ERS Vienna 2009 Congress September 12–16, 2009

PG1 – EU GRACE Network Full-day Course:

the community: what’s new?

Saturday, September 12, 2009 09:30–17:30

Room Schubert 5

Vaccination and preventive measures for LRTIs in

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Debate: is there a place for oral mucolytics in the prevention of LRTI? – CON

Dr Marc Miravitlles Servicio de Neumologia Institut Clínic del Tòrax

Hospital Clinic Villarroel 170

8036 Barcelona, Spain marcm@separ.es

Aims 1. Describe the main clinical studies with mucolytics in chronic lung disease in adults and

understand the methodology 2. Compare the results of mucolytics and other drugs in prevention of exacerbations in chronic

bronchitis and COPD 3. Define the role of mucolytics in the contemporary management of COPD

Summary Obstructive lung diseases, particularly chronic obstructive pulmonary disease (COPD) are one of the main causes of morbidity and mortality in developed countries. It is estimated that more than 15 million persons in the United States have COPD, and more than 12 million have chronic bronchitis, with this numbers having grown over recent decades. The age-adjusted mortality rate from COPD doubled from 1970 to 2002 in the United States, whereas rates from stroke and heart disease decreased by 63% and 52%, respectively (1). The chronic and progressive course of COPD is often aggravated by short periods of increasing symptoms, particularly increasing cough, dyspnea and production of sputum which can become purulent. Exacerbations have demonstrated to have a negative impact on the quality of life of patients with COPD (2,3). Furthermore, acute exacerbations are the most frequent cause of medical visits, hospital admissions and death among patients with chronic lung disease. There is evidence that these patients with chronic bronchitis and/or COPD have mucociliary dysfunction with increased sputum production and impaired ability to clear it (4,5). There is evidence that chronic mucus hypersecretion is associated both with an accelerated decline in FEV1 and increased mortality in COPD (6,7). It is less clear whether this is due to a causal relationship or whether mucus hypersecretion is just a marker for more severe disease. However it is not difficult to imagine how sputum retention may contribute to airflow obstruction and how it might also lead to an increase in infections because of reduced clearance of microbes. If this was the case, the use of drugs that may help to eliminate the excessive mucus production should have an impact in bronchial bacterial colonisation and the development of exacerbations. Although mechanistic studies of the anti-inflammatory and anti-oxidant actions of mucolytics are of interest the most important question is whether they influence clinical outcomes in patients with chronic bronchitis and/or COPD. A recent review was published in the Cochrane Database of Systematic Reviews (CDSR) in 2006 (8). There were 7335 participants in the 26 studies selected for inclusion and the primary outcome measure was the number of acute exacerbations which were defined as an increase in cough and in the volume and/or purulence of sputum. All of the studies were randomised, double blind and placebo controlled with a parallel group design. The duration of the studies ranged from 2-36 months. The mean age of the participants in the different studies ranged from 40 to 67 years. The most studied mucolytic was N-acetylcysteine which accounted for 13 studies. There were 3 studies with ambroxol. No other mucolytic accounted for more than two studies. Twenty-one of the studies were conducted in patients with chronic bronchitis although it is likely that a proportion of these participants in these studies would have also had airflow obstruction and would have met the definition of COPD. Five studies only enrolled participants who had a diagnosis of COPD.

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There were significantly fewer exacerbations with mucolytics than with placebo. In the most recent review the weighted mean difference was -0.05 exacerbations per patient per month (95% CI -0.05 to -0.04, P<0.01) and this represents a 20% reduction in exacerbations. However, the largest clinical trial with mucolytics, the BRONCUS study, had negative results. It enrolled 523 patients of whom half were randomised to NAC 600mg once daily (9). The findings warrant a more detailed discussion for a number of reasons. This was one of the larger studies with NAC, it enrolled patients with COPD (FEV1 had to be between 40 and 70% of predicted), it measured quality of life and participants were treated for three years which was long enough to determine if there was an effect on decline in FEV1 and in frequency of exacerbations. There was however no difference in the rate of decline in FEV1 with NAC compared with placebo. The exacerbation rates in BRONCUS did not differ between NAC (1.25 exacerbations per year) and placebo (1.31 exacerbations per year). This would appear to represent a major difference between the results of this trial and the systematic review but interestingly in a prespecified subgroup analysis the subjects who were not taking inhaled steroids (ICS) (n=155) had fewer exacerbations with NAC (0.96 exacerbations per year) than with placebo (1.29 exacerbations per year). In this subgroup analysis the difference was significant (Hazard Ratio 0.79, 95% CI 0.63 to 0.99, p=0.04). The reduction in exacerbations seen in patients not taking ICS is comparable to that seen in the meta-analysis. Quality of life was measured using the St George’s Respiratory Questionnaire or the EuroQoL-5D questionnaire. There were no significant differences between NAC and placebo with either questionnaire. Although the results of the BRONCUS study appears to be at odds with the systematic review it is important to remember that most of the trials reported in the systematic review were conducted at a time when very few patients with COPD (let alone chronic bronchitis) were on treatment with ICS. It is possible that NAC acts to reduce exacerbations in a similar way to ICS and the benefit of NAC and other mucolytics to reduce exacerbations are not observed if the patients are on concomitant treatment with ICS. Another of the largest studies with mucolytics in COPD observed an increase in the incidence of patients without exacerbations during a six-month winter period in patients treated continously with carbocysteine compared to placebo (10). However, no information on concomitant medication is provided and the groups were disbalanced with respect to severity. Patients in the carbocysteine arm had amean FEV1 of 4.6 L compared with 3.3 L in the placebo group (10); therefore, making the interpretation of the results very difficult. In the same line, the results of a recent large, placebo-controlled trial, with carbocysteine perfomed in China observed a significant reduction in the frequency of exacerbations in patients treated with the active drug, but only 16.7% of the participants were concomitantly treated with ICS (11). This is particularly important because in European countries aproximately 60-70% of COPD patients managed in Primary Care are treated with ICS (12), and guidelines recommed the use of these drugs in COPD patients with an FEV1<50% (or 60% predicted in the case of salmetrol/fluticasone) and frequent exacerbations (13). In this setting, is still there a place in therapy for mucolytics? If mucolytics reduce exacerbations of COPD one would anticipate that their use would also lead to a reduction in hospitalisations for exacerbations but few of the studies have reported on hospitalisations and it is not possible to come to a firm conclusion on the basis of the randomised, controlled trials. A Dutch study has taken another approach to this question. They linked hospital records of admissions for COPD to a pharmacy database which recorded the outpatient drug use for 450,000 patients in the Netherlands (14). They identified 1,219 patients who were hospitalised between 1986 and 1989. They then compared those who received NAC immediately after discharge and those who didn’t. The use of NAC was associated with a significantly lower risk of rehospitalisation (Relative Risk = 0.67, 95% CI 0.53-0.85). In this population 36% were on treatment with ICS compared with 70% in the BRONCUS study. Clearly an observational study like this has the potential to be confounded. In fact, a similar study perfomed in Canada suggested that ICS prevented subsequent hospitalisation (15), but further analyses demonstrated that the results were affected by the immortal time bias and no effect of ICS on reduction of hospitalisation existed (16). Conclusions The use of mucolytics for the treatment of COPD has been controversial. They are used infrequently in the United Kingdom, North America and Australasia. Although they are used more often in continental Europe there is uncertainty about their place in therapy. The GOLD guidelines note that a

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reduction in exacerbations has been observed with mucolytics but they did not feel that the evidence warranted the use of mucolytics as part of the standard management of COPD (13). The BRONCUS study which is perhaps the best conducted study failed to confirm the effect of NAC on exacerbations. Nonetheless in the BRONCUS study a reduction in exacerbations was seen in the subgroup of patients who were not using ICS. In the current situation in which up to 70% of patients with COPD (particularly those with frequent exacerbations) are treated with ICS (12,17), the role of mucolytics in the management of COPD is not clear or even unnecesary. References

1. Jemal A, Ward E, Hao Y, Thun M. Trends in the leading causes of death in the United States, 1970-2002. JAMA 2005; 294: 1255-1259.

2. Seemungal TAR, Donaldson GC, Paul EA, Bestall JC, Jeffries DJ, Wedzicha JA. Effect of exacerbation on quality of life in patients with chronic obstructive pulmonary disease. Am J Respir Crit Care Med 1998; 157: 1418-1422.

3. Miravitlles M, Ferrer M, Pont A, Zalacain R, Alvarez-Sala JL, Masa JF, et al. Exacerbations impair quality of life in patients with chronic obstructive pulmonary disease. A two-year follow-up study. Thorax 2004; 59: 387-395.

4. Goodman RM, Yergin BM, Landa JF, Golivanux MH.. Relationship of smoking history and pulmonary function tests to tracheal mucous velocity in nonsmokers, young smokers, ex-smokers and patients with chronic bronchitis. Am Rev Respir Dis 1978; 117: 205-14.

5. Santa Cruz R, Landa J. Hirsh J. Tracheal mucous velocity in normal man and patients with obstructive lung disease. Am Rev Respir Dis 1974; 109: 458-63.

6. Vestbo J, Prescott E, Lange P. Association of chronic mucus hypersecretion with FEV1 decline and chronic obstructive pulmonary disease morbidity. Copenhagen City Heart Study Group. Am J Respir Crit Care Med 1996; 153: 1530-5.

7. Lange P, Nyboe J, Appleyard M, Jensen G, Schnor P. Relation of ventilatory impairment and of chronic mucus hypersecretion to mortality from chronic obstructive lung disease and all causes. Thorax 1990; 45: 579-85.

8. Poole PJ, Black PN. Mucolytic agents for chronic bronchitis or chronic obstructive pulmonary disease. Cochrane Database Syst Rev 2006; Jul 19: 3:CD001287.

9. Decramer M, Rutten-van Mölken, Dekhuijzen PNR, Troosters T, van Herwarden C, Pellegrino R, van Schayk CPO, Oliveri D, Del Donno M, De Backer W, Lankhorst I, Ardia A. Effects of N-acetylcysteine on outcomes in chronic obstructive pulmonary disease (Bronchitis Randomized on NAC Cost-Utility Study, BRONCUS): a randomised placebo-controlled trial. Lancet 2005; 365: 1552-1560.

10. Allegra L, Cordaro CI, Grassi C. Prevention of acute exacerbations of chronic obstructive bronchitis with carbocysteine lysine salt monohydrate: a multicenter, double-blind, placebo-controlled trial. Respiration 1996; 63: 174-180.

11. Zheng JP, Kang J, Huang SG, Chen P, Yao WZ, Yang L, et al. Effect of carbocisteine on acute exacerbation of chronic obstructive pulmonary disease (PEACE study): a randomised placebo-controlled study. Lancet 2008, 371: 2013-2018.

12. Miravitlles M, de la Roza C, Naberan K, Lamban M, Gobartt E, Martín A. Use of spirometry and patterns of prescribing in COPD in primary care. Respir Med 2007; 101: 1753-1760.

13. Rabe KF, Hurd S, Anzueto A, Barnes PJ, Buist SA, Calverley P, et al. Global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease: GOLD executive summary. Am J Respir Crit Care Med 2007: 176: 532-555.

14. Gerritts CMJM, Herings RMC, Leufkens HGM, Lammers J-W J. N-acetylcysteine reduces the risk of re-hospitalisation among patients with chronic obstructive pulmonary disease. Eur Respir J 2003; 21: 795-798.

15. Sin DD, Tu JV. Inhaled corticosteroids and the risk of mortality and readmission in elderly patients with chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2001; 164: 580-584.

16. Suissa S. Inhaled steroids and mortality in COPD: bias from unaccounted immortal time. Eur Respir J 2004; 23: 391-395.

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17. Miravitlles M, Murio C, Tirado-Conde G, Levy G, Muellerova H, Soriano JB, Ramirez-Venegas A, Ko FWS, Canelos-Estrella B, Giugno E, Bergna M, Chérrez I, Anzueto A. Geographic differences in clinical characteristics and management of COPD: the EPOCA study. Int J COPD 2008; 3: 803-814.

Evaluation

1. Which of the following is false regarding clinical trials with mucolytics: a. They consistently show a reduction in hospitalisations compared with placebo b. There is a reduction in exacerbations with mucolytics in patients not treated with

inhaled corticosteroids c. Mucolytics are well tolerated d. There is no signficant difference in results between NAC and carbocysteine

2. The BROCHUS trial with NAC versus placebo:

a. Followed more than 500 patients for 4 years b. Demonstrated a reduction in the rate of decline of FEV1 in patients treated with NAC c. Did not show any difference in the rate of exacerbations between the 2 treatment arms d. Patients with concomitant teratment with theophyllines showed a trend towards a

reduction in exacerbations in the NAC arm

3. Which is the role of mucolytics in COPD: a. Should be used in moderate to severe patients not treated with inhaled corticosteroids

and with frequent exacerbations. b. Should be used in moderate to severe patients with frequent exacerbations irrespective

of concomitant medication. c. Should be used in early disease irrespective of the frequency of exacerbations d. They have no role in COPD treatment

Answers on page 109

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Oral mucolytics in COPD: CON

Marc MiravitllesServicio de Neumología

Hospital Clínic. Barcelonamarcm@clinic.ub.es

IJCP 2008;62:585-592

Types of COPD

Chronic cough andsputum as riskfactors for frequentexacerbations

Burgel et al. Chest 2009; 135: 975-982

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NAC and COPD

Mean epithelial lining fluid and BALF concentrations in a control group and patients

treated with NAC 600 mg thrice daily for 5 days

Bridgeman et al. Thorax 1994; 49: 670-675

Tatsumi et al. JAGS 2007;55:1884-1885

Carbocysteinein COPD

Small studyDisbalance in groupsNo ICSVery low rate ofexacerbations

Yasuda et al. JAGS 2006;54:378-379

Carbocysteine in COPD

NO TT withICS

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Oral NAC and exacerbations

Dekhuijzen. Eur Respir J 2004;23:629-636

Prevention ofexacerbations withNAC compared to

placebo. Arrows show mean

values

Dekhuijzen. Eur Respir J 2004;23:629-636

Oral NAC and exacerbations

Poole & Black. BMJ 2001;322:1271-1274

Mucolytics and COPD

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Ambroxol and exacerbations

Malerba et al. Pulm Pharmacol Ther 2004;17:27-34.

One-year study onmild-moderateCOPD.Never smokers 25% ICS were forbidden

Carbocysteine in COPD

Allegra et al. Respiration 1996; 63: 174-180

Allegra et al. Respiration 1996; 63: 174-180

Carbocysteine in COPD

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Gerrits et al. ERJ 2003; 21: 795-798

Risk ofreadmission tohospital forCOPD according totreatment withNAC

NAC and re-hospitalisation

Sin & Tu. AJRCCM 2001;164:580-584

Ontario study

Death

Death

0

0

Time zero:Cohort entry

ICS Rx filled

ICS user

ICS non-user

Unexposed and immortal time period

IMMORTAL TIME BIAS

Suissa et al. Proc Am Thorac Soc 2007;4:535-542

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TORCH

Calverley et al NEJM 2007

Cochrane Library 2009, issue 2

Mucolytics in LRTI

Cochrane Library 2009, issue 2

Mucolytics in LRTI

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Cochrane Library 2009, issue 2

Mucolytics in LRTI

Cochrane Library 2009, issue 2

Mucolytics in LRTI

Oral NAC and COPD

Decramer et al. Lancet 2005;365:1552-60

BRONCHUS study:523 patients

followed for 3 yearsSame decline in

FEV1 in bothgroups of treatment.

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Decramer et al. Lancet 2005;365:1552-60

BRONCHUS study: No effect on HRQL.

Oral NAC and COPD

Decramer et al. Lancet 2005;365:1552-60

Group NAC Placebo RR (95%CI) p

All 693 658 0.99 (0.89-1.1) 0.847

ICS 563 471 1.06 (0.93-1.2) 0.359

No ICS 130 187 0.79 (0.63-0.98) 0.040

No effect on frequency of exacerbations.

Oral NAC and COPD

Zheng et al. Lancet 2008;371:2013-2018

Prevention of exacerbationswith carbocysteine

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Zheng et al. Lancet 2008;371:2013-2018

Prevention of exacerbationswith carbocysteine

One-year RCT with 709 patients from 22 centres in China. Mean FEV1=44%, only 15% received ICS and 28% xanthines.

Ex per pt/yr

Placebo 1.35 (0.06)

Carbocysteine 1.01 (0.06)

Reduction 0.75 (0.62-0.92)

Incidence of exacerbations

0,5

0,6

0,7

0,8

0,9

1

1,1

1,2

- 25 %

- 14%

0.85

0.73

1.13

0.85

Exac

erba

tions

per

pat

ient

-ye

ar

UPLIFT TORCHPlacebo

SFCControl

Tiotropium

“Floor”

Miravitlles & Anzueto. Int J COPD 2009;4:185-201

Exacerbations and FEV1

Miravitlles et al. Int J COPD 2008; 3: 803-814

R= -0.256; p<0.001

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AUC of sputum inflammatory markers. RCT of tiotropiumor placebo in 142 pts with mean FEV1=50%.

Reduction of exacerbations of 52% with TIO (p=0.001)

P=0.34 P=0.043 P=0.079

Powrie et al. ERJ 2007;30:472-478

Tiotropium and E-COPD

Time to eventanalysis ofsurgicalresponders(improvement> 200 ml), nonrespondersand controls

Washko et al. AJRCCM 2008;177:164-169

Prevention of E-COPD

Forms of COPD

Snoeck-Stroband et al. ERJ 2008;31:70-77

Percentages ofeosinophils andmacrophages in induced sputum in COPD patients withor without chronicbronchitis

70

0

0,4

0,8

1,2

1,6

2

>50% <50%

Fluticasona Placebo

Ex/yr

Reduction ofexacerbationswith Fluticasone.FEV1<50% (391)FEV1>50% (359)

Jones et al. ERJ 2003;21:68-73

P=0.02

P=0.45

Inhaled corticosteroids in COPD

Kardos et al. AJRCCM 2007;175:144-149.

Reduction in frequency ofexacerbations: 35%

Estimated treatmenteffect ratio: 0.65 (95%CI= 0.57-0.76)

LABAs and ICs in COPD

Tiotropium + combination in COPD

Aaron et al. Ann Intern Med 2007;146:545-555

Outcome Tio Tio + Sal Tio + Flu/Sal

Patients with ex. 62.8 64.8-2 (-12 to 9)

602.8 (-8 to 14)

Ex. per patient-year 1.61 1.751.1 (0.8 to 1.3)

1.370.85 (0.6 to 1.1)

Urgent visits 185 1841.06 (0.9 to 1.3)

1490.81 (0.6 to 1.01)

Hospitalizations for COPD 49 380.83 (0.5 to 1.3)

260.53 (0.3 to 0.8)

All –cause hospitalizations 62 480.83 (0.6 to 1.2)

410.67 (0.4 to 0.99)

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Miravitlles et al. Respir Med 2007; 101: 1753-1760

Treatment of COPD in PC

Treatment of COPD

Miravitlles et al. Int J COPD 2008; 3: 803-814

Time to the firstexacerbation. Theophylline 100 mg/12 h vs placebo.Frequency ofexacerbations:T= 0.98 (1.3)Pla= 2.07 (2.7)P=0.036

Zhou et al. Respirology 2006;11:603-610

Theophylline in COPD

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Theophyllineand ICS

Cosío et al. Thorax 2009; 64: 424-429

Mean levels ofinflammatory markersin sputum in patientswith exacerbations ofCOPD treated with oral steroids with or withoutlow-dose theophylline

Bronchial colonisation

Relationshipbetween LABC and exacerbationfrequency

Patel et al. Thorax 2002;57:759-764

Prevention of exacerbationswith macrolides

Proportion ofpatients withoutan exacerbationvs time to thefirst exacerbationin placebo andmacrolide arms(p=0.02)

Seemungal et al. AJRCCM 2008;178:1139-1147

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119 patients included

Not colonized61

High bacterial load (≥106)36

Colonized58

Low bacterial load (< 106)22

Miravitlles et al. ERJ 2009 (in press)

Bronchial colonisation

Colonisation at 2 and8 weeks.

Bottom: persistenceUpper: acquired

*p<0.01

Bronchial colonisation

Miravitlles et al. ERJ 2009 (in press)

Mod-severe CBstable phase

Moxi 400mgOD x 5 days

Screened & Randomized

Primary variable:no. of

exacerbations

PlaceboOD x 5 days

Pulse#2

Pulse#2

8 wks

Pulse#6

Pulse#6

8 wks

ET

8 wks 8 wks

ET

FU#1

8 wks

FU#1

FU#3

FU#3

Secondary variables:•no. of exacerbations •diff in lung function•HEOR•QoL, etc.

48 week treatment period 24 week follow-up period

N=1132

Trialoverview

74

*adjusted for region and pre-therapy %PFEV1

Clinical efficacyPurulent/muco-purulent sputum

GOLD Guidelines

Rabe et al. AJRCCM 2007;176:532-555

Mild

Increasing Disability and Lung Function Impairment

Infrequent AECOPD(< 1/year)

Frequent AECOPD(> 1/year)

Optimal Pharmacotherapy in COPD

LAAC or LABA+ SABA prn

LAAC + LABA + SABA prn

LAAC + ICS/LABA + SABA prn

LAAC + ICS/LABA +SABA prn

SABD prnpersistent disability

LAAC + SABA prnor

LABA + SABA prn

persistent disability

LAAC + ICS/LABA +SABA prn +/- Theophyline

persistent disability

Moderate Severe

persistent disability

O’Donnell et al. Can Respir J 2007; 14 (Suppl B): 5-32

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Frequent AECOPD(> 1/year requiring systemic steroids or antibiotics)

Long-acting anticholinergic (LAAC) +

Inhaled corticosteroid/Long-acting beta-2-agonist (ICS/LABA)

+Short-acting beta-2-agonist (SABA) prn

Consider adding Theophylline

persistent disability

Can Respir J 2007;14(Suppl B):3B-32B.

Optimal Pharmacotherapy of Moderate to Severe COPD

Conclusions• No changes in mucus viscosity.

• No increase in glutation in BAL.

• No impact in bronchial colonisation.

• Most studies are small, not wellcharacterised COPD.

• The best study was negative.

• Possible effect in untreated patients (?).

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Answers to evaluation questions

Debate: is there a place for oral mucolytics in the prevention of LRTI? – CON 1. b 2. c 3. a

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Faculty disclosure forms

Marc Miravitlles has received honoraria for consultancy and lecturing from Bayer Schering. Wisia Wedzicha is the advisory board member of GSK, Astra Zeneca, Boehringer Ingelheim, Pfizer and Novartis. He has received lecture fee from GSK, Astra Zeneca, Boehringer Ingelheim, Pfizer and Novartis.

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