Which one should be the first choise for moderate COPD?

Long-acting 2-agonists

Dr. Tülay YarkınSB Süreyyapaşa Göğüs Hast. Eğitim Hastanesi

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

2

Spirometric Classification of COPD Severity Based on Post-Bronchodilator FEV1

Stage I: Mild FEV1/FVC <0.70

FEV1 ≥ 80% pred. Stage II: Moderate FEV1/FVC <0.70

50% ≤ FEV1 <80% pred. Stage III: Severe FEV1/FVC <0.70

30% ≤ FEV1 < 50% pred. Stage IV : Very Severe FEV1/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

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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 4

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

5

Breathlessness and Exercise Tolerance in COPD Patients

6

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).

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IV: Very Severe III: Severe II: Moderate I: Mild

Therapy at Each Stage of COPD

FEV1/FVC < 70%

FEV1 > 80% predicted

FEV1/FVC < 70%

50% < FEV1 < 80%

predicted

FEV1/FVC < 70%

30% < FEV1 < 50% predicted

FEV1/FVC < 70%

FEV1 < 30% predicted

or FEV1 < 50% predicted plus chronic respiratory failure

Add regular treatment with one or more long-acting bronchodilators (when needed); Add rehabilitation

Add inhaled glucocorticosteroids if repeated exacerbations

Active reduction of risk factor(s); influenza vaccinationAdd short-acting bronchodilator (when needed)

Add long term oxygen if chronic respiratory failure. Consider surgical treatments

8

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

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Effects of β2-agonists

Provide bronchodilation

Improve quality of life

Improve dypnea

Reduce exacerbations

Anti-inflamatory effect

10

Lipid tabaka

LABA

ATPcAMP

Bronkodilatasyon

Effects of LABAsEffects of LABAs

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Effects of Effects of 22 -ag-agonistonists other than s other than

bronchodilationbronchodilation

Barnes PJ., Science Press Ltd, 1999

LABALABA

↓nötrofiller↓eozinofiller↓nötrofiller

↓eozinofiller

↑mukosilyer hareketlerde artma

↑mukosilyer hareketlerde artma

Hücre membranında

kaçağı azaltma

Hücre membranında

kaçağı azaltma

↑mukosilyer klirens

↑mukosilyer klirens

↓inflamatuar eksüda

↓inflamatuar eksüda

↓lokal inflamasyon

↓lokal inflamasyon

İnflamasyon aracılı doku

hasarının azalması

İnflamasyon aracılı doku

hasarının azalması

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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

13

14Bouros D. Curr Med Research and Opinion 2004;20:58114

Uzun süreli bronkodilatasyon

15

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

Dahl et al. Am J Respir Crit Care Med 2001;164: 778–784

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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: 77817

Twelve-hour profile of mean FEV1 measurements performed following the morning dose of study medications after 12 wk of treatment

Bronchodilator effect of LABAs is fairly stable in COPD pts on regular treatment with these agents

Dahl et al. Am J Respir Crit Care Med 2001;164: 77818

Health Status

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

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

20

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; 19:93621

p < 0.03

Formoterol (9 and 18 µg BID) significantly increased symptom-free days (71% and 86%)

Aalbers et al. ERJ 2002; 19:93622

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

Salmeterol Improves Lung Volumes During Exercise

24

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; 21:8625

Patients’ Characteristics

All patients N= 20

Basal IC <80%pred

N=12

Basal IC >80%pred

N=8

p

IC, %pred 74±3 64 ±2 89 ±2 <0.001

FEV1 %pred 52 ±3 46 ±3 60 ±4 0.01

FRC %pred 134 ± 3 145±8 118±9 0.04

PaO2 mmHg 74 ±2 72 ±2 77 ±2 0.04

Dyspnea score 1.9 ±0.3 2.3 ±0.3 1.5 ±0.3 0.04

Baseline VAS score %

31 ±4 38 ±4 21 ±3 0.03

Smoking histo pack-yrs

46 ± 7 53 ±6 37 ±3 0.04

Di Marco. ERJ 2003; 21:86

26

*: p< 0.05 compared with baseline. #: time at which plateau was reached, i.e. no further significant change

salbutamol

placeboformoterol

salmeterol oxitropium

27

salbutamol

placebo

formoterol

salmeterol oxitropium

*: p< 0.05 compared with baseline. #: time at which plateau was reached, i.e. no further significant change

28

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 29

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; 21:8630

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; 21:8631

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

Wilt et al. Ann Intern Med. 2007;147:639-653

32

* 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 33

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. 34

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

35

Change in FEV1 from baseline to end of the study

Boyd 1997Dauletbaev 2001 Gupta 2002Hanania 2003Mahler 2002SMS 40318Subtotal (95% CI)

Calverley 2003Chapman 2002Subtotal (95% CI)

Total

FEV1

liters

FEV1

% pred.

36

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

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

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

39

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

Quality of Life

40

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): 775-8941

Mortality Analysis

Placebo

(N: 1524)

Salmeterol

(N: 1521)

p

No of deaths, any cause

Probability of death at 3yr- %

231

15.2

205

13.5 0.18

COPD-related deaths

Probability of death at 3-yr- %

91

6.0

93

6.1 0.93

Calverley et al. NEJM 2007; 356(8): 775-8942

Primary Cause of Death

Placebo

(N: 1524)

Salmeterol

(N: 1521)

Cardiovascular, n (%)

Pulmonary, n (%)

Cancer, n (%)

Other, n (%)

Unknown, n (%)

71 (5)

74 (5)

45 (3)

23 (2)

18 (1)

45 (3)

80 (5)

44 (3)

22 (1)

14 (1)

Calverley et al. NEJM 2007; 356(8): 775-8943

Annual Rate of Exacerbations

Placebo

(N: 1524)

Salmeterol

(N: 1521)

Rate Ratio

(95% CI)

p

Moderate/severe exacerbations

1.13 0.97 0.85

(0.78-0.93)

< 0.001

Requiring syst. corticosteroids

0.80 0.64 0.80

(0.72-0.90)

< 0.001

Severe exacerb (requiring hospitalization)

0.19 0.16 0.82

(0.69–0.96)

0.02

Calverley et al. NEJM 2007; 356(8): 775-8944

Health Status (SGRQ)

Placebo

(N = 1524)

Salmeterol

(N = 1521)

p

No of pts completed questionnaire

1231 1232

No of pts included analysis

928 980

Mean baseline score

48.4 49.4

Mean change over 3 years (unit)

+ 0.2 - 0.8 0.06

Calverley et al. NEJM 2007; 356(8): 775-8945

Postbronchodilator FEV1

Placebo

(N = 1524)

Salmeterol

(N = 1521)

p

No of pts included analysis

1261 1334

Mean baseline FEV1 (liters)

1.26 1.23

Mean change over 3 year (liters)

- 0.062 - 0.021 < 0.001

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

46

Adverse Events

Reported during treatment

(% of pts)

Placebo

(N = 1524)

Salmeterol

(N = 1521)

Any event 90 90

Serious event 41 40

Drug-related event 13 12

Event resulting withdrawal of study drug

24 20

Calverley et al. NEJM 2007; 356(8): 775-8947

Effect of Pharmacotherapy on Rate of Decline of Lung Function in COPD: Results from TORCH Study

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

Bartolome. AJRCCM 2008;178:332

P = 0.003

48

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

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Cardiovascular Effects of β-Agonists in Patients with Asthma and COPD: A Meta-Analysis.

Salpeter, Chest 2004; 125:2309

Cardiovascular effects of beta-agonist use: Single dose- heart rate (bpm)

Author Age Diagnose

Bennett 29-54 Asthma

Burgess 21-26 Asthma

Jartti 11 Asthma

Marlin 32-72 Asthma

Cr. Bronchitis

Wong 18-40 Asthma

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Author Age Diagnose Duration

Bensch 35 Asthma 3mo Boyd 47 Asthma 3mo Fitzpatrick 39 Asthma 2wk Milgrom 9 Asthma 3wk Nathan 12-73 Asthma 3mo Pearlman 27-35 Asthma 4wk Siegel 18-55 Asthma 2wk Spector 14-65 Asthma 3d Anderson 52 Asthma 3d D’Urzo 46 Asthma 6mo Yates 26 Asthma 2wk

Salpeter, Chest 2004; 125:230951

Critics of Salpeter’s Meta-Analysis

Study duration: a very wide range (3d-1 yr) Patients’ age: a very wide range (from 9 to 73) Patients: asthma, chronic bronchitis, COPD Interventions: SABAs, LABAs Methodologic quality assesment: by interrater

agreement instead of 5-point scale (0=worst to 5=best) describe by Jadad

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Adverse effects: predictable, rarely a problem Serious adverse effects: unusual with usual doses

(salm 50µg bid, form 12µg bid), more common with higher doses

LABAs have been more effective than IPRA in patients with COPD, with no difference in adverse events

More information is needed on the relative merits of tiotropium bromide compared with the long-acting β2-agonists in these patients

53

Inclusion criteria of the studies: Target population: age >35yr, only COPD (GOLD) Intervention: only LABA Lenght of treatment: 4 week Design: RCT (paralel group or crossover) Methodologic quality assesment: 5-point scale (like

Cochrane reviews) Primary outcomes: severe exacerbations, all cause

mortality, respiratory deaths Secondary outcomes: Δ FEV1, ΔSGRQ, need for

rescue medication54

A total 27 RCT, All of good quality (Jadad>2) No of pts: 20.527 Mean age: 63.3±10.3 yr GOLD severity: 2-3 (moderate-severe) Mean FEV1: 43%

Rodrigo et al. CHEST 2008; 133:1079

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Main Results

Exacerbations: LABA vs placebo: 14 trialsOverall cumulative insidence: 7.5 % with LABA

10.8 % with placeboRate reduction: 3.3%

Mortality:Respiratory deaths: no significant difference between LABA and placebo groups

Significant benefits in airflow limitation, health-related quality of life, and use of rescue medication with LABAs

Rodrigo et al. CHEST 2008; 133:1079 56

No pf patients: 1426 Study duration: 12 week Interventions: a) nebulized arformoterol 15µg

BID, b) 25µg BID, or c) 50µg QD; d) salmeterol MDI 42µg BID; or e) placebo

The 24-hour Holter monitoring data: pretreatment; at weeks 0 (first day), 6, and 12

A total 5226 Holter recordings

Hanrahan, Medicine 2008;87:319-32857

At baseline: atrial fibrillation/flutter (0.1%), nonsustained ventricular tachycardia (3.1%), >10 beat ventricular tachycardia (0.3%). Atrial tachycardia: 41.8%

Treatment-emergent atrial tachycardia ranged from 27% to 32% and was non-significantly higher, by ~ 2%-5% (p = 0.70), in the LABA groups than placebo group

The rates of the other more serious arrhythmias did not increase with LABA treatment

All treatment groups (LABA and placebo) had consistent small decreases from baseline in mean 24-hour and maximum hourly heart rate

Hanrahan, Medicine 2008;87:319-32858

Sonuç 1

Uzun etkili beta-agonistler KOAH’da etkili bronkodilatasyon sağlar Semptomları azaltır Atak sıklığını ve hastane yatışlarını azaltır Yaşam kalitesini yükseltir Akciğer fonksiyonlarındaki azalma hızını

etkiler Yan etkileri öngörülebilir ve nadiren ciddidir

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60

Sonuç 2

İnhale steroidler ile additif ve sinerjik etki Mukosiliyer klirensi arttırır Etkileri hızlı başlar, dolayısıyla hastada hızla

semptomatik düzelme olur Formoterol ataklarda da kullanılabilir Uyum sağlayamayan hastalarda per oral

verilebilir ve bu şekli çok ucuzdur

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…teşekkür ederim. 61