COPD: How to Manage Early and Late Disease

December 1, 2006

The goals of therapy in chronic obstructive pulmonary disease are to ameliorate symptoms, improve daily function, preserve lung function, identify and reduce exacerbations and, if possible, decrease mortality. A comprehensiveapproach that includes prevention, early identification, and pharmacotherapy-and oxygen therapy, pulmonary rehabilitation, and/or surgery when appropriate-can optimize patient outcomes.

The goals of therapy in chronic obstructivepulmonary disease (COPD)are to ameliorate symptoms, improvedaily function, preserve lung function,identify and reduce exacerbations and,if possible, decrease mortality. A comprehensiveapproach that includes prevention,early identification, and pharmacotherapy--and oxygen therapy,pulmonary rehabilitation, and/orsurgery when appropriate--can optimizepatient outcomes.Here we describe the latest developmentsin the management ofCOPD, including new, longer-acting bronchodilators and refined criteriafor lung volume reduction surgery(LVRS) based on recent data. In Part 1on page 21, we addressed prevention.Comprehensive treatment guidelinesfor COPD were developed in acollaborative effort of the NationalHeart, Lung, and Blood Institute andthe World Health Organization. TheGlobal Initiative for Chronic ObstructiveLung Disease (GOLD) recommendationsare available on the GOLDWeb site (www.goldcopd.com).1 Weprovide select highlights of the GOLDguidelines as well as those of theAmerican Thoracic Society (ATS) inthis article.PHARMACOTHERAPY
Bronchodilators.
These agentsare the mainstay of pharmacotherapyand should be used by all patients withCOPD (Table 1). Bronchodilators effectivelyreduce symptoms and relievedyspnea. Despite the amelioration ofdyspnea, spirometric indices are oftenunchanged (in contrast to the improvementobserved in patients withasthma).Inhalation of a ß2-agonist or anticholinergicthrough a metered-doseinhaler (MDI), nebulizer, or otheraerosol delivery system is preferred.Reserve nebulization for patients whoare severely short of breath and unableto use other inhalation methods.Oral agents play a minimal role; theyare primarily for the few personsunable to take inhaled medications.Newer formulations of bronchodilatorshave been developed to be more specific, less toxic, and longer-acting toimprove overall compliance and symptomcontrol.Anticholinergics. These agentshave long been used to treat pulmonarysymptoms. They interfere withacetylcholine receptors at parasympatheticcholinergic junctions, therebydecreasing bronchial smooth muscletone.Although the GOLD guidelinesare not specific as to which bronchodilatorshould be started first,1 ipratropium,an inhaled anticholinergicagent, is recommended as the first-linebronchodilator by the ATS guidelinesfor the management of COPD.2 Wegenerally follow the ATS guidelinesand start ipratropium for our patients.It may be more effective than inhaledß2-agonists in patients with COPD andhas a very good side-effect profile. Althoughipratropium's onset of action(60 to 90 minutes) is longer than thatof ß2-agonists, its duration of action (6to 8 hours) is longer, making it a goodagent for maintenance therapy.Newer, longer-acting anticholinergicagents are under investigationand may be available soon. Tiotropiumis a once-daily inhaled anticholinergicapproved for use in severalcountries and currently under reviewby the FDA for approval in the UnitedStates. In a 13-week clinical trial, itwas shown to improve both spirometricand symptomatic measures to agreater extent than placebo.3 In a follow-up study comparing it to salmeterol,tiotropium demonstrated similarimprovements in dyspnea and disease-specific health-related quality oflife and slightly better spirometricmeasures after 6 months of continuoususe.4 The once-daily dosing oftiotropium may facilitate adherence tolong-term therapy.ß2-Agonists. Nonspecific ß-adrenergicagonists cause rapid-onset bronchodilationvia stimulation of the ß2-receptor. Newer and preferred agentshave less ß1-agonist activity, which translates into fewer cardiovascularside effects, such as tachycardia andpalpitations.Advances in ß2-therapy have focusedon the development of long-actingagents, such as salmeterol. Theseagents can provide more than 12hours of relief and can reduce dyspneawith a minimal increase in forced expiratoryvolume in 1 second (FEV1).They are particularly helpful in patientswith nocturnal symptoms and inthose who require frequent ß2-agonisttherapy. Long-acting ß2-agonists canbe used as sole maintenance therapyin patients with mild to moderateCOPD. These medications should notbe used as needed to relieve acutesymptoms, because they have a delayedonset of action.Combination bronchodilator therapy.The combination of an anticholinergicwith a ß2-agonist has been shown to be synergistic and to improvelung function more than eitheragent used alone.Ipratropium and albuterol are deliveredin an MDI that provides a fixeddose with each puff; this reduces theneed for multiple inhalers and may improvecompliance. The drawback ofcombination MDI delivery is the inabilityto change bronchodilator doses,particularly in relieving acute symptoms,and the need to use both agentswhen (typically) one agent might suffice.Despite these concerns, regularuse of combined therapy is useful insome patients and is recommended forthose with moderate to severe disease.Corticosteroids. The benefit ofinhaled or oral corticosteroids in asthmais well recognized. However, inCOPD (primarily, emphysema andchronic bronchitis), the appropriateuse of corticosteroids is controversial.Approximately 10% to 30% of patientswith COPD (excluding patients withasthma) have a significant response tooral corticosteroid therapy.Because of the many side effects,routine use of systemic corticosteroidsin COPD should be avoided. Acute exacerbationsmay be treated with ashort course of corticosteroids, such as2 weeks or less of prednisone, 60 mg/d(or the equivalent) with a rapid taper;longer therapy may not provide anyfurther benefit.5Regular use of inhaled corticosteroidsmay be associated with clinicalbenefits, such as reduced exacerbationsand hospitalizations, even withoutdocumented improvement in lungfunction.6 However, prolonged use ofthese agents--particularly at highdoses--may produce systemic side effects(such as subcapsular cataractsand decreased bone mineral density).7,8In addition, a recent meta-analysis ofrandomized controlled trials found thatuse of inhaled corticosteroids in patientswith COPD followed for 24 to 52months was not associated with a slowerrate of decline in FEV1 when comparedwith placebo.9 This continues tobe an area of controversy.10Therefore, in view of the significantside effects of inhaled and oralcorticosteroids and the fact that only aminority of patients will benefit fromthem, we advocate the GOLD recommendationsof reserving long-term useof these agents for1:

  • Patients with a documented spirometricresponse to corticosteroids.
  • Those with an FEV1 of less than 50%of predicted and repeated exacerbationsthat require treatment withantibiotics and oral corticosteroids.


Oxygen therapy.

Long-term oxygentherapy is one of the only treatmentsshown to improve overallsurvival in patients with

COPD.

Secondaryadvantages may include improvementin quality of life andneuropsychological function and stabilizationof pulmonary hypertension these are less well characterized in theliterature.Oxygen delivery has improvedduring the past 10 years, and neweroxygen conservation devices increaseefficiency and prolong use. Some unitsprovide pulse doses of oxygen, initiatedby the patient's breath. Other facialand nasal reservoir devices allow oxygento be stored before inhalation.For maximal benefit, oxygenshould be used more than 15 hoursdaily. Assess patient compliance regularly,because use is often suboptimal.Criteria for long-term oxygentherapy are severe hypoxemia (PaO

2

,55 mm Hg or lower) or a PaO

2

of60 mm Hg or lower with signs ofcor pulmonale or secondary polycythemia(hematocrit higher than55%). Measure the patient's oxygenlevel at rest and during exercise, becausehypoxemia may worsen withphysical activity.

11

Leukotriene modifiers

. Agentsthat interfere with the leukotrienepathway are useful in asthma therapy.They may be corticosteroid-sparingand are particularly helpful in aspirinsensitivepatients. In addition, neutrophilicairway inflammation is thehallmark of

COPD

, and leukotrieneinhibitors have been shown to slow this process in vivo.

12

However, no clinicalend point data yet suggest thatleukotriene modifiers have any role inthe treatment of patients with

COPD

who do not have a significant asthmacomponent. Therefore, use of theseagents for

COPD

alone is not currentlyrecommended.

Mucolytics

. These agents decreasethe viscosity of sputum, makingit easier to cough up. Theoretically,the result is fewer respiratory exacerbationsand improved airflow. ACochrane review and meta-analysisshowed a marginal reduction in exacerbationsand disability days in patientswith chronic bronchitis who alreadyhad a higher-than-average rateof annual exacerbations.

13

These findingscannot be generalized to all patientswith

COPD

.Genetically engineered deoxyribonuclease(dornase) breaks up

DNA

in mucus, can dramatically decreasesecretions, and has been shown toplay a role in the treatment of selectcystic fibrosis patients. Such data donot exist for

COPD

, and results so farhave been disappointing. Therefore,until further research is done, thisagent is not recommended for patientswho have

COPD

.

PULMONARYREHABILITATION


This multidisciplinary programfor patients with chronic lung diseaseis individually tailored to optimize autonomyas well as physical and socialperformance. The clinical effectivenessand scientific validity of pulmonaryrehabilitation have been well establishedin recent years through randomized,controlled clinical trials. Tworeviews have summarized the resultsof these studies and provide importantguidelines about the referral and managementof these patients.

14,15

Programs vary and can be adaptedto an inpatient, outpatient, or homesetting. Supervised sessions are typicallyoffered several times weekly for 6 to 12 weeks while patients learn to performtheir daily home-care program.Program components include exercisetraining, education, and psychosocial/behavioral interventions. The interdisciplinaryteam includes nurses;exercise specialists; and respiratory,physical, and occupational therapists.Pulmonary rehabilitation is for patientswith chronic lung disease who,despite optimal standard medical management,continue to have dyspnea, reducedexercise tolerance, restricted activity,and/or reduced quality of life

(Table 2)

.

15

Pulmonary rehabilitationreduces dyspnea, increases functionalability, and improves quality of life forpersons with

COPD

, even in the faceof irreversible abnormalities in lung architecture.Some studies have shown areduction in

COPD

exacerbations aswell as fewer hospital days and admissions.There is a trend toward decreasedlong-term mortality, but studiesare not conclusive. In this age ofmanaged care, pulmonary rehabilitationis proving itself to be cost-effectiveand is covered by many insuranceplans.

LUNG VOLUMEREDUCTION SURGERY


In the 1950s,

LVRS

was first usedto treat emphysema by removingareas of hyperinflated lung. Althoughthe condition of some patients improved,high rates of mortality andmorbidity discouraged widespreaduse. In the 1990s, better surgical techniquesfacilitated the resurrection ofthis procedure.

16

LVRS

currently involvesa bilateral resection of emphysematouslung via a stapling techniquethrough either a median sternotomyor via thoracoscopy.The primary goal of

LVRS

in patientswith emphysema is to reducehyperexpansion of the lungs by removingless functional emphysematous/bullous lung tissue. This relievesthe compression of the remaininghealthy lung and allows the diaphragm to regain a more efficient position inthe thoracic cavity. Expansion of thehealthy lung may increase its elasticrecoil, helping to maintain patent airwaysand increasing expiratory flowrates. These combined effects can leadto reduced dyspnea, greater exercisetolerance, and diminished need forsupplemental oxygen.Early studies of

LVRS

with shorttermfollow-up in series of select patientssuggest that about 50% to 80% ofpatients have a significant improvementin

FEV

1

postoperatively at 3 to 6months.

16

Several years ago, the procedure started to become more widelyused despite the absence of adequatelong-term data on the relativebenefits, risks, and costs of surgery ascompared with usual treatment.To that end, a nationwide, multicenter,randomized controlled trialto examine the safety and efficacy of

LVRS

in the treatment of emphysemawas recently completed. The NationalEmphysema Treatment Trial (

NETT

)was cosponsored by the Centers forMedicare and Medicaid Services(Medicare), the National Heart Lungand Blood Institute, and the Agencyfor Healthcare Research and Quality.17In

NETT

, all patients received maximalmedical therapy, including pulmonaryrehabilitation, before random assignmentto either surgical or medicaltherapy.In

NETT

, overall results indicatedthat after 24 months, exercise capacityand quality of life were significantly improvedand symptoms were significantlydiminished in patients who underwentsurgery compared with thosewho received medication. There wasno difference in mortality. Additionalsubgroup analyses suggested that patientswith both upper lobe-predominantemphysema and low exercisecapacity had the best results withsurgery, evidenced by significantlybetter survival, exercise tolerance,symptom relief, and quality of life. Incontrast, patients with non-upperlobe-predominant disease with highexercise tolerance had better survival

without

surgery and had no functionalor symptomatic benefits.

Table 3

outlinesselection criteria for

LVRS

basedon the

NETT

results.

LUNGTRANSPLANTATION


COPD

is the most common indicationfor single-lung transplantation.The benefits of lung transplantationcan include the resumption of normalactivities of daily living, normalizationof lung function and hemodynamic parameters, and elimination of the needfor supplemental oxygen.Improved surgical techniques,better patient selection, and new immunosuppressivetherapies for lungtransplantation have improved outcomes.Patients with

COPD

have 1-and 3-year survival rates of 81% and64%, respectively, after lung transplantation.Five-year survival at one UShospital has been recently reported tobe as high as 59%,

18

although the Registryof the International Society forHeart and Lung Transplantation reportsa worldwide 5-year survival ratethat approaches 50%.

19

Unfortunately,progress in lung transplantation hasnot paralleled that for other organs; forexample, in kidney transplantation, the5-year survival rate is greater than 70%.The major factors limiting long-termsurvival of lung transplant recipientsremain infection and chronic rejection.Therefore, carefully considertransplantation when there is severeclinical and physiologic lung disease,medical therapy is no longer effective,and survival is expected to be less than2 to 3 years

(Table 4)

. A 1- to 2-yearwaiting period is typically expected.The survival benefit for patients with

COPD

has not been demonstratedclearly and is difficult to estimate,because many patients with severe

COPD

can live for years.

20

References:

REFERENCES:


1.

Pauwels RA, Buist AS, Calverley PM, et al, forthe GOLD Scientific Committee. Global strategy forthe diagnosis, management, and prevention ofchronic obstructive pulmonary disease. NHLBI/WHO Global Initiative for Chronic ObstructiveLung Disease (GOLD) Workshop summary.

Am JRespir Crit Care Med.

2001;163:1256-1276.


2.

American Thoracic Society. Standards for the diagnosisand care of patients with chronic obstructivepulmonary disease.

Am J Respir Crit Care Med.

1995;152:S77-S121.


3.

Casaburi R, Briggs DD Jr, Donohue JF, et al. Thespirometric efficacy of once-daily dosing withtiotropium in stable COPD: a 13-week multicentertrial. The US Tiotropium Study Group.

Chest.

2000;118:1294-1302.

4.

Donohue JF, van Noord JA, Bateman ED, et al. A6-month, placebo-controlled study comparing lungfunction and health status changes in COPD patientstreated with tiotropium or salmeterol.

Chest.

2002;122:47-55.


5

. Niewoehner DE, Erbland ML, Deupree RH, et al.Effect of systemic glucocorticoids on exacerbationsof chronic obstructive pulmonary disease. Departmentof Veterans Affairs Cooperative Study Group.

N Engl J Med.

1999;340:1941-1947.


6.

Alsaeedi A, Sin DD, McAlister FA. The effects ofinhaled corticosteroids in chronic obstructive pulmonarydisease: a systematic review of randomizedplacebo-controlled trials.

Am J Med.

2002;113:59-65.


7.

Lung Health Study Research Group. Effect of inhaledtriamcinolone on the decline in pulmonaryfunction in chronic obstructive pulmonary disease.

N Engl J Med.

2000;343:1902-1909.


8.

Pauwels RA, Lofdahl CG, Laitinen LA, et al. Longtermtreatment with inhaled budesonide in personswith mild chronic obstructive pulmonary diseasewho continue smoking. European RespiratorySociety Study on Chronic Obstructive PulmonaryDisease.

N Engl J Med.

1999;340:1948-1953.

9.

Highland KB, Strange C, Heffner JE. Long-termeffects of inhaled corticosteroids on FEV

1

in patients with chronic obstructive pulmonary disease.A meta-analysis.

Ann Intern Med.

2003;138:969-973.


10.

Calverly PMA, Barnes PJ. Are inhaled steroidsbeneficial in COPD? A pro/con debate.

Am J RespirCrit Care Med.

2000;161:341-344.

11.

Anthonisen NR. Long-term oxygen therapy inmoderate hypoxaemia.

Thorax.

1997;52:667-668.


12.

Kilfeather S. 5-Lipoxygenase inhibitors for thetreatment of COPD.

Chest.

2002;121:S197-S200.


13.

Poole PJ, Black PN. Mucolytic agents for chronicbronchitis or chronic obstructive pulmonary disease.

Cochrane Database Syst Rev.

2003:CD001287.


14.

ACCP/AACVPR Pulmonary RehabilitationGuidelines Panel. Pulmonary rehabilitation: jointACCP/AACVPR evidence-based guidelines.

Chest.

1997;112:1363-1396.


15.

American Thoracic Society. Pulmonary rehabilitation:1999.

Am J Respir Crit Care Med.

1999;159:1666-1682.

16.

Fessler HE, Wise RA. Lung volume reductionsurgery: is less really more?

Am J Respir Crit CareMed.

1999;159:1031-1035.


17.

Fishman A, Martinez F, Naunheim K, et al, forthe National Emphysema Treatment Trial ResearchGroup. A randomized trial comparing lung-volumereductionsurgery with medical therapy for severeemphysema.

N Engl J Med.

2003;348:2059-2073.


18.

Cassivi SD, Meyers BF, Battafarano RJ, et al.Thirteen-year experience in lung transplantation foremphysema.

Ann Thorac Surg.

2002;74:1663-1670.


19.

Trulock EP, Edwards LB, Taylor DO, et al. TheRegistry of the International Society for Heart andLung Transplantation: Twentieth Official adult lungand heart-lung transplant report-2003.

J HeartLung Transplant.

2003;22:625-635.


20.

International guidelines for the selection of lungtransplant candidates. The American Society forTransplant Physicians (ASTP)/American ThoracicSociety (ATS)/European Respiratory Society(ERS)/International Society for Heart and LungTransplantation (ISHLT).

Am J Respir Crit Care Med.

1998;158:335-339.