Reduce and Prevent exacerbation in COPD patients: Is it easy? รศ. นพ. วัชรา บุญสวัสดิ์ M.D., Ph.D. ประธานเครือข่ายคลินิกโรคหืดและปอดอุดกั้นเรื้อรังแบบง่าย ภาควิชาอายุรศาสตร์ คณะแพทยศาสตร์ มหาวิทยาลัยขอนแก่น

An exacerbation of COPD is: “an acute event characterized by a worsening of the patient’s respiratory symptoms that is beyond normal day-to-day variations and leads to a change in medication.” © 2014 Global Initiative for Chronic Obstructive Lung Disease

Exacerbations Patients with frequent exacerbations Lower quality of life Increased mortality rate Increased inflammation Increased risk of recurrent exacerbations Speaker notes Some patients with COPD are susceptible to frequent exacerbations.1,2 Cohort studies have reported evidence of a phenotypic exacerbator,3 and other studies have reported differences in exacerbation rate despite similar FEV1 levels.4 While exacerbation frequency is linked to disease severity, it is important to consider that not only patients with severe COPD are frequent exacerbators.2 Exacerbations are associated with increased inflammation, which persists after the attack and affects the length of recovery period.5 In addition, patients who suffer from frequent exacerbations have increased airway inflammation in the stable state.6 Frequent exacerbators display worse quality of life,1,7 faster decline in lung function,1,2,7 and higher mortality rates than patients with less frequent exacerbations.1,2,8,9 Managing exacerbations, including reducing their frequency and severity, is a major goal of COPD disease management in the GOLD Global strategy for the diagnosis, management, and prevention of COPD.10 References Wedzicha JA and Seemungal TA. COPD exacerbations: defining their cause and prevention. Lancet. 2007;370:786-796. Donaldson GC and Wedzicha JA. COPD exacerbations: Epidemiology. Thorax 2006;61:164-168. Seemungal TAR, Hurst JR and Wedzicha JA. Exacerbation rate, health status and mortality in COPD – a review of potential interventions. Int J COPD 2009;4:203-223. Kim V, Han MK, Vance GB, et al. Chronic bronchitic symptoms are associated with worse symptoms and greater exacerbation frequency in COPD. Am J Respir Crit Care Med 2010;181:A1533. Perera W, Hurst JR, Wilkinson TM, et al. Inflammatory changes, recovery and recurrence at COPD exacerbation. Eur Respir J 2007;29:527-534. Bhowmilk A, Seemungal TA, Sapsford RJ, et al. Relation of sputum inflammatory markers to symptoms and lung function changes in COPD exacerbations. Thorax 2000;55:114-120. Decramer M, Celli B, Kesten S et al. Frequency of exacerbations adversely impacts the course of COPD. Am J Respir Crit Care Med 2010;181:A1526. Soler-Cataluna JJ, Martinez-Garcia MÁ, Román Sánchez P, et al. Severe acute exacerbations and mortality in patients with chronic obstructive pulmonary disease. Thorax 2005;60:925-931. Groenewegen KH, Schols AMWJ, Wouters EFM. Mortality and mortality-related factors after hospitalization for acute exacerbation of COPD. Chest 2003;124:459-467. Global Initiative for Chronic Obstructive Lung Disease. Global strategy for the diagnosis, management, and prevention of COPD. 2009. www.goldcopd.com Faster disease progression Increased likelihood of hospitalisation Adapted from Wedzicha JA et al, 2007; Donaldson GC et al, 2006.

Reduce and Prevent exacerbation is easy We can predict high risk patients We can prevent exacerbation We have guidelines

COPD Airway inflammation Airflow Obstruction Air Trapping Dyspnea on exertion Infection, pollution More Obstruction More inflammation Exacerbation

Association of disease severity and exacerbations Hurst JR(ECLIPSE), NEJM. 363; 1128::2010

Number of exacerbations per year stratified by baseline FEV1 ICS สามารถลดการกำเริบได้ ISOLDE. BMJ2000;320:1297-1303

Rate of moderate and severe exacerbations over three years Mean number of exacerbations/year 25% reduction 1.2 1.13 0.97* 1 0.93* 0.85*†‡ 0.8 0.6 0.4 Moderate exacerbations are defined as those which require treatment with systemic corticosteroids and/or antibiotics; severe exacerbations are defined as those which require hospitalisation. The exacerbation rate was calculated as the total number of moderate and/or severe exacerbations experienced by a patient during the treatment period. The number of exacerbations was analysed using a generalised linear model, assuming the Negative Binomial distribution, with time on treatment as an offset variable. The model included adjustments for the effects of smoking status, age, gender, baseline FEV1, number of exacerbations reported in the 12 months prior to screening, and region.1 SFC significantly lowered the rate of moderate/severe exacerbations compared with placebo (25% reduction, p < 0.001), SALM (12% reduction, p = 0.002) and FP (9% reduction, p = 0.024). SALM and FP also had significantly lower exacerbation rates than placebo (15%, p < 0.001 and 18%, p < 0.001, respectively).1 SFC reduced the rate of moderate-to-severe exacerbations to a much greater extent than placebo or either of the component monotherapies.1 Exacerbations and hospitalisations predict the risk of dying from COPD over 5 years.2 Reference Calverley PMA, Anderson JA, Celli B. for the TORCH investigators. Salmeterol and fluticasone propionate and survival in chronic obstructive pulmonary disease. NEJM 2007; 356(8): 775-789 & Online Supplement Soler-Cataluna JJ, Martinez-Garcia MA, Roman Sanchez P, et al. Severe acute exacerbations and mortality in patients with chronic obstructive pulmonary disease. Thorax 2005;60:925–31. 0.2 Placebo SALM FP SFC Treatment Calverley et al. NEJM 2007 *p < 0.001 vs placebo; †p = 0.002 vs SALM; ‡p = 0.024 vs FP

Exacerbation rate by baseline post-bronchodilator FEV1 % predicted Jenkins. Respir Res 2009: 59

SFC: impact of exacerbation history (TORCH)1 In patients with a history of more frequent exacerbations, there were trends to higher rates overall, and a greater effect of treatment Reductions in exacerbation rates associated with treatment are not dependent on a history of frequent exacerbations, and the benefits of SFC on exacerbations are still seen in patients who had no history of an exacerbation in the previous 12 months Exacerbation history: impact of SFC % reduction No recalled exacerbations 19 1 exacerbation in previous year 26 ≥2 exacerbations in previous year 31 Notes A sub-group analysis of TORCH data showed trends to higher rates of exacerbation, and a greater effect of treatment, in patients with a history of more frequent exacerbations. [par5/ln1–2] However, there was no significant interaction between exacerbation history and effect of treatment (p=0.34). [par5/ln2–3] Adjusted mean exacerbation rates among SFC patients were 0.64 in those with no exacerbations in the previous year, 0.89 in those with one exacerbation and 1.21 in those with two or more exacerbations; percentage reductions versus placebo were 19%, 26% and 31%, respectively. [Table] Reference Jenkins C et al. Poster 227, ERS 2007. 1. Jenkins C et al. Poster (227) presented at ERS 2007.

Pharmacotherapy: Glucocorticosteroids Management of Stable COPD Pharmacotherapy: Glucocorticosteroids The addition of regular treatment with inhaled glucocorticosteroids to bronchodilator treatment is appropriate for symptomatic COPD patients with an FEV1 < 50% predicted (Stage III: Severe COPD and Stage IV: Very Severe COPD) and repeated exacerbations (Evidence A).

GOLD pharmacological treatment Regular bronchodilator treatment inhaled corticosteroids Oxygen therapy FEV1 <30% Regular bronchodilator treatment Consider inhaled corticosteroids FEV1 30-50% Regular bronchodilator treatment FEV1 50-80% Short acting bronchodilator as needed FEV1>80%

GOLD pharmacological treatment LABA ICS Oxygen therapy Regular bronchodilator treatment inhaled corticosteroids Oxygen therapy FEV1 <30% Regular bronchodilator treatment Consider inhaled corticosteroids LABA ICS FEV1 30-50% Regular bronchodilator treatment FEV1 50-80% Short acting bronchodilator as needed FEV1>80%

บทบาทของ ICS/LABA Short-acting bronchodilator prn Short-acting bronchodilator regular Long-acting bronchodilator Add ICS ( >1 exacerbation) บทบาทของ ICS/LABA

Identification of patient at risks ไม่ทำอะไร เป็นน้อยอยู่ Arterial stenosis Airway obstruction Identification of patient at risks ไม่ทำอะไร เป็นน้อยอยู่ Heart attack COPD exacerbation Catheterization and revascularzation ????????? Antiplatelete Anticoagulation ACEI

GOLD 2011 revision Future risks MRC 0-1 CAT<10 MRC 2+ CAT 10+ Current symptoms

C D A B GOLD 2011 revision GOLD 4 >2 GOLD 3 2 Future risks Exacerbations / y 1 GOLD 2 A B GOLD 1 MRC 0-1 CAT<10 MRC 2+ CAT 10+ Current symptoms

C D A B GOLD 2011 revision SABA or SAMA LABA or LAMA ICS/LABA ICS/LABA >2 ICS/LABA or LAMA C D GOLD 3 2 Future risks Exacerbations / y 1 GOLD 2 SABA or SAMA LABA or LAMA A B GOLD 1 MRC 0-1 CAT<10 MRC 2+ CAT 10+ Current symptoms

Antiinflamation Bronchodilator (ICS) (LABA) Influenza vaccine COPD Airway inflammation Airflow Obstruction Bronchodilator (LABA) Antiinflamation (ICS) Air Trapping Dyspnea on exertion Influenza vaccine Infection, pollution More Obstruction More inflammation Exacerbation

ปัญหา เราทำนายได้ง่ายๆว่าใครมีความเสี่ยงสูงที่จะกำเริบ Exacerbation เราทำนายได้ง่ายๆว่าใครมีความเสี่ยงสูงที่จะกำเริบ เราสามารถป้องกันการกำเริบได้ด้วยการใช้ยา ICS/LABA วัคซีน เรามีแนวทางการรักษา GOLD 2012 ปัญหา อยู่ที่เรายังไม่เห็นความสำคัญของการกำเริบ

Asthma and COPD Admissions (UC)

ผลงานที่ได้รับการชดเชย COPD 2556

สรุป การกำเริบสามารถป้องกันได้ไม่ยาก ด้วยการใช้ยา ICS/LABA, influenza vaccine. แต่เรายังไม่ได้ออกแรงเต็มที่ ที่จะป้องกัน