ERS Vienna 2009 Congress                   September 12–16, 2009 PG1 – EU GRACE Network Full-day Course:Vaccination and pr...
Debate: is there a place for oral mucolytics in the prevention of LRTI? – CON                                         Dr M...
There were significantly fewer exacerbations with mucolytics than with placebo. In the most recentreview the weighted mean...
reduction in exacerbations has been observed with mucolytics but they did not feel that the evidencewarranted the use of m...
17. Miravitlles M, Murio C, Tirado-Conde G, Levy G, Muellerova H, Soriano JB, Ramirez-       Venegas A, Ko FWS, Canelos-Es...
Oral mucolytics in COPD:                          CON                                 Marc Miravitlles                    ...
NAC and COPD                Mean epithelial lining fluid and BALF       concentrations in a control group and patients    ...
Oral NAC and exacerbations     Prevention ofexacerbations with NAC compared to         placebo.Arrows show mean           ...
Ambroxol and exacerbationsOne-year study onmild-moderateCOPD.Never smokers 25%ICS were forbidden       Malerba et al. Pulm...
NAC and re-hospitalisationRisk ofreadmission tohospital forCOPDaccording totreatment withNAC                          Gerr...
TORCHCalverley et al NEJM 2007                        Mucolytics in LRTI                            Cochrane Library 2009,...
Mucolytics in LRTI                         Cochrane Library 2009, issue 2                       Mucolytics in LRTI        ...
Oral NAC and COPD               BRONCHUS study: No effect on HRQL.              Decramer et al. Lancet 2005;365:1552-60   ...
Prevention of exacerbations                                               with carbocysteine                              ...
Tiotropium and E-COPD    P=0.34               P=0.043              P=0.079  AUC of sputum inflammatory markers. RCT of tio...
Inhaled corticosteroids in COPD  Ex/yr      2                                           P=0.02     1,6                    ...
Treatment of COPD in PC         Miravitlles et al. Respir Med 2007; 101: 1753-1760                          Treatment of C...
Theophylline        and ICS Mean levels of inflammatory markers in sputum in patients with exacerbations of COPD treated w...
Bronchial colonisation                                  119 patients included                    Colonized                ...
Clinical efficacy            Purulent/muco-purulent sputum    *adjusted for region and pre-therapy %PFEV1                 ...
Optimal Pharmacotherapy of Moderate                     to Severe COPD                Frequent AECOPD  (> 1/year requiring...
Answers to evaluation questionsDebate: is there a place for oral mucolytics in the prevention of LRTI? – CON   1. b   2. c...
Faculty disclosure formsMarc Miravitlles has received honoraria for consultancy and lecturing from Bayer Schering.Wisia We...
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Debate on mucolytics

  1. 1. ERS Vienna 2009 Congress September 12–16, 2009 PG1 – EU GRACE Network Full-day Course:Vaccination and preventive measures for LRTIs in the community: what’s new? Thank you for viewing this document. We would like to remind you that this material is theproperty of the author. It is provided to you by the ERSfor your personal use only, as submitted by the author. © 2009 by the author Saturday, September 12, 2009 09:30–17:30 Room Schubert 5
  2. 2. 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.esAims 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 COPDSummaryObstructive lung diseases, particularly chronic obstructive pulmonary disease (COPD) are one of themain causes of morbidity and mortality in developed countries. It is estimated that more than 15million 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 COPDdoubled from 1970 to 2002 in the United States, whereas rates from stroke and heart disease decreasedby 63% and 52%, respectively (1).The chronic and progressive course of COPD is often aggravated by short periods of increasingsymptoms, 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 admissionsand death among patients with chronic lung disease.There is evidence that these patients with chronic bronchitis and/or COPD have mucociliarydysfunction with increased sputum production and impaired ability to clear it (4,5). There is evidencethat chronic mucus hypersecretion is associated both with an accelerated decline in FEV1 andincreased mortality in COPD (6,7). It is less clear whether this is due to a causal relationship orwhether mucus hypersecretion is just a marker for more severe disease. However it is not difficult toimagine how sputum retention may contribute to airflow obstruction and how it might also lead to anincrease in infections because of reduced clearance of microbes. If this was the case, the use of drugsthat may help to eliminate the excessive mucus production should have an impact in bronchialbacterial colonisation and the development of exacerbations.Although mechanistic studies of the anti-inflammatory and anti-oxidant actions of mucolytics are ofinterest the most important question is whether they influence clinical outcomes in patients withchronic bronchitis and/or COPD. A recent review was published in the Cochrane Database ofSystematic Reviews (CDSR) in 2006 (8). There were 7335 participants in the 26 studies selected forinclusion and the primary outcome measure was the number of acute exacerbations which weredefined 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 differentstudies ranged from 40 to 67 years. The most studied mucolytic was N-acetylcysteine whichaccounted for 13 studies. There were 3 studies with ambroxol. No other mucolytic accounted for morethan two studies. Twenty-one of the studies were conducted in patients with chronic bronchitisalthough it is likely that a proportion of these participants in these studies would have also had airflowobstruction and would have met the definition of COPD. Five studies only enrolled participants whohad a diagnosis of COPD. 57
  3. 3. There were significantly fewer exacerbations with mucolytics than with placebo. In the most recentreview 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. Itenrolled 523 patients of whom half were randomised to NAC 600mg once daily (9). The findingswarrant a more detailed discussion for a number of reasons. This was one of the larger studies withNAC, it enrolled patients with COPD (FEV1 had to be between 40 and 70% of predicted), it measuredquality of life and participants were treated for three years which was long enough to determine ifthere was an effect on decline in FEV1 and in frequency of exacerbations. There was however nodifference in the rate of decline in FEV1 with NAC compared with placebo. The exacerbation rates inBRONCUS did not differ between NAC (1.25 exacerbations per year) and placebo (1.31exacerbations per year). This would appear to represent a major difference between the results of thistrial and the systematic review but interestingly in a prespecified subgroup analysis the subjects whowere not taking inhaled steroids (ICS) (n=155) had fewer exacerbations with NAC (0.96 exacerbationsper year) than with placebo (1.29 exacerbations per year). In this subgroup analysis the difference wassignificant (Hazard Ratio 0.79, 95% CI 0.63 to 0.99, p=0.04). The reduction in exacerbations seen inpatients not taking ICS is comparable to that seen in the meta-analysis. Quality of life was measuredusing the St George’s Respiratory Questionnaire or the EuroQoL-5D questionnaire. There were nosignificant 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 isimportant to remember that most of the trials reported in the systematic review were conducted at atime when very few patients with COPD (let alone chronic bronchitis) were on treatment with ICS. Itis possible that NAC acts to reduce exacerbations in a similar way to ICS and the benefit of NAC andother mucolytics to reduce exacerbations are not observed if the patients are on concomitant treatmentwith ICS. Another of the largest studies with mucolytics in COPD observed an increase in theincidence of patients without exacerbations during a six-month winter period in patients treatedcontinously with carbocysteine compared to placebo (10). However, no information on concomitantmedication is provided and the groups were disbalanced with respect to severity. Patients in thecarbocysteine 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 recentlarge, placebo-controlled trial, with carbocysteine perfomed in China observed a significant reductionin the frequency of exacerbations in patients treated with the active drug, but only 16.7% of theparticipants were concomitantly treated with ICS (11). This is particularly important because inEuropean countries aproximately 60-70% of COPD patients managed in Primary Care are treated withICS (12), and guidelines recommed the use of these drugs in COPD patients with an FEV1<50% (or60% predicted in the case of salmetrol/fluticasone) and frequent exacerbations (13). In this setting, isstill there a place in therapy for mucolytics?If mucolytics reduce exacerbations of COPD one would anticipate that their use would also lead to areduction in hospitalisations for exacerbations but few of the studies have reported on hospitalisationsand it is not possible to come to a firm conclusion on the basis of the randomised, controlled trials. ADutch study has taken another approach to this question. They linked hospital records of admissionsfor COPD to a pharmacy database which recorded the outpatient drug use for 450,000 patients in theNetherlands (14). They identified 1,219 patients who were hospitalised between 1986 and 1989. Theythen compared those who received NAC immediately after discharge and those who didn’t. The use ofNAC was associated with a significantly lower risk of rehospitalisation (Relative Risk = 0.67, 95% CI0.53-0.85). In this population 36% were on treatment with ICS compared with 70% in the BRONCUSstudy. Clearly an observational study like this has the potential to be confounded. In fact, a similarstudy perfomed in Canada suggested that ICS prevented subsequent hospitalisation (15), but furtheranalyses demonstrated that the results were affected by the immortal time bias and no effect of ICS onreduction of hospitalisation existed (16).ConclusionsThe use of mucolytics for the treatment of COPD has been controversial. They are used infrequentlyin the United Kingdom, North America and Australasia. Although they are used more often incontinental Europe there is uncertainty about their place in therapy. The GOLD guidelines note that a 58
  4. 4. reduction in exacerbations has been observed with mucolytics but they did not feel that the evidencewarranted the use of mucolytics as part of the standard management of COPD (13). The BRONCUSstudy 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 patientswho 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 inthe 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. 59
  5. 5. 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 treatmentAnswers on page 109 60
  6. 6. Oral mucolytics in COPD: CON Marc Miravitlles Servicio de Neumología Hospital Clínic. Barcelona marcm@clinic.ub.es IJCP 2008;62:585-592 Types of COPDChronic cough andsputum as riskfactors for frequentexacerbations Burgel et al. Chest 2009; 135: 975-982 61
  7. 7. 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: 670-675Carbocysteine in COPDSmall studyDisbalance in groupsNo ICSVery low rate ofexacerbations Tatsumi et al. JAGS 2007;55:1884-1885 Carbocysteine in COPD NO TT with ICS Yasuda et al. JAGS 2006;54:378-379 62
  8. 8. Oral NAC and exacerbations Prevention ofexacerbations with NAC compared to placebo.Arrows show mean values Dekhuijzen. Eur Respir J 2004;23:629-636 Oral NAC and exacerbations Dekhuijzen. Eur Respir J 2004;23:629-636 Mucolytics and COPD Poole & Black. BMJ 2001;322:1271-1274 63
  9. 9. Ambroxol and exacerbationsOne-year study onmild-moderateCOPD.Never smokers 25%ICS were forbidden Malerba et al. Pulm Pharmacol Ther 2004;17:27-34. Carbocysteine in COPD Allegra et al. Respiration 1996; 63: 174-180 Carbocysteine in COPD Allegra et al. Respiration 1996; 63: 174-180 64
  10. 10. NAC and re-hospitalisationRisk ofreadmission tohospital forCOPDaccording totreatment withNAC Gerrits et al. ERJ 2003; 21: 795-798 Ontario study Sin & Tu. AJRCCM 2001;164:580-584 Unexposed and immortal time period Time zero: Cohort entry Death ICS Rx filled ICS user 0 Death IMMORTAL ICS non-user TIME BIAS 0 Suissa et al. Proc Am Thorac Soc 2007;4:535-542 65
  11. 11. TORCHCalverley et al NEJM 2007 Mucolytics in LRTI Cochrane Library 2009, issue 2 Mucolytics in LRTI Cochrane Library 2009, issue 2 66
  12. 12. Mucolytics in LRTI Cochrane Library 2009, issue 2 Mucolytics in LRTI Cochrane Library 2009, issue 2 Oral NAC and COPD BRONCHUS study: 523 patientsfollowed for 3 years Same decline in FEV1 in bothgroups of treatment. Decramer et al. Lancet 2005;365:1552-60 67
  13. 13. Oral NAC and COPD BRONCHUS study: No effect on HRQL. Decramer et al. Lancet 2005;365:1552-60 Oral NAC and COPDGroup 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) 0.359No ICS 130 187 0.79 (0.63-0.98) 0.040 No effect on frequency of exacerbations. Decramer et al. Lancet 2005;365:1552-60 Prevention of exacerbations with carbocysteine Zheng et al. Lancet 2008;371:2013-2018 68
  14. 14. Prevention of exacerbations with carbocysteine Ex per pt/yr Placebo 1.35 (0.06) Carbocysteine 1.01 (0.06) Reduction 0.75 (0.62-0.92) One-year RCT with 709 patients from 22 centres in China.Mean FEV1=44%, only 15% received ICS and 28% xanthines. Zheng et al. Lancet 2008;371:2013-2018 Incidence of exacerbations 1,2 UPLIFT TORCH Exacerbations per patient - year 1.13 Placebo 1,1 - 25 % 1 0,9 0.85 Control 0.85 SFC 0,8 - 14% 0.73 Tiotropium 0,7 0,6 “Floor” 0,5 Miravitlles & Anzueto. Int J COPD 2009;4:185-201 Exacerbations and FEV1 R= -0.256; p<0.001 Miravitlles et al. Int J COPD 2008; 3: 803-814 69
  15. 15. Tiotropium and E-COPD P=0.34 P=0.043 P=0.079 AUC of sputum inflammatory markers. RCT of tiotropium or placebo in 142 pts with mean FEV1=50%. Reduction of exacerbations of 52% with TIO (p=0.001) Powrie et al. ERJ 2007;30:472-478 Prevention of E-COPDTime to eventanalysis ofsurgicalresponders(improvement> 200 ml),nonrespondersand controls Washko et al. AJRCCM 2008;177:164-169Forms of COPD Percentages of eosinophils and macrophages in induced sputum in COPD patients with or without chronic bronchitis Snoeck-Stroband et al. ERJ 2008;31:70-77 70
  16. 16. Inhaled corticosteroids in COPD Ex/yr 2 P=0.02 1,6 Reduction of 1,2 P=0.45 exacerbations 0,8 with Fluticasone. FEV1<50% (391) 0,4 FEV1>50% (359) 0 >50% <50% Fluticasona Placebo Jones et al. ERJ 2003;21:68-73 LABAs and ICs in COPDReduction infrequency ofexacerbations: 35%Estimated treatmenteffect ratio: 0.65(95%CI= 0.57-0.76) Kardos et al. AJRCCM 2007;175:144-149. Tiotropium + combination in COPD Outcome Tio Tio + Sal Tio + Flu/Sal Patients with ex. 62.8 64.8 60 -2 (-12 to 9) 2.8 (-8 to 14) Ex. per patient-year 1.61 1.75 1.37 1.1 (0.8 to 1.3) 0.85 (0.6 to 1.1) Urgent visits 185 184 149 1.06 (0.9 to 1.3) 0.81 (0.6 to 1.01) Hospitalizations for COPD 49 38 26 0.83 (0.5 to 1.3) 0.53 (0.3 to 0.8) All –cause hospitalizations 62 48 41 0.83 (0.6 to 1.2) 0.67 (0.4 to 0.99) Aaron et al. Ann Intern Med 2007;146:545-555 71
  17. 17. Treatment of COPD in PC Miravitlles et al. Respir Med 2007; 101: 1753-1760 Treatment of COPD Miravitlles et al. Int J COPD 2008; 3: 803-814 Theophylline in COPDTime to the firstexacerbation.Theophylline 100mg/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 72
  18. 18. Theophylline and ICS Mean levels of inflammatory markers in sputum in patients with exacerbations of COPD treated with oral steroids with or without low-dose theophylline Cosío et al. Thorax 2009; 64: 424-429 Bronchial colonisationRelationshipbetween LABCand exacerbationfrequency Patel et al. Thorax 2002;57:759-764 Prevention of exacerbations with macrolidesProportion ofpatients withoutan exacerbationvs time to thefirst exacerbationin placebo andmacrolide arms(p=0.02) Seemungal et al. AJRCCM 2008;178:1139-1147 73
  19. 19. Bronchial colonisation 119 patients included Colonized Not colonized 58 61 High bacterial load (≥ Low bacterial load (< 106) 106) 22 36 Miravitlles et al. ERJ 2009 (in press) Bronchial colonisation Colonisation at 2 and 8 weeks. Bottom: persistence Upper: acquired *p<0.01 Miravitlles et al. ERJ 2009 (in press) Secondary Trial Primary variable: variables: •no. of exacerbations overview no. of exacerbations •diff in lung function •HEOR •QoL, etc. Moxi 400mg Pulse Pulse ET FU FU OD x 5 #2 #6 #1 #3 daysN=1132Mod-severe CB stable phase Placebo Pulse Pulse ET FU FU OD x 5 #2 #6 #1 #3 days Screened & Randomized 8 wks 8 wks 8 wks 8 wks 8 wks 48 week treatment period 24 week follow-up period 74
  20. 20. Clinical efficacy Purulent/muco-purulent sputum *adjusted for region and pre-therapy %PFEV1 GOLD Guidelines Rabe et al. AJRCCM 2007;176:532-555 Optimal Pharmacotherapy in COPD Increasing Disability and Lung Function Impairment Mild Moderate Severe Infrequent AECOPD Frequent AECOPD (< 1/year) (> 1/year) SABD prn LAAC or LABA+ SABA prn LAAC + ICS/LABA + persistent persistent disability SABA prn disability LAAC + LABA + SABA prn persistent disabilityLAAC + SABA prn persistent disability or LAAC + ICS/LABA + LAAC + ICS/LABA +LABA + SABA prn SABA prn +/- Theophyline SABA prn O’Donnell et al. Can Respir J 2007; 14 (Suppl B): 5-32 75
  21. 21. Optimal Pharmacotherapy of Moderate to Severe COPD 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 persistent disability Consider adding Theophylline Can Respir J 2007;14(Suppl B):3B-32B. Conclusions • No changes in mucus viscosity. • No increase in glutation in BAL. • No impact in bronchial colonisation. • Most studies are small, not well characterised COPD. • The best study was negative.• Possible effect in untreated patients (?). 76
  22. 22. Answers to evaluation questionsDebate: is there a place for oral mucolytics in the prevention of LRTI? – CON 1. b 2. c 3. a 109
  23. 23. Faculty disclosure formsMarc Miravitlles has received honoraria for consultancy and lecturing from Bayer Schering.Wisia Wedzicha is the advisory board member of GSK, Astra Zeneca, Boehringer Ingelheim, Pfizerand Novartis. He has received lecture fee from GSK, Astra Zeneca, Boehringer Ingelheim, Pfizer andNovartis. 111

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