 10 8 8 Patients reporting an exacerbation (%) Patients reporting an exacerbation (%) 6 6 4 4 2 2 Reference Jenkins CR et al. Eur Respir J 2012;39:38-45. Jan Feb Mar Apr May Jun Jul Aug Sep Oct Nov Dec Jan Feb Mar Apr May Jun Jul Aug Sep Oct Nov Dec Month Month Northern Southern Tropics *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 Jenkins CR et al. Eur Respir J 2012;39:38-45

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

6 Risk factors for an exacerbation
Proportion of COPD patients reporting exacerbation by GOLD severity stage1 COPD severity (GOLD stage)1 Older age2 Degree of FEV1 impairment2 Chronic bronchial mucus hypersecretion2 Frequent past exacerbations2 Daily cough and wheeze Persistent symptoms of chronic bronchitis2 Exacerbation requiring hospitalization within past yr GOLD Stage 4 GOLD Stage 3 GOLD Stage 2 GOLD Stage 1 Exacerbation requiring doctor visit within past yr Exacerbation within past yr Patients with GOLD Stage 3 or 4 (severe or very severe) COPD are much more likely to have exacerbations and be hospitalized for an exacerbation than those with mild to moderate disease.1 Additionally, older age, severity of forced expiratory volume in 1 second (FEV1) impairment, chronic bronchial mucus hypersecretion, frequent past exacerbations, daily cough and wheeze, and persistent symptoms of chronic bronchitis increase the likelihood of exacerbations, and have been found to be risk factors for more than 2 exacerbations per year.2 References de Oca MM, Talamo C, Halbert RJ, et al. Frequency of self-reported COPD exacerbation and airflow obstruction in five Latin American cities: the Proyecto Latinoamericano de Investigacion en Obstruccion Pulmonar (PLATINO) study. Chest. 2009;136(1):71-78. Anzueto A, Sethi S, Martinez FJ. Exacerbations of chronic obstructive pulmonary disease. Proc Am Thorac Soc. 2007;4(7): Ever had exacerbation Ever had an exacerbation, p<0.0001; Exacerbation within past year, p=0.0002; Exacerbation requiring doctor visit, p=0.0001 Exacerbation requiring hospitalization, p=0.0077 COPD = chronic obstructive pulmonary disease; GOLD = Global Initiative for Chronic Obstructive Lung Disease; FEV1 = forced expiratory volume in 1 s De Oca MM, et al. Chest 2009;136:71–78; Anzueto A, et al. Proc Am Thorac Soc 2007;4:554–64 Proportion of subjects (%)

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 FEV1 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 1x109 increase in white blood cell count OR: 1.08 [1.03, 1.14], p=0.007 In the ECLIPSE study, the occurrence of exacerbations during the previous year was the best predictor of future exacerbations. Individuals who had had two or more exacerbations in the past year were almost six fold more likely to have an exacerbation (odds ratio 5.72), compared with individuals who had not had an exacerbation in the past year. Other significant predictors of exacerbations included a 100 mL decrease in FEV1 (11% increase in risk), a 4-point decrease in St George’s Respiratory Questionnaire score (7% increase), history of reflux/heartburn (two-fold increase) and 1 x 109 increase in white blood cells (8% increase). Reference Hurst JR, et al. Susceptibility to exacerbation in chronic obstructive pulmonary disease. N Engl J Med 2010:363:1128–38. FEV1 = 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 ‘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 Year 3 Percentage Percentage Year 1 Percentage 1 1 ≥2 ≥2 Exacerbations/year Percentage Percentage 1 ≥2 Reference Hurst JR, et al. N Engl J Med 2010;363:1128–38. 1 1 Data are for 1679 patients with COPD who completed the study ≥2 ≥2 COPD = chronic obstructive pulmonary disease Hurst J, et al. N Engl J Med 2010:363:1128–38

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 patients1–3 Under-recognition, under-reporting and delayed treatment can impact negatively on outcomes Slower recovery1 Increased hospitalization risk1 Worse HRQoL1,2 References Wilkinson TM et al. Am J Respir Crit Care Med 2004;169:1298–303. Xu W et al. Eur Respir J 2010;35:1022–30. Langsetmo L et al. Am J Respir Crit Care Med 2008;177:396–401. COPD = chronic obstructive pulmonary disease; GOLD = Global Initiative for Chronic Obstructive Lung Disease; HRQoL, health-related quality of life Wilkinson TM et al. Am J Respir Crit Care Med 2004;169:1298–303 Xu W et al. Eur Respir J 2010;35:1022–30 Langsetmo L et al. Am J Respir Crit Care Med 2008;177:396–401

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

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

12 COPD exacerbations have a significant impact on personal well being
Due to flare-ups Had to cancel public outings Lost energy/interest of doing what I had planned Was frightened of the onset of winter Wanted to be alone/with few close friends/family I was very frustrated with myself I was very scared I was bed-ridden/hospitalized A random telephone contact survey in six countries was performed. From the 83,592 households screened, 1100 patients with symptoms compatible with COPD were identified.1 Reference Miravitlles M et al. Respir Med 2007;101:453–60 [data depicted are from a personal communication]. Intimacy with my partner was impossible Results from 1,100 patient interviews, in five European countries and the USA. COPD = chronic obstructive pulmonary disease Miravitlles M et al. Respir Med 2007;101:453–60

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, stroke5–7 Worsening lung function8 Impaired quality of life 9,10 Frequent exacerbations Worsening lung function Between 3 and 16% of patients experiencing an exacerbation require hospitalization, and some of these will develop respiratory failure and require ICU admission.1 Between 8% and 14% of patients hospitalized with acute COPD exacerbations will die during their admission.2–4 Patients with COPD exacerbation are also at high risk of venous thromboembolism, pulmonary embolism, myocardial infarction and stroke.5–7 The prognosis is particularly poor for patients who require ICU admission and mechanical ventilation. More frequent exacerbations are also associated with more rapid decline in lung function8 and QoL.9,10 References 1. MacIntyre N, Huang YC. Acute exacerbations and respiratory failure in chronic obstructive pulmonary disease. Proc Am Thorac Soc. 2008;5(4): 2. Fuso L, et al. Predicting mortality of patients hospitalized for acutely exacerbated chronic obstructive pulmonary disease. Am J Med. Mar 1995;98(3): 3. Connors AF, Jr., et al. Outcomes following acute exacerbation of severe chronic obstructive lung disease. The SUPPORT investigators (Study to Understand Prognoses and Preferences for Outcomes and Risks of Treatments). Am J Respir Crit Care Med. 1996;154(4 Pt 1): 4. Gunen H, et al. Factors affecting survival of hospitalized patients with COPD. Eur Respir J. 2005;26(2): 5. Gunen H, et al. Venous thromboemboli and exacerbations of COPD. Eur Respir J 2010;35: 6. Rizkallah J, et al. Prevalence of pulmonary embolism in acute exacerbations of COPD: a systematic review and metaanalysis. Chest. 2009;135(3): 7. Donaldson GC, et al. Increased risk of Myocardial Infarction and Stroke following Exacerbation of Chronic Obstructive Pulmonary Disease. Chest. 2010;137(5): 8. Donaldson GC, et al. Relationship between exacerbation frequency and lung function decline in chronic obstructive pulmonary disease. Thorax. 2002;57(10): 9. Llor C, et al. Exacerbations worsen the quality of life of chronic obstructive pulmonary disease patients in primary healthcare. Int J Clin Pract. 2008;62(4): 10. Spencer S, Calverley PM, Burge PS, Jones PW. Impact of preventing exacerbations on deterioration of health status in COPD. Eur Respir J. 2004;23(5): 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 COPD exacerbations increase mortality risk
Group A: no exacerbations Group B: 1–2 exacerbations Group C: ≥3 exacerbations 1.0 0.8 A p<0.0002 0.6 Survival probability B p<0.0001 0.4 p=0.069 C Reference Soler-Cataluña JJ et al. Thorax 2005;60:925–31. 0.2 Time (months) COPD = chronic obstructive pulmonary disease Soler-Cataluña JJ et al. Thorax 2005;60:925–31

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 Limited evidence for reduction in exacerbation rate with salmeterol/fluticasone vs tiotropium
In the INSPIRE study, rates of ‘All exacerbations’ at 2 years were similar between tiotropium and salmeterol/fluticasone treatment groups 2.0 Tiotropium 18 μg o.d. (n=665) Salmeterol/fluticasone 50/500 μg b.i.d. (n=658) p=ns 1.5 p=0.028 p=0.039 Rate per year 1.0 For the primary efficacy endpoint, tiotropium and salmeterol/fluticasone (SFC) had similar impacts on healthcare-utilization exacerbations (defined as those that required treatment with oral corticosteroids and/or antibiotics or required hospitalization). Estimated exacerbation rates per year were 1.28 for SFC and 1.32 for tiotropium (rate ratio [RR]: [95% CI, to 1.119], p=0.656).1 Exacerbations requiring antibiotics occurred more frequently in patients treated with SFC (SFC, 0.97/yr; tiotropium, 0.82/yr; RR: 1.19 [95% CI, 1.02 to 1.38], p=0.028), but those requiring systemic corticosteroids were less frequent than in the tiotropium-treated patients (SFC, 0.69/yr; tiotropium, 0.85/yr; RR: 0.81 [95% CI, 0.67 to 0.99], p=0.039).1 Reference 1. Wedzicha JA et al. Am J Respir Crit Care Med 2008;177:19–26. 0.5 All exacerbations Exacerbations requiring antibiotics Exacerbations requiring systemic corticosteroids b.i.d. = twice daily; ICS = inhaled corticosteroid; LABA = long-acting β2-agonist; LAMA = long-acting muscarinic antagonist; o.d. = once daily Wedzicha JA et al. Am J Respir Crit Care Med 2008;177:19–26 16

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 Glycopyrronium 50 μg o.d. Tiotropium Placebo 90 80 Patients exacerbation-free (%) 70 60 50 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 Glycopyrronium significantly reduced the risk of exacerbations (in terms of time to first moderate or severe exacerbation) by 34% vs placebo (HR, 0.66; 95% CI 0.520–0.850; p=0.001).1 Comparable to tiotropium, which provided a 39% risk reduction vs placebo (HR, 0.61; 95% CI, 0.456–0.821; p=0.001).1 Glycopyrronium reduced the rate of moderate or severe COPD exacerbations by 35% vs placebo (0.54/yr vs 0.80/yr; rate ratio 0.66; CI 0.496–0.869; p=0.003).1 The effect of tiotropium was not significantly different from placebo (rate ratio 0.80; CI 0.586–1.105; p=0.179).1 Glycopyrronium 50 μg and tiotropium 18 μg once daily were comparable and were both superior to placebo in reducing moderate exacerbations requiring systemic corticosteroids (glycopyrronium/placebo OR, 0.61; 95% CI, 0.434–0.870; p=0.006; tiotropium/placebo OR, 0.62; 95% CI 0.413–0.930; p=0.021) and those requiring treatment with antibiotics (glycopyrronium/placebo OR, 0.69; 95% CI 0.495–0.957; p=0.026; tiotropium/placebo OR, 0.65; 95% CI 0.438–0.949; p=0.026).1 GLOW2 study details Design: 52-week, randomized, double-blind, placebo-controlled, parallel-group, open-label tiotropium.1 Patient population: N=1066.1 Key inclusion criteria: moderate to severe COPD (GOLD Stage II–III), age ≥40 years, at least 10-pack-year smoking history, post-bronchodilator FEV1 of <80% and ≥30% of predicted normal and post-bronchodilator FEV1/FVC ratio of <0.7.1 Key exclusion criteria: history/diagnosis of asthma, history of clinically significant cardiac abnormalities/prolongation of QTc interval1 Treatment groups: Seebri Breezhaler o.d., open-label tiotropium 18 µg o.d. and placebo (2:1:1).1 Primary outcome measure: trough FEV1 at 12 weeks.1 Key/important secondary outcome measures: TDI at 26 weeks, SGRQ at 52 weeks, time to first COPD exacerbation over 52 weeks, and daily rescue medication over 52 weeks.1 Additional secondary variables: trough FEV1 at Day 1, Week 26 and Week 52; serial spirometry on Day 1 and Weeks 12 and 52 (at time points 5, 15, 30 mins and 1,2,3 and 4 h post-dose); IC on Day 1 and Weeks 12 and 52 (time points 25 mins, 1 h 55mins and 3 h 55 mins post dose); rate of COPD exacerbations in the 52 weeks.1 76% completed the study.1 Reference Kerwin E et al. Eur Respir J 2012;40:1106–14. Time to first exacerbation (weeks) 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

18 Conclusions Exacerbations are characterized by worsening of respiratory symptoms beyond normal day-to-day variation and requiring a change in medication1 60–70% of patients with COPD will have an exacerbation over 2–4 years2,3 Risk factors for exacerbations include: COPD severity (GOLD stage)4 Older age5 Degree of FEV1 impairment5 Frequent past exacerbations (the best predictor of future exacerbations)5,6 ‘Frequent exacerbators’ and ‘non-exacerbators’ are stable phenotypes6 Patients with frequent exacerbations have poorer clinical outcomes7 Failure to identify and treat exacerbations promptly can adversely affect outcomes8,9 COPD exacerbations significantly affect clinical outcomes7 and personal well being,10 result in an increased mortality risk,11 and lead to hyperinflation and inactivity12 There is limited evidence that LABA/ICS therapy reduces exacerbation rates compared with a LAMA3 LAMAs have been shown to reduce the risk of exacerbations vs placebo13 COPD = chronic obstructive pulmonary disease; GOLD = Global Initiative for Chronic Obstructive Lung Disease; ICS= inhaled corticosteroid; LABA = long-acting β2 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; 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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