Which one should be the first choise for moderate COPD? Long-acting 2-agonists

1. Which one should be the first choise for moderate COPD?Long-acting 2-agonists Dr. Tülay Yarkın SB Süreyyapaşa Göğüs Hast. Eğitim Hastanesi

2. Plan • Characteristics of moderate COPD • Effects of long-acting beta2-agonists (LABAs) • Studies and meta-analysis about using LABAs in COPD • Safety of LABAs in COPD • Conclusions

3. Spirometric Classification of COPD Severity Based on Post-Bronchodilator FEV1 • Stage I: MildFEV1/FVC <0.70 FEV1 ≥ 80% pred. • Stage II: ModerateFEV1/FVC <0.70 50% ≤ FEV1 <80% pred. • Stage III: SevereFEV1/FVC <0.70 30% ≤ FEV1 < 50% pred. • Stage IV : Very SevereFEV1/FVC <0.70 FEV1<30% pred or FEV1 < 50% plus CRF Stage II: Moderate COPD FEV1/FVC <0.70 50% ≤ FEV1 <80% pred with mild to moderate symptoms

4. Symptoms generally develop only after a significant decline in FEV1 has occurred; they progress as lung function deteriorates further Sutherland and Cherniack. N Engl J Med 2004;350:2689-97

5. Symptoms of Moderate COPD • Shortness of breath typically developing on exertion • Cough and sputum production • Patients typically seek medical attention because of chronic respiratory symptoms or an exacerbation of their disease • Exacerbations usually do not required hospitalisation

6. Breathlessness and Exercise Tolerance in COPD Patients

7. Management of Stable COPD Pharmacotherapy: Bronchodilators • Bronchodilator medications are central to the symptomatic management of COPD (Evidence A). They are given on an as-needed basis or on a regular basis to prevent or reduce symptoms and exacerbations. • The principal bronchodilator treatments are ß2- agonists, anticholinergics, and methylxanthines used singly or in combination (Evidence A). • Regular treatment with long-acting bronchodilators is more effective and convenient than treatment with short-acting bronchodilators (Evidence A).

8. Active reduction of risk factor(s); influenza vaccination Addshort-acting bronchodilator (when needed) I: Mild II: Moderate III: Severe IV: Very Severe Addregular treatment with one or more long-acting bronchodilators (when needed); Addrehabilitation Addinhaled glucocorticosteroids if repeated exacerbations Addlong term oxygenif chronic respiratory failure. Considersurgical treatments

9. Management of Stable COPD (GOLD) • No medication has been shown to affect the rate of lung function decline • Aim of pharmacotherapy: to improve symptoms and/or decrease complications - Bronchodilator medications are central - The side effects of bronchodilators are predictable and dose dependent - The choise between β2-agonist, anticholinergic, theophylline, or combination therapy depends on availability and individual response

10. Effects of β2-agonists • Provide bronchodilation • Improve quality of life • Improve dypnea • Reduce exacerbations • Anti-inflamatory effect

11. Effects of LABAs LABA Lipid tabaka cAMP ATP Bronkodilatasyon

12. ↓nötrofiller ↓eozinofiller ↓lokal inflamasyon İnflamasyon aracılı doku hasarının azalması LABA ↑mukosilyer hareketlerde artma ↑mukosilyer klirens Hücre membranında kaçağı azaltma ↓inflamatuareksüda Effects of 2-agonists other than bronchodilation Barnes PJ., Science Press Ltd, 1999

13. Faster Bronchodilation • The onset of action with formoterol is faster than that with anticholinergic agents and similar to that of SABAs (Benhamou 2001, Bouros 2004, Cazzola 2004, Cazzola 2002, Çelik 1999) • Duration of effect of LABAs ( 12 h) is consistent with the twice-daily dosing schedule approved for these agents

14. Bouros D. Curr Med Research and Opinion 2004;20:581 14

15. Uzun süreli bronkodilatasyon

16. Dahl et al. Am J Respir Crit Care Med 2001;164: 778–784 • A multicenter, double-blind, parallel-group study • No of pts: 780 • Study period: 12 wk • Study drugs: formoterol 12/24 µg BID, ipratropium bromide (IPR) 40 µg QID, or placebo • Both dose of formoterol * Provided greater mean FEV1 than IPR (p≤0.024) or PL (p < 0.001) * Clinically relevant ( 0.120 L) increase in FEV1 * Efficacy sustained from 5 min to 12 h

17. Twelve-hour profile of mean FEV1 measurements performed following the morning dose of study medications on the first day Dahl et al. Am J Respir Crit Care Med 2001;164: 778

18. Bronchodilator effect of LABAs is fairly stable in COPD pts on regular treatment with these agents Twelve-hour profile of mean FEV1 measurements performed following the morning dose of study medications after 12 wk of treatment Dahl et al. Am J Respir Crit Care Med 2001;164: 778

19. Health Status Dahl et al. Am J Respir Crit Care Med 2001;164: 778

20. Randomized, double-blind, placebo controlled, multicentre trial • No of patients: 692 • Mean baseline FEV1: 54% (range: 30-73) • Study drugs: formoterol (4.5, 9 or 18 µg b.i.d.) or placebo • Study period: 12 weeks Aalbers et al. ERJ 2002; 19:936

21. Results • Formoterol 18 µg reduced the mean total symptom score by 13%, and increased the percentage of nights without awakenings by 15% • Formoterol 9 and 18 µg significantly reduced symptom scores, reduced the need for rescue medication, and increased symptom-free days • All 3 doses significantly improved FEV1 (vs placebo) Aalbers et al. ERJ 2002; 19:936

22. p < 0.03 Formoterol (9 and 18 µg BID) significantly increased symptom-free days (71% and 86%) Aalbers et al. ERJ 2002; 19:936

23. All doses of formoterol produced significant increases in FEV1 compared with placebo (p=0.010, 0.039, and 0.001; respectively)

24. Salmeterol Improves Lung Volumes During Exercise

25. A randomised, double-blind, placebo-controlled trial • No of patients: 20 pts with COPD • Study drugs:salbutamol, formoterol, salmeterol, oxitropium and placebo • Measurements: FEV1, FVC, inspiratory capacity (IC), and dyspnea scores • Evaluations: Basal condition and 5, 15, 30, 60 and 120 min after bronchodilator or placebo Di Marco et al. ERJ 2003; 21:86

26. Patients’ Characteristics Di Marco. ERJ 2003; 21:86

27. salbutamol formoterol placebo salmeterol oxitropium *: p< 0.05 compared with baseline. #: time at which plateau was reached, i.e. no further significant change

28. salbutamol formoterol placebo salmeterol oxitropium *: p< 0.05 compared with baseline. #: time at which plateau was reached, i.e. no further significant change

29. Patients with baseline IC <80% (r=0.52; r2=0.27; p<0.001) (r=0.70; r2=0.48; p<0.001) Di Marco. ERJ 2003; 21:86

30. Patients with baseline IC > 80% (r=0.21; r2=0.05; p=0.26) (r=0.38; r2=0.15; p<0.05) Di Marco. ERJ 2003; 21:86

31. Form and salb: increased FEV1 and IC at 5 min • Salm and oxitro: increased IC at 15 and 30 min, respectively • All bronchodilators: reached a maximum increase (plato) in FEV1 and IC at 30 min • LABAs: led to changes in FEV1 at 30, 60 and 120 min significantly greater than oxitropium • Formoterol: elicited changes in IC significantly higher than oxitropium, at 15 and 30 min Di Marco. ERJ 2003; 21:86

32. Wilt et al. Ann Intern Med. 2007;147:639-653 • 8 meta-analyses + 42 RCTs • Interventions: long-acting anticholinergics (n 10), long-acting β2-agonists (n 22), other (n 10) • Question: Which inhaled therapies are effective for treatment and maintenance of stable COPD? • Comments: * Good evidence supports long-acting inhaled anticholinergics, and β2-agonists, as having similar effectiveness in reducing exacerbations

33. * Fair evidence: monotherapy or combination therapy generally fails to achieve clinically significant improvements in respiratory health status * Fair evidence: reductions in hospitalizations are inconsistent and does not permit definitive conclusions about relative effectiveness * Good evidence: monotherapies do not reduce mortality rates Wilt et al. Ann Intern Med. 2007;147:639-653

34. 23 clinical trials, 6061 patients • Significant improvement in lung function in favour of salmeterol (50 μg BID) compared with placebo • Significant differences in health-related quality of life in favour of salmeterol (50 μg BID) compared with placebo • Regular use of salmeterol reduced the incidence of COPD exacerbations compared with placebo (number needed to treat = 21) Cochrane Database of Systematic Reviews 2006, Issue 3.

35. Authors’ judgements about each methodological quality item for each included study

36. Change in FEV1 from baseline to end of the study Boyd 1997 Dauletbaev 2001 Gupta 2002 Hanania 2003 Mahler 2002 SMS 40318 Subtotal (95% CI) Calverley 2003 Chapman 2002 Subtotal (95% CI) Total FEV1 liters FEV1 % pred.

37. 24 people with COPD would need to be treated with salmeterol 50mcg BID in order to prevent one exacerbation in the short term

38. 46 people with COPD would need to be treated with salmeterol 50µg BID in order to prevent one withdrawal due to lack of efficacy

39. Exercise Tolerance (a) Salmeterol 50 µg versus placebo Six minute walk test, Borg score (< 3) : Boyd 1997 Significantly more patients in the salmeterol group had Borg scores <3 compared with placebo (c) Formoterol 18 µg versus placebo Wadbo 2002 Significant increase in shuttle walking distance from baseline in the formoterol group Post-shuttle Borg scores significant improved in favour of formoterol

40. Quality of Life • Significant differences in the total and activity scores of the SGRQ in favour of salmeterol 50 µg BID • Findings from other health status measurements and symptom scores were conflicting

41. A randomized, double-blind trial • Salmeterol 50 μg + fluticasone propionate (FP) 500 μg (BID), placebo, salmeterol alone, or FP • Study period: 3 years • Number of patients: 6112 • End-points: mortality rates, COPD related mortality, annual rate of exacerbations, and adverse effects Calverley et al. NEJM 2007; 356(8): 775-89

42. Mortality Analysis Calverley et al. NEJM 2007; 356(8): 775-89

43. Primary Cause of Death Calverley et al. NEJM 2007; 356(8): 775-89

44. Annual Rate of Exacerbations Calverley et al. NEJM 2007; 356(8): 775-89

45. Health Status (SGRQ) Calverley et al. NEJM 2007; 356(8): 775-89

46. Postbronchodilator FEV1 Calverley et al. NEJM 2007; 356(8): 775-89

47. Adverse Events Calverley et al. NEJM 2007; 356(8): 775-89

48. Effect of Pharmacotherapy on Rate of Decline of Lung Function in COPD: Results from TORCH Study Bartolome. AJRCCM 2008;178:332 • Randomized, double-blind, placebo-controlled study • No of patients: 5343 • Duration: 3 years • Spirometric measurement: every 24 weeks • The adjusted rate of decline in FEV1: - 55 ml/year for placebo - 42 ml/year for salmeterol P = 0.003

49. Safety of Long-acting β2-agonists • Cardiovascular Effects of β-Agonists in Patients with Asthma and COPD: A Meta-Analysis. Salpeter, Chest 2004; 125:2309 • A Benefit-Risk Assessment of Inhaled Long-Acting β2-Agonists in the Management of Obstructive Pulmonary Disease.Sovani, Drug Safety 2004; 27 (10): 689 • Safety of Long-Acting β-Agonists in Stable COPD: A Systematic Review. Rodrigo, CHEST 2008; 133:1079 • Arrhythmias in Patients With Chronic Obstructive Pulmonary Disease (COPD): Occurrence, Frequency and the Effect of Treatment With the Inhaled Long-Acting β2-Agonists Arformoterol and Salmeterol. Hanrahan, Medicine 2008;87:319Y328

50. Cardiovascular Effects of β-Agonists in Patients with Asthma and COPD: A Meta-Analysis. Salpeter, Chest 2004; 125:2309 Author Age Diagnose Bennett 29-54 Asthma Burgess 21-26 Asthma Jartti 11 Asthma Marlin 32-72 Asthma Cr. Bronchitis Wong 18-40 Asthma Cardiovascular effects of beta-agonist use: Single dose- heart rate (bpm)