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Respiratory Medicine (2006) 99, S28–S40

KEYWORDCOPD;BronchodilInhaledcorticosteLong-termtherapy;Non-invasiventilationLung-volumreduction

0954-6111/$ - sdoi:10.1016/j.r

Abbreviationand 2; ERS, EurDisease; HRQoLventilation; LANAC, N-acetylcventilation; PDRespiratory Qu�CorrespondE-mail addr

Treatments for COPD

Nicola A. Hananiaa,�, Nicolino Ambrosinob, Peter Calverleyc,Mario Cazzolad, Claudio F Donnere, Barry Makef

aPulmonary and Critical Care Medicine, Baylor College of Medicine, 1504 Taub Loop, Houston,TX 77030, USAbPulmonary Unit, Cardio-Thoracic Department, University Hospital Pisa. Via Paradisa 2, Cisanello,56124 Pisa, ItalycClinical Science Centre, University Hospital Aintree, Longmoor Lane, Liverpool L9 7AL, UKdUnit of Pneumology and Allergology, Department of Respiratory Medicine, A. Cardarelli Hospital,Via A. Cardarelli 9, 80131 Naples, ItalyeDivision of Pulmonary Disease, Fondazione S. Maugeri, IRCCS, Istituto Scientifico di Veruno,Via per Revislate, 13, 28010 Veruno (NO), ItalyfNational Jewish Medical and Research Center, 1400 Jackson Street, Denver, CO 80206, USA

Received 5 August 2005; accepted 7 September 2005

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s: ATS, American Thoracopean Respiratory Socie, health-related qualitBA, long-acting b2-agoniysteine; NETT, NationalE4, phosphodiesterase-4estionnaire; TNF-a, tuming author. Tel.: +1 713ess: hanania@bcm.tmc.

Summary The multicomponent nature of chronic obstructive pulmonary disease(COPD) has provided a challenging environment in which to develop successfultreatments. A combination of pharmacological and non-pharmacological approachesis used to combat this problem, and an overview of these approaches and theirpossible future direction is given.

Bronchodilators are the mainstay of COPD treatment and can be combined withinhaled corticosteroids for greater efficacy and fewer side effects. A new generationof pharmacotherapeutic agents, most notably phosphodiesterase-4 inhibitors, whichare already in the advanced stages of clinical development, and leukotriene B4inhibitors (in early clinical development), may shape future treatment as furtherinsight is gained into the pathological mechanisms underlying COPD.

Non-pharmacologic treatments for COPD include long-term oxygen therapy(LTOT), nasal positive pressure ventilation (nPPV), pulmonary rehabilitation andlung-volume-reduction surgery (LVRS). Apart from smoking cessation, LTOT is the

Elsevier Ltd. All rights reserved.

ic Society; COPD, chronic obstructive pulmonary disease; CXCR1/CXCR2, chemokine receptors 1ty; FEV1, forced expiratory volume in 1 s; GOLD, Global Initiative for Chronic Obstructive Lungy of life; ICS, inhaled corticosteroid; IL-8, interleukin-8; INPV, intermittent negative pressurest; LTB4, leukotriene B4; LTOT, long-term oxygen therapy; LVRS, lung-volume-reduction surgery;Emphysema Treatment Trial; NF-kB, nuclear factor-kappa B; nPPV, nasal positive pressure; QoL, quality of life; SFC, salmeterol/fluticasone propionate combination; SGRQ, St. George’sour necrosis factor-alpha; V 0=Q 0, ventilation/perfusion ratio873 3454; fax: +1 713 873 3346.edu (N.A. Hanania).

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only treatment to date which has been shown to modify survival rates in severecases; thus its role in COPD is well defined. The roles of nPPV and LVRS are less clear,though recent progress is reported here.

In the future, it will be important to establish the precise value of the differenttreatments available for COPD—evaluating both clinical and physiological endpointsand using the data to more accurately define candidate patients accordingly. Thechallenge will be to develop this base of knowledge in order to shape future researchand allow clinicians to deliver tailored COPD management programmes for thegrowing number of patients afflicted with this disease.& 2005 Elsevier Ltd. All rights reserved.

Introduction

Chronic obstructive pulmonary disease (COPD) is amulticomponent disease with inflammation at itscore, in which patients experience progressivelyworsening lung function, disease symptoms andquality of life (QoL), as well as increasing exacer-bations.1 The therapeutic difficulty presented byCOPD arises from the need to target all componentsof the disease. To this end, a clinician’s paradigmfor COPD management has been introduced—

Global Initiative for Chronic Obstructive LungDisease 2003 (GOLD 2003).1,2 Current managementoptions can be divided into pharmacologic and non-pharmacologic categories. Pharmacologic treat-ments include bronchodilators, inhaled corticoster-oids (ICS), combination therapies and long-termoxygen therapy (LTOT). Non-pharmacologic inter-ventions include smoking cessation, optimisingnutrition, pulmonary rehabilitation, mechanicalventilation and lung-volume-reduction surgery(LVRS). Novel medications such as selective phos-phodiesterase-4 (PDE4) inhibitors are already in theadvanced stages of clinical development; leuko-triene B4 (LTB4) inhibitors also show potential forshaping future therapy, although they are only inthe early stages of clinical development. Apartfrom smoking cessation, LTOT is the only treatmentto date that has been shown to modify survivalrates in severe COPD; thus it has a clear role to playin patients with COPD and chronic respiratoryfailure. The aim of this article is to provide anoverview of the current and future treatmentoptions available in COPD management.

Pharmacotherapeutic agents in COPD

Bronchodilators

Optimising treatment responseBronchodilators are central to the symptomaticmanagement of COPD and come in several for-ms—short-acting bronchodilators, including the b2-

agonist salbutamol and the anticholinergic ipratro-pium bromide, and long-acting bronchodilators,including the b2-agonists salmeterol and formoter-ol, the anticholinergic tiotropium and theophylline.A fixed-dose combination of salbutamol/ipratro-pium (Combivents) is also available.

Current guidelines recommend the inhaled de-livery of long-acting bronchodilators as the pre-ferred method of therapy. Several facts should beconsidered when choosing a bronchodilator fortreatment of COPD. First, the lack of acuteresponse to one class of bronchodilator does notnecessarily imply non-responsiveness to another.Donohue3 reported that 73% of 813 COPD patientsincreased their forced expiratory volume in 1 s(FEV1) by 412% or 200mL following long-termsalmeterol treatment. However, 11% of patientsshowed a similar increase in FEV1 following acuteadministration of ipratropium, 27% following salbu-tamol and 35% with both drugs combined. A secondconsideration is that a patient’s FEV1 response toacute bronchodilator therapy does not predictlong-term response to bronchodilator therapy andmay vary from day to day. Calverley et al.4

performed acute bronchodilator testing using sal-butamol, ipratropium bromide or a combination ofthe two on 660 COPD patients who had beenclassified according to both European RespiratorySociety (ERS) and American Thoracic Society (ATS)spirometric criteria.5,6 Over the 2-month studyperiod, 55% of patients classified as irreversibleunder ATS criteria changed to reversible status onat least one of the visits.

In summary, the acute response to short-actingbronchodilators is of limited value in decidingfuture response to long-acting agents. Further-more, while improvement in FEV1 is important inassessing response to bronchodilator therapy, otheroutcome measures such as improvements in lungvolumes, symptoms, exercise capacity, QoL andexacerbations may be of greater value in assessingthe long-term response. The effects of commonlyused bronchodilators on clinical outcomes in COPDare listed in Table 1.

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Table 1 Summary of the effects of commonly used bronchodilators on clinical outcomes in COPD.

Bronchodilator FEV1 Lung volume Dyspnoea HRQoL Exercise endurance

Short-acting b-agonist Yes� Yesy Yes� — Yesy

Ipratropium bromide Yes� Yesy Yes� Noy Yesy

Long-acting b-agonist Yes� Yes� Yes� Yes� Yesy

Tiotropium Yes� Yes� Yes� Yes� Yesy

Theophylline Yes� Yesy Yes� Yesy Yesy

FEV1 ¼ forced expiratory volume in 1 s.�Randomised clinical trial, substantial numbers of studies with large study populations.yRandomised clinical trial, few studies or studies with small study populations.

N.A. Hanania et al.S30

Combination bronchodilator therapyCurrent guidelines highlight the fact that a combi-nation of more than one class of bronchodilatormay be more effective than the use of single agentswith respect to improvements in lung function,symptoms, and reducing the risk of adverseevents.1 This has been supported by several clinicaltrials. For example, in a 12-week trial, ZuWallacket al.7 showed that salmeterol plus theophyllinecaused significantly greater improvements in pul-monary function and symptoms, compared witheither single agent (N ¼ 943). Additionally, thecombination of salmeterol and the short-actinganticholinergic ipratropium provided greaterbronchodilation than either agent alone.8 Theseadditive effects are not surprising since theseagents may have complementary mechanisms ofaction.9

Assessing bronchodilator efficacyFEV1 is not the only useful physiological endpoint inevaluating bronchodilator efficacy—changes insymptoms and QoL often occur independently ofchanges in lung function. Other important physio-logical effects of bronchodilators include thereduction of air trapping and dynamic hyperinfla-tion. Assessments of bronchodilator efficacy shouldtake these factors into consideration. For example,the degree of lung hyperinflation, determined usinglung volume measurements of inspiratory capacity,may provide a better correlation than FEV1, withimproved exercise performance following broncho-dilator therapy.10 Clinical endpoints, such as thefrequency of exacerbations, mortality, degree ofbreathlessness, exercise tolerance and healthstatus should equally be incorporated.11,12

It should also be noted that some bronchodilatorsexhibit beneficial non-bronchodilator behaviour,such as the potential anti-inflammatory effects oftheophylline13 and other non-bronchodilatory ef-fects of long-acting b2-agonists (LABA).

14

Safety of bronchodilatorsIt has been reported that the continued use of b2-agonists may be associated with an increase incardiovascular risk compared with placebo.15 How-ever, a recent meta-analysis (N ¼ 2853) showed noclinically significant difference in the incidence ofcardiovascular events between salmeterol andplacebo.16 Furthermore, a study in patients withcardiovascular disease showed no increased riskwith the use of salmeterol, compared with place-bo.17 It has also been suggested that tolerance tothe bronchodilator effects of LABAs may occur withtheir prolonged use. A recent study examining thebronchodilator effect of long-term use of salmeter-ol failed to demonstrate such an effect.18

The use of anticholinergics may be associatedwith class side effects, such as dry mouth, anincreased risk of glaucoma and urinary retention.Long-term effects of ipratropium bromide mayinclude an increased risk of cardiac events, asshown in the Lung Health Study, although thesefindings need further evaluation.19 Theophylline isassociated with tremors and nausea and lessfrequently, with cardiac arrhythmias and sei-zures.20 The risk of such adverse events can bereduced, however, by monitoring drug plasmalevels and reducing the dose accordingly.

Future challenges in bronchodilator therapySeveral new bronchodilators, currently in ongoingclinical trials, may improve the future treatment ofCOPD. These include b2-agonists, which can beadministered once a day or through nebulisation,PDE4 inhibitors and combination therapies. Specificresearch targets include determining the long-termefficacy of ICS/LABA combinations and tiotropium,their effects on the natural history of COPD whenused early in disease progression, and their long-term safety. The exploration of more reliable andsensitive markers for response to bronchodilatortherapy is also a key objective.

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Inhaled corticosteroids

The role of ICS in COPD was once controversial, butis now better established as a result of large clinicaltrials. Regular treatment with ICS is recommended(GOLD) for symptomatic patients who suffer fre-quent exacerbations, and whose FEV1 is o50% ofpredicted.1 The rationale for the use of ICS in COPDwill be examined below.

Attempts to elucidate the ICS mechanism ofaction have been inconclusive. Although theseagents appear to have minimal significant effectson key inflammatory chemoattractants, such asinterleukin-8 (IL-8), tumour necrosis factor-alpha(TNF-a) and matrix metalloproteinases,21 there aredata to suggest an association with reducedneutrophil chemotaxis.22

Figure 1 The effects of ICS/LABA combination therapyon (A) the number of exacerbations requiring oral steroidcourses (FEV1o50% predicted),36 and (B) QoL in patientswith COPD, as measured with the St. George’s Respira-tory Questionnaire (SGRQ).32,33

ICS in COPD: physiological versus clinicalendpointsFour large, 3-year, randomised trials have failed toshow a significant effect of ICS on the rate ofdecline of FEV1, compared with placebo.23 How-ever, a meta-analysis by Sutherland et al.24 showedthat high-dose ICS reduced the rate of decline inFEV1 by 9.9mL per year compared with placebo(P ¼ 0:01). Whether this effect is clinically impor-tant remains unresolved. Less contentious datashowed that post-bronchodilator FEV1 was signifi-cantly higher during ICS treatment compared withplacebo in two long-term studies,25,26 with parti-cularly strong data in one study of fluticasonepropionate.25

Despite the controversy regarding the effects ofICS on physiological endpoints, it is generallyagreed that ICS have a positive influence on clinicalendpoints in patients with COPD. For example, inthe Inhaled Steroids in Obstructive Lung Disease inEurope trial, the median exacerbation rate wasreduced by 25% with fluticasone propionate com-pared with placebo, with a concomitant significantreduction in health status deterioration.25,27

Furthermore, these effects may be more pro-nounced in patients with severe airflow limit-ation—although the recent ATS/ERS statementput as much emphasis on symptoms to guidemanagement decisions as lung function.2 It isimportant to note that the COPE study also showedthat withdrawal from treatment with ICS wasassociated with a more rapid onset and increasedrecurrence of exacerbations, and also with asignificant deterioration in health-related qualityof life (HRQoL).28 Despite the contention surround-ing the physiological effects of ICS, their effect onclinical endpoints supports their use in COPD.

Combining ICS and LABA for greater effectivenessPhysiological and clinical data concur that combin-ing ICS and LABA is more effective than eithertreatment alone.29–33 More recently, it has beenshown that short-term treatment with combinedfluticasone propionate/salmeterol improves lungfunction and symptoms more effectively than thecombination of salbutamol and ipratropium bro-mide.34,35 In a pivotal study, Calverley et al.29

(N ¼ 1465) reported that treatment for 12 monthswith salmeterol/fluticasone propionate combina-tion (SFC) significantly improved pre-treatmentFEV1 compared with placebo or either single agentalone. A clinically significant improvement inhealth status and a reduction in daily symptomswere also observed with combination treatment,together with a significant reduction in exacerba-tions (Fig. 1).36 Other studies by Szafranski 32 andCalverley33 showed that patients treated with abudesonide/formoterol combination have an im-proved QoL, as measured by the St George’sRespiratory Questionnaire (SGRQ) score (Fig.1).32,33,37 Furthermore, a database study by Sorianoet al.38 indicated that there may be a survivaladvantage in using SFC combination treatmentor fluticasone propionate alone—the 3-year TO-wards a Revolution in COPD Health survival study

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including over 6000 patients aims to evaluate thishypothesis further.39

In summary, ICS may have limitations as mono-therapy in COPD. However, they have been shownto significantly improve important clinical out-comes in combination with LABAs, thus maintainingthe rationale for their use among these patients.

The next generation of pharmacotherapeuticagents

Further insight into the pathogenesis of the chronicairway inflammation which underlies COPD hasestablished new therapeutic targets, most of whichare based on components of inflammatory path-ways (Fig. 2).40,41

PDE4 inhibitorsPDE4 is commonly expressed in neutrophils, CD8+cells and macrophages. The inhibition of PDE4causes an increase in cyclic adenosine monopho-sphate in immunomodulatory and inflammatorycells, with subsequent suppression of inflammatorycell function. A number of PDE4 inhibitors areundergoing investigation (Fig. 3). Selective PDE4inhibitors,42 such as cilomilast and roflumilast, areeffective in COPD patients (Fig. 3). In particular,cilomilast treatment is associated with reductionsin the numbers of CD8+ and CD68+ cells, indicatinganti-inflammatory action.43 The development of

Figure 2 Components of inflammatory pathways wit

PDE4 inhibitors is restricted by gastrointestinal sideeffects, although this problem could be overcomeby the use of PDE4B-selective inhibitors, which maybe more specific and exert fewer side effects.44

LTB4 inhibitorsAnother inflammatory mediator, LTB4, is a keychemoattractant of neutrophils, thereby making itan attractive target for therapeutic intervention inCOPD. Antagonists of the two subtypes of LTB4receptor (e.g. LY2931144 and SB20114645) are at theearly stages of clinical development and have beenshown to inhibit sputum-induced neutrophil che-motaxis (Fig. 4). Alternatively, inhibitors of LTB4synthesis (e.g. BAYx1005) produce a modest reduc-tion in sputum LTB4 concentrations,

46 although theclinical relevance of this result is still to beestablished.

Inhibiting cytokines and chemokinesThere are a number of chemokines and cytokinesthat play important roles in mediating inflamma-tion in COPD, and are therefore potential ther-apeutic targets. For example, IL-8 recruits andactivates neutrophils via the chemokine receptorsCXCR1 and CXCR2, and it can be inhibited by thesmall-molecule CXCR1/CXCR2 antagonist, reper-taxin.47 In addition, CXCR2-specific antagonists,such as SB 225002, block the CXCR2 receptor whichis required for the recruitment of neutrophils.44

h potential as therapeutic targets in COPD.40,41

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Figure 3 The next generation of phosphodiesterase-4 inhibitors.42

Figure 4 Effect of a leukotriene B4 (LTB4) receptorantagonist, SB 201146, on sputum-induced neutrophilchemotaxis.46

Treatments for COPD S33

An alternative means of intercepting the IL-8pathway is to use a human anti-IL-8 monoclonalantibody. However, chemokine pathways exhibit adegree of redundancy, so inhibiting any oneelement may not be effective. Thus Beeh et al.45

investigated the effect of combining an anti-IL-8antibody with an LTB4 antagonist, and found thatthe combined effect was not significantly greaterthan the effect of either single agent alone.

A further addition to the list of therapeutictargets is TNF-a, which induces IL-8 via nuclearfactor-kappa B (NF-kB). The use of humanisedmonoclonal antibodies (infliximab) and solubleTNF-a receptors (etanercept) is currently beinginvestigated.44 In addition, the direct inhibition ofNF-kB is another means of intercepting the cyto-kines and chemokines involved in COPD. The p38mitogen-associated protein kinase pathway, whichalso regulates the expression of inflammatorycytokines, is a further potential target for thedevelopment of small-molecular inhibitors, such asSB 239063, which has demonstrated anti-inflamma-tory activity in animal models.48

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COPD: new treatment perspectivesCentral to the pathogenesis of COPD, and inaddition to inflammation, is the imbalance in thelung between endogenous proteinases and antipro-teinases, and the production of oxidative stress.The use of N-acetylcysteine (NAC), to provideintracellular cysteine for the production of theendogenous antioxidant, glutathione, is one ofseveral treatment options under investigation.Initial research suggests that oral NAC reducesthe number of exacerbations in COPD49,50 but amore recent randomised controlled trial failedto show that the addition of NAC, to treat-ment with corticosteroids and bronchodilators,can modify the outcome in acute exacerbationsof COPD.51

In terms of restoring the balance betweenproteases and protease inhibitors in COPD, thedevelopment of small-molecular inhibitors of pro-teinases, especially those which show elastolyticactivity, is a promising area.

Long-term oxygen therapy (LTOT)

Rationale

Supplemental oxygen therapy is the only existingapproach shown to modify the long-term decline inlung function that is associated with COPD—nopharmacological treatment has so far demon-strated this ability. LTOT has also been associatedwith a variety of other benefits in patients withsevere COPD, including increased survival,52 re-duced secondary polycythaemia, improved cardiacfunction during rest and exercise,53 reduction inthe oxygen cost of ventilation54 and improvedexercise tolerance.55 Of particular note are theresults of a longitudinal study showing that LTOTsignificantly improved HRQoL at 2 and 6 months,compared with a progressive decline in HRQoL inthe non-LTOT group. In the LTOT group, 67% and68% of patients (at 2 and 6 months, respectively)showed a clinically significant improvement in theirchronic respiratory questionnaire scores.49 Hencethere is a convincing rationale for including LTOTin the treatment paradigm for patients withsevere COPD.

Candidate patients for LTOT

Patients with PaO2o7.3 kPa (55mmHg; correspond-ing to SaO2o88%) whose disease is stable despitereceiving otherwise comprehensive medical treat-ment, should receive LTOT. A patient whose PaO2 is

7.3–7.8 kPa (55–59mmHg; SaO2 89%) should receiveLTOT if they show signs of pulmonary hyper-tension, cor pulmonale, erythrocytosis, oedemafrom right heart failure or impaired mental state.If oxygen desaturation only occurs during exerciseor sleep, then oxygen therapy should be con-sidered specifically under those conditions. Anoptimal medical regimen can be established in-corporating these guidelines (Fig. 5),2 with thechief aim of achieving optimised ventilation:perfu-sion ratio matching (V 0=Q ) as a means of correctinghypoxaemia.

Oxygen therapy during sleep

COPD patients undergo episodes of O2 desaturationof arterial blood during rapid eye movement sleep.Fletcher et al.56 revealed that these desaturationsoccur both in non-hypoxaemic patients, and inpatients who are hypoxaemic during the day.Further research by Plywaczewski et al.57 showedthat 47.6% of COPD patients treated with LTOTspent430% of the night with an SaO2 of o90%, andthus required increased oxygen flow during sleep.The administration of oxygen at a flow rate higherthan the daytime setting usually corrects nocturnalhypoxaemia.

Conflicting evidence surrounds the contentionthat patients who only desaturate during sleepwill benefit from nocturnal oxygen treatment.Kimura et al. reported increased mortality amongpatients with nocturnal desaturation and daytimePaO2X8 kPa (60mmHg).58 But while Fletcheret al.56 found a beneficial effect of supplementaloxygen treatment in this patient group, other well-controlled studies have not shown that the use ofnocturnal supplemental oxygen alters mortality orclinical course, other than slightly lowering pul-monary artery pressure.59

Oxygen therapy during exercise

Oxygen therapy during exercise decreases dys-pnoea and improves exercise tolerance at submax-imal exertion. The mechanical rationale underly-ing this observation is a decrease in dynamichyperinflation, and reduced ventilatory drive.55

LTOT is prescribed for patients who become morehypoxaemic during exercise, or who only becomehypoxaemic during exercise, with oxygen settingsdetermined while the patient is undergoing atypical level of exertion. Studies evaluating thelong-term benefit of oxygen treatment solely forexercise have yet to be conducted.

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Figure 5 Algorithm for long-term oxygen therapy (LTOT).2

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LTOT: cause for concern?

Carbon dioxide retentionAlthough LTOT may lead to hypercapnia withresulting respiratory acidosis,60 this can usually beminimised by titrating the oxygen flow to maintainthe PaO2 at 8.0–8.6 kPa (60–65mmHg). In fact,many patients with COPD have chronic CO2 reten-tion but because they have intact renal systems,they are able to maintain their pH within thenormal range.

Patient education and complianceA more immediate obstacle for successful LTOTadministration is patient compliance. The meannumber of oxygen breathing hours actually com-pleted by patients may be fewer than prescribed,perhaps due to deficiencies in the practicalimplementation or understanding of the condition.Social barriers and psychological fears also play animportant role. Increasing patient education istherefore a key challenge for the future. Interna-tional agreement on the prescription of LTOT,

selecting appropriate candidates and individualis-ing oxygen prescriptions should establish clearunderstanding of treatment by both patients andclinicians.

Noninvasive ventilation

Introducing nasal positive pressureventilation (nPPV)

Mechanical ventilation increases or substitutes foran individual’s spontaneous respiration, as in thecase of acute respiratory or ventilatory pumpfailure. Non-invasive ventilation, for example,intermittent negative pressure ventilation (INPV)or nPPV, have recently re-emerged as popularoptions that avoid the risks associated with invasiveventilation. nPPV is thought to assist ventilation, byimproving inspiratory flow rate and correctinghypoventilation. Other possible mechanisms ofaction include resting respiratory muscles andresetting the central respiratory drive. In the

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following section, the use of non-invasive ventila-tion in stable, chronically hypercapnic COPDpatients will be examined.

Physiological endpoints revisited

In contrast to the evidence supporting the use ofnPPV to tackle other causes of chronic respiratoryfailure, there is conflicting evidence regarding thebenefits of nPPV in COPD.61 Ambrosino et al.62

presented evidence that nPPV corrects hypoventi-lation in patients with severe stable COPD andchronic hypercapnia (n ¼ 8). In a study by Meec-ham-Jones et al.,63 nocturnal and daytime gasexchange, total sleep time and QoL significantlyimproved with oxygen plus nPPV, compared withoxygen alone. Indeed, the level of improvement indaytime PaCO2 correlated with the level of im-provement in mean overnight PaCO2 (R ¼ 0:69,P ¼ 0:01). Taken together, these studies providesupport for the idea that non-invasive ventilation,and nPPV in particular, may be a useful addition tothe treatment armoury for chronic hypercapnicCOPD.

Randomised trials: conflicting results

Do randomised clinical trials of non-invasive venti-lation support the use of this treatment modality?Results for INPV are unconvincing. In a 12-weekdouble-blind study of 184 patients with severeCOPD, no significant difference was observed in 6-min walk test results, cycle endurance time,severity of dyspnoea, HRQoL, respiratory musclestrength or arterial blood gas compared with shamtreatment.64 This suggests that inspiratory musclerest has no benefits for patients with severe stableCOPD, although poor patient compliance may havecontributed to the results.

Regarding the administration of nPPV in patientswith severe COPD, two 3-month crossover trials ofsimilar design came to different conclusions.Strumpf et al.65 found no improvement in physio-logical outcomes (N ¼ 19). In contrast to this resultis the study by Meecham-Jones et al.63 mentionedin the previous section, in which nocturnal anddaytime gas exchange, total sleep time and QoLsignificantly improved with oxygen plus nPPV(N ¼ 18). The discrepancy between these resultsmay be explained by the difference betweenpatient sets at baseline: patients with greater CO2

retention and more frequent nocturnal oxygendesaturations may benefit more from nPPV admin-istration.

Unfortunately, this neat solution is not supportedby subsequent trials. Despite efforts to recruithypercapnic patients with severe COPD, Gay etal.66 found no significant improvements in gasexchange, lung function or sleep quality comparedwith the sham group. A recent 1-year study wasunable to demonstrate a beneficial effect ofnocturnal nPPV in addition to LTOT in a similarpatient group.67

In addition to these conflicting data on physiolo-gical endpoints is a lack of data showing whethernPPV treatment actually improves survival rates.Therefore, it appears that larger studies withgreater statistical power are required, along withfollow-up data on morbidity and mortality.

nPPV in COPD—bigger trials, better results?

Two large, multicentre trials have focused on nPPVin patients with severe hypercapnic COPD. One trialpublished as an abstract by Muir et al., whichcompared home nPPV plus LTOT with LTOT alone,indicates that there is no overall survival benefit inpatients receiving nPPV plus LTOT, although theremay be a slight improvement in survival for patientsover 65.68 A 2-year Italian multicentre study alsoexamined the effects of nPPV plus LTOT comparedwith LTOT alone (N ¼ 122). In this trial, nPPV plusLTOT improved PaCO2 during breathing of the usualoxygen inspiratory fraction. Long-term improve-ments were also noted in dyspnoea and HRQoL inthe nPPV plus LTOT group, but survival was similarbetween treatment groups.69

Currently, there is little evidence for the use ofmechanical ventilatory support in the routinemanagement of COPD. However, further largestudies may be able to identify subsets of patientsfor whom nPPV would be beneficial.

LVRS for emphysema

Current understanding of LVRS

LVRS was originally proposed as a palliative treat-ment for patients with severe emphysema. Therationale for LVRS is based on the premise thatthese patients have severe hyperinflation and thegoal of surgery is to remove functionally uselessemphysematous lung. Generally, this involves theremoval of 25–30% of lung tissue from both the leftand the right sides. Benefits associated with LVRSare improved lung function (reduced lung volumeand increased FEV1) and exercise (including thedistance walked in 6min).70 Although carefully

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selected patients benefit from LVRS, questionsremain concerning the magnitude and duration ofpositive outcome.

The National Emphysema Treatment Trial(NETT)

The NETT was a multicentre, randomised, large-scale clinical trial (N ¼ 1218) to evaluate theeffects of LVRS.71 Eligible patients (FEV1o45%predicted and bilateral emphysema) underwent aperiod of medical therapy plus pulmonary rehabi-litation. After this period, patients were rando-mised to receive either LVRS (n ¼ 608) or continuemedical therapy (n ¼ 610), with a mean follow-uptime of 29 months. The two primary outcomesmeasured were survival and maximum exercisecapacity 2 years after randomisation. Of note wasthe early identification of a subgroup of patientswho suffered a high 30-day mortality rate andshowed little benefit after LVRS. These patientsexhibited an FEV1p20% of predicted and either ahomogenous distribution of emphysema or a carbonmonoxide diffusion capacity o20% of predicted.72

NETT results

Overall results from the NETT at 2-years post-randomisation indicate that LVRS improves exercise

Figure 6 Algorithm for lung-volume-reduction surgery (LVRTreatment Trial results and independent outcome predictors.7

lower exercise performance had substantially improved outupper lobe emphysema and higher levels of exercise perform

capacity, but does not improve survival comparedwith medical therapy. Patients in the LVRS groupalso reported improved health status and lessdyspnoea compared with the medical group. Sub-group analyses showed that patients with upper-lobe predominant emphysema and low exercisecapacity had improved survival with LVRS, com-pared with medical therapy; those patients withmainly non-upper-lobe emphysema and high ex-ercise capacity showed reduced survival.71 Fromthese results, two key outcome predictors can beidentified: distribution of emphysema and exercisecapacity following pulmonary rehabilitation. Com-bined with the factors placing patients at high riskfor LVRS, these predictors allow more targetedpatient selection than was previously possible(Fig. 6).71

Future directions for LVRS research

Key questions remaining concern the role of pre-operative pulmonary rehabilitation, the mechan-isms by which LVRS improves lung function andsurvival, and the impact of different surgicaltechniques on LVRS outcomes. The identificationof long-term predictors of LVRS outcomes would bea welcome development, while investigating uni-lateral or repeated LVRS, as well as non-invasive

S) patient selection based on the National Emphysema1 Patients with predominately upper lobe emphysema andcomes from LVRS, while those with predominately non-ance had poorer outcomes from this procedure.

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techniques to reduce lung volume, may provesuccessful in the future.

Conclusions

Much recent progress has been made in themanagement of COPD, but there are still manyoutstanding questions to be resolved. There is animpetus to evaluate combination therapies, noveldrugs such as PDE4 and LTB4 inhibitors, LTOT andLVRS and learn whether they will have a role inshaping future developments in patient-specifictherapy. It is hoped that this momentum will bemaintained and that, in years to come, COPDmanagement will combine pharmacological andnon-pharmacological therapies to drive and refinetreatment algorithms for the individual patientwith COPD.

References

1. Global Initiative for Chronic Obstructive Lung Disease.Global strategy for the diagnosis, management, andprevention of chronic obstructive pulmonary disease—2004update. 2005. Available at: www.goldcopd.com (accessedApril 2005).

2. Celli BR, MacNee W. Standards for the diagnosis andtreatment of patients with COPD: a summary of the ATS/ERS position paper. Eur Respir J 2004;23:932–46.

3. Donohue JF. Therapeutic responses in asthma and COPD.Bronchodilators. Chest 2004;126:125S–37S.

4. Calverley PM, Burge PS, Spencer S, Anderson JA, Jones PW.Bronchodilator reversibility testing in chronic obstructivepulmonary disease. Thorax 2003;58:659–64.

5. American Thoracic Society. Standards for the diagnosis andcare of patients with chronic obstructive pulmonary disease.Am J Respir Crit Care Med 1995;152:S77–S121.

6. Siafakas NM, Vermeire P, Pride NB, et al. Optimal assessmentand management of chronic obstructive pulmonary disease(COPD). The European Respiratory Society Task Force. EurRespir J 1995;8:1398–420.

7. ZuWallack RL, Mahler DA, Reilly D, et al. Salmeterol plustheophylline combination therapy in the treatment of COPD.Chest 2001;119:1661–70.

8. van Noord JA, de Munck DR, Bantje TA, Hop WC, Akveld ML,Bommer AM. Long-term treatment of chronic obstructivepulmonary disease with salmeterol and the additive effectof ipratropium. Eur Respir J 2000;15:878–85.

9. COMBIVENT Inhalation Aerosol Study Group. In chronicobstructive pulmonary disease, a combination of ipratro-pium and albuterol is more effective than either agentalone. An 85-day multicenter trial. Chest 1994;105:1411–9.

10. O’Donnell DE, Lam M, Webb KA. Spirometric correlatesof improvement in exercise performance after anticholiner-gic therapy in chronic obstructive pulmonary disease. Am JRespir Crit Care Med 1999;160:542–9.

11. Mahler DA. The effect of inhaled beta2-agonists onclinical outcomes in chronic obstructive pulmonary disease.J Allergy Clin Immunol 2002;110:S298–303.

12. Sin DD, McAlister FA, Man SF, Anthonisen NR. Contemporarymanagement of chronic obstructive pulmonary disease:scientific review. JAMA 2003;290:2301–12.

13. Barnes PJ. Theophylline: new perspectives for an old drug.Am J Respir Crit Care Med 2003;167:813–8.

14. Johnson M, Rennard S. Alternative mechanisms for long-acting beta(2)-adrenergic agonists in COPD. Chest 2001;120:258–70.

15. Salpeter SR. Cardiovascular safety of beta(2)-adrenoceptoragonist use in patients with obstructive airway disease: asystematic review. Drugs Aging 2004;21:405–14.

16. Ferguson GT, Funck-Brentano C, Fischer T, Darken P, ReisnerC. Cardiovascular safety of salmeterol in COPD. Chest2003;123:1817–24.

17. Daley-Yates P. Cardiovascular (CV) pharmacodynamics (PD)and pharmacokinetics (PK) of salmeterol (SALM) followingsingle and repeated dosing in chronic obstructive pulmonarydisease. ATS, Seattle, WA, USA, 16–21 May 2003, AbstractA319.

18. Hanania NA, Kalberg C, Yates J, Emmett A, Horstman D,Knobil K. The bronchodilator response to salmeterol ismaintained with regular, long-term use in patients withCOPD. Pulm Pharmacol Ther 2005;18:19–22.

19. Anthonisen NR, Connett JE, Enright PL, Manfreda J.Hospitalizations and mortality in the Lung Health Study.Am J Respir Crit Care Med 2002;166:333–9.

20. Barnes PJ. Current therapies for asthma. Promise andlimitations. Chest 1997;111:17S–26S.

21. Barnes PJ. Inhaled corticosteroids are not beneficial inchronic obstructive pulmonary disease. Am J Respir CritCare Med 2000;161:342–4.

22. Confalonieri M, Mainardi E, Della PR, et al. Inhaledcorticosteroids reduce neutrophilic bronchial inflammationin patients with chronic obstructive pulmonary disease.Thorax 1998;53:583–5.

23. Burge S. Should inhaled corticosteroids be used in the longterm treatment of chronic obstructive pulmonary disease?Drugs 2001;61:1535–44.

24. Sutherland ER, Allmers H, Ayas NT, Venn AJ, Martin RJ.Inhaled corticosteroids reduce the progression of airflowlimitation in chronic obstructive pulmonary disease: a meta-analysis. Thorax 2003;58:937–41.

25. Burge PS, Calverley PM, Jones PW, Spencer S, Anderson JA,Maslen TK. Randomised, double blind, placebo controlledstudy of fluticasone propionate in patients with moderate tosevere chronic obstructive pulmonary disease: the ISOLDEtrial. Br Med J 2000;320:1297–303.

26. Pauwels RA, Lofdahl CG, Laitinen LA, et al. Long-termtreatment with inhaled budesonide in persons with mildchronic obstructive pulmonary disease who continue smok-ing. European Respiratory Society Study on Chronic Ob-structive Pulmonary Disease. N Engl J Med 1999;340:1948–53.

27. Spencer S, Calverley PM, Sherwood BP, Jones PW. Healthstatus deterioration in patients with chronic obstructivepulmonary disease. Am J Respir Crit Care Med 2001;163:122–8.

28. van der Valk P, Monninkhof E, van der Palen J, Zielhuis G, vanHerwaarden C. Effect of discontinuation of inhaled corti-costeroids in patients with chronic obstructive pulmonarydisease: the COPE study. Am J Respir Crit Care Med 2002;166:1358–63.

29. Calverley P, Pauwels R, Vestbo J, et al. Combined salmeteroland fluticasone in the treatment of chronic obstructivepulmonary disease: a randomised controlled trial. Lancet2003;361:449–56.

ARTICLE IN PRESS

Treatments for COPD S39

30. Hanania NA, Darken P, Horstman D, et al. The efficacy andsafety of fluticasone propionate (250microg)/salmeterol(50microg) combined in the Diskus inhaler for the treatmentof COPD. Chest 2003;124:834–43.

31. Mahler DA, Wire P, Horstman D, et al. Effectiveness offluticasone propionate and salmeterol combination deliv-ered via the Diskus device in the treatment of chronicobstructive pulmonary disease. Am J Respir Crit Care Med2002;166:1084–91.

32. Szafranski W, Cukier A, Ramirez A, et al. Efficacy and safetyof budesonide/formoterol in the management of chronicobstructive pulmonary disease. Eur Respir J 2003;21:74–81.

33. Calverley PM, Boonsawat W, Cseke Z, Zhong N, Peterson S,Olsson H. Maintenance therapy with budesonide andformoterol in chronic obstructive pulmonary disease. EurRespir J 2003;22:912–9.

34. Donohue JF, Kalberg C, Emmett A, Merchant K, Knobil K. Ashort-term comparison of fluticasone propionate/salmeterolwith ipratropium bromide/albuterol for the treatment ofCOPD. Treat Respir Med 2004;3:173–81.

35. Make B, Hanania NA, ZuWallack R. The efficacy and safety ofinhaled fluticasone propionate/salmeterol compared withipratropium bromide/albuterol in the treatment of COPD.Clin Ther 2005;5:531–42.

36. Calverley P, Pauwels R, Vestbo J, et al. Clinical improve-ments with salmeterol/fluticasone propionate combinationin differing severities of COPD. American Thoracic Society2003 Abstract A90.

37. Jones PW, Quirk FH, Baveystock CM, Littlejohns P. A self-complete measure of health status for chronic airflowlimitation. The St. George’s Respiratory Questionnaire. AmRev Respir Dis 1992;145:1321–7.

38. Soriano JB, Vestbo J, Pride NB, Kiri V, Maden C, Maier WC.Survival in COPD patients after regular use of fluticasonepropionate and salmeterol in general practice. Eur Respir J2002;20:819–25.

39. Vestbo J. The TORCH (towards a revolution in COPD health)survival study protocol. Eur Respir J 2004;24:206–10.

40. Matera MG, Cazzola M. New anti-inflammatory approachesin COPD. Drug Discov Today: Ther Strat 2004;1:335–43.

41. Barnes PJ. COPD: is there light at the end of the tunnel? CurrOpin Pharmacol 2004;4:263–72.

42. Huang Z, Ducharme Y, MacDonald D, Robichaud A. The nextgeneration of PDE4 inhibitors. Curr Opin Chem Biol 2001;5:432–8.

43. Gamble E, Grootendorst DC, Brightling CE, et al. Antiin-flammatory effects of the phosphodiesterase-4 inhibitorcilomilast (Ariflo) in chronic obstructive pulmonary disease.Am J Respir Crit Care Med 2003;168:976–82.

44. Donnelly LE, Rogers DF. Therapy for chronic obstructivepulmonary disease in the 21st century. Drugs 2003;63:1973–98.

45. Beeh KM, Kornmann O, Buhl R, Culpitt SV, Giembycz MA,Barnes PJ. Neutrophil chemotactic activity of sputum frompatients with COPD: role of interleukin 8 and leukotriene B4.Chest 2003;123:1240–7.

46. Gompertz S, Stockley RA. A randomized, placebo-controlledtrial of a leukotriene synthesis inhibitor in patients withCOPD. Chest 2002;122:289–94.

47. Bertini R, Allegretti M, Bizzarri C, et al. Noncompetitiveallosteric inhibitors of the inflammatory chemokine recep-tors CXCR1 and CXCR2: prevention of reperfusion injury.Proc Natl Acad Sci USA 2004;101:11791–6.

48. Underwood DC, Osborn RR, Bochnowicz S, et al. SB 239063,a p38 MAPK inhibitor, reduces neutrophilia, inflammatory

cytokines, MMP-9, and fibrosis in lung. Am J Physiol LungCell Mol Physiol 2000;279:L895–902.

49. Eaton T, Lewis C, Young P, Kennedy Y, Garrett JE, Kolbe J.Long-term oxygen therapy improves health-related qualityof life. Respir Med 2004;98:285–93.

50. Poole PJ, Black PN. Preventing exacerbations of chronicbronchitis and COPD: therapeutic potential of mucolyticagents. Am J Respir Med 2003;2:367–70.

51. Black PN, Morgan-Day A, McMillan TE, Poole PJ, Young RP.Randomised, controlled trial of N-acetylcysteine for treat-ment of acute exacerbations of chronic obstructivepulmonary disease [ISRCTN21676344]. BMC Pulm Med 2004;4:13.

52. Nocturnal Oxygen Therapy Trial Group. Continuous ornocturnal oxygen therapy in hypoxemic chronic obstructivelung disease: a clinical trial. Ann Intern Med 1980;93:391–8.

53. Zielinski J. Effects of long-term oxygen therapy in patientswith chronic obstructive pulmonary disease. Curr Opin PulmMed 1999;5:81–7.

54. Mannix ET, Manfredi F, Palange P, Dowdeswell IR, Farber MO.Oxygen may lower the O2 cost of ventilation in chronicobstructive lung disease. Chest 1992;101:910–5.

55. Somfay A, Porszasz J, Lee SM, Casaburi R. Dose-res-ponse effect of oxygen on hyperinflation and exerciseendurance in nonhypoxaemic COPD patients. Eur Respir J2001;18:77–84.

56. Fletcher EC, Luckett RA, Goodnight-White S, Miller CC, QianW, Costarangos-Galarza C. A double-blind trial of nocturnalsupplemental oxygen for sleep desaturation in patients withchronic obstructive pulmonary disease and a daytime PaO2

above 60mm Hg. Am Rev Respir Dis 1992;145:1070–6.57. Plywaczewski R, Sliwinski P, Nowinski A, Kaminski D,

Zielinski J. Incidence of nocturnal desaturation whilebreathing oxygen in COPD patients undergoing long-termoxygen therapy. Chest 2000;117:679–83.

58. Kimura H, Suda A, Sakuma T, Tatsumi K, Kawakami Y,Kuriyama T. Nocturnal oxyhemoglobin desaturation andprognosis in chronic obstructive pulmonary disease and latesequelae of pulmonary tuberculosis. Respiratory FailureResearch Group in Japan. Intern Med 1998;37:354–9.

59. Chaouat A, Weitzenblum E, Kessler R, et al. A randomizedtrial of nocturnal oxygen therapy in chronic obstruc-tive pulmonary disease patients. Eur Respir J 1999;14:1002–8.

60. Dunn WF, Nelson SB, Hubmayr RD. Oxygen-induced hyper-carbia in obstructive pulmonary disease. Am Rev Respir Dis1991;144:526–30.

61. Mehta S, Hill NS. Noninvasive ventilation. Am J Respir CritCare Med 2001;163:540–77.

62. Ambrosino N, Nava S, Bertone P, Fracchia C, Rampulla C.Physiologic evaluation of pressure support ventilation bynasal mask in patients with stable COPD. Chest 1992;101:385–91.

63. Meecham Jones DJ, Paul EA, Jones PW, Wedzicha JA. Nasalpressure support ventilation plus oxygen compared withoxygen therapy alone in hypercapnic COPD. Am J Respir CritCare Med 1995;152:538–44.

64. Shapiro SH, Ernst P, Gray-Donald K, et al. Effect of negativepressure ventilation in severe chronic obstructive pulmonarydisease. Lancet 1992;340:1425–9.

65. Strumpf DA, Millman RP, Carlisle CC, et al. Nocturnalpositive-pressure ventilation via nasal mask in patients withsevere chronic obstructive pulmonary disease. Am RevRespir Dis 1991;144:1234–9.

66. Gay PC, Hubmayr RD, Stroetz RW. Efficacy of nocturnal nasalventilation in stable, severe chronic obstructive pulmonary

ARTICLE IN PRESS

N.A. Hanania et al.S40

disease during a 3-month controlled trial. Mayo Clin Proc1996;71:533–42.

67. Casanova C, Celli BR, Tost L, et al. Long-term controlledtrial of nocturnal nasal positive pressure ventilation inpatients with severe COPD. Chest 2000;118:1582–90.

68. Muir JF, cuvelier A, Tenang B, European task force onmechanical ventilation COPD. Long-term home nasal inter-mittent positive pressure ventilation (NIPPV) plus oxygentherapy (LTOT) versus LTOT alone in severe hypercapnicCOPD. Preliminary results of a European multicentre trial.Am J Respir Crit Care Med 1997;155:A408.

69. Clini E, Sturani C, Rossi A, et al. The Italian multi-centre study on noninvasive ventilation in chronic obstruc-

tive pulmonary disease patients. Eur Respir J 2002;20:529–38.

70. The National Emphysema Treatment Trial Research Group.Rationale and design of The National Emphysema TreatmentTrial: a prospective randomized trial of lung volumereduction surgery. Chest 1999;116:1750–61.

71. Fishman A, Martinez F, Naunheim K, et al. A randomized trialcomparing lung-volume-reduction surgery with medicaltherapy for severe emphysema. N Engl J Med 2003;348:2059–73.

72. National Emphysema Treatment Trial Research Group.Patients at high risk of death after lung-volume-reductionsurgery. N Engl J Med 2001;345:1075–83.