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A ccording to the latest report released in December 2010 from the Center for National Health Statistics at the US Centers for Disease Control and Prevention, chronic lower respiratory diseases, which include chronic obstructive pulmonary disease (COPD), have replaced stroke as the third leading cause of death in the United States. 1,2 Emerging Drugs for COPD Target Lung Function, Inflammation, Smooth-Muscle Cells in Airways By Wayne Kuznar ©2011 Engage Healthcare Communications, LLC T he annual cost of maintenance and exacerbation therapy for chronic obstructive pulmonary disease (COPD) exceeds $4000 per patient in Canada, reported M. Reza Maleki- Yazdi, MD, FRCPC, Division of Res- piratory Medicine, Women’s College Hospital, University of Toronto, Canada. The cost becomes higher as the number of exacerbations increases and as COPD severity increases. “There are substantial cost, exacer- bation frequency, and impairment in quality of life in all stages of COPD,” Dr Maleki-Yazdi said. “The results of this study highlight the importance of early detection of the subjects at risk of COPD exacerbations even in earlier stages of the disease.” This 1-year study included 285 men (59.3%) and women, aged 50 years (mean age, 70.4), who had a diagnosis Total Annual COPD Costs Top $4000 per Patient Disease Severity, Exacerbations Increase Economic Burden By Wayne Kuznar INTRODUCTION Chest 2010 Explores State-of- the-Art Management of COPD and Treatments on the Horizon By Wayne Kuznar THE PEER-REVIEWED FORUM FOR EVIDENCE IN BENEFIT DESIGN Patients with COPD and Their Caregivers Are Satisfied with Nebulizer Therapy By Wayne Kuznar FOR PAYERS, PURCHASERS, POLICYMAKERS, AND OTHER HEALTHCARE STAKEHOLDERS FEBRUARY 2011 I VOL 4, NO 1 I SUPPLEMENT 1 Continued on page S3 Continued on page S8 Continued on page S2 Continued on page S5 ACCP 2010: Payers’ Perspectives American College of Chest Physicians 2010 Vancouver, BC, Canada N ebulizer therapy for chronic obstructive pulmonary disease (COPD) receives high marks from patients and their caregivers, accord- ing to the results of 2 separate surveys presented at Chest 2010. Inhalation therapy is a cornerstone of the treatment of COPD, because it is a targeted mode of delivery, pro- duces high local concentrations of the active drug, and lessens systemic exposure. Several devices for inhala- tion therapy are available, including metered-dose inhalers, dry powder inhalers, and nebulizers. caregivers acknowledge Benefits of nebulization In the first survey, 400 caregivers of patients with COPD who are currently using nebulized therapy were inter- viewed over the telephone. “The majority of caregivers recognized the benefits of nebulization therapy and its positive impact on the quality of life of their friend or family member with © Copyright P harmacologic approaches to the treatment of chronic obstructive pulmonary disease (COPD) are evolv- ing rapidly. Thinking outside of the current comfort zone will be required if treatment of COPD is to be improved, said respiratory experts during a sym- posium sponsored by Forest Lab- oratories at Chest 2010. Current pharmacotherapies do not change the natural history of COPD, and many patients remain sympto- matic despite the available therapies, said Nicola Hanania, MD, MS, Director of the Asthma Clinical Research Center, Baylor College of Medicine, Houston, TX. Furthermore, inadequate adher- ence to inhaled therapy is a major cause of poor clinical outcomes in the treatment of COPD, he added. This supplement was made possible by funding from Sunovion, Inc. HealtH economics Burden of COPD . . . . . . . . . . . . . . . . . . . S3 Treatment complexity affects resource utilization . . . . . . . . . . . . . . . . S4 inHalation systems Selecting inhalation device for COPD . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S6 Updates on aerosol delivery . . . . S7 emerging tHerapies Investigational anticholinergic . . S9 Novel PDE 4 inhibitor . . . . . . . . . . . . . S9 Indacaterol shows promise . . . . S10 copD management Systemic effects of COPD and comorbidities . . . . . . . . . . . . . . . . . S11 Heading off exacerbations is crucial . . . . . . . . . . . . . . . . . . . . . . . . . . . . S12 The risk of first acute exacerbation . . . . . . . . . . . . . . . . . . . . . . . S12 proviDers’ perspective COPD: What’s state-of-the-art, what’s in the future? . . . . . . . . . . . . . . . S13 payers’ perspective COPD and associated costs . . . S14 IN THIS ISSUE

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American Health & Drug Benefits February 2011 I Vol 4, No 1 I Supplement 1

Transcript of ACCP 2010: Payers' Perspectives

Page 1: ACCP 2010: Payers' Perspectives

According to the latest reportreleased in December 2010 from

the Center for National HealthStatistics at the US Centers forDisease Control and Prevention,

chronic lower respiratory diseases,which include chronic obstructivepulmonary disease (COPD), havereplaced stroke as the third leadingcause of death in the United States.1,2

Emerging Drugs for COPD TargetLung Function, Inflammation,Smooth-Muscle Cells in AirwaysBy Wayne Kuznar

©2011 Engage Healthcare Communications, LLC

The annual cost of maintenanceand exacerbation therapy for

chronic obstructive pulmonary disease(COPD) exceeds $4000 per patient inCanada, reported M. Reza Maleki-Yazdi, MD, FRCPC, Division of Res -pi ratory Medicine, Women’s CollegeHospital, University of Toronto,Canada. The cost becomes higher asthe number of exacerbations increasesand as COPD severity increases.

“There are substantial cost, exacer-bation frequency, and impairment inquality of life in all stages of COPD,”Dr Maleki-Yazdi said. “The results ofthis study highlight the importance ofearly detection of the subjects at risk ofCOPD exacerbations even in earlierstages of the disease.”This 1-year study included 285 men

(59.3%) and women, aged ≥50 years(mean age, 70.4), who had a diagnosis

Total Annual COPD Costs Top $4000 per PatientDisease Severity, Exacerbations Increase Economic BurdenBy Wayne Kuznar


Chest 2010 Explores State-of-the-Art Management of COPD and Treatments on the HorizonBy Wayne Kuznar


Patients with COPD and TheirCaregivers Are Satisfied withNebulizer TherapyBy Wayne Kuznar



Continued on page S3

Continued on page S8

Continued on page S2

Continued on page S5

ACCP 2010: Payers’ Perspectives

American College of Chest Physicians 2010

Vancouver, BC, Canada

Nebulizer therapy for chronicobstructive pulmonary disease

(COPD) receives high marks frompatients and their caregivers, accord-ing to the results of 2 separate surveyspresented at Chest 2010.Inhalation therapy is a cornerstone

of the treatment of COPD, because itis a targeted mode of delivery, pro-duces high local concentrations of theactive drug, and lessens systemicexposure. Several devices for inhala-tion therapy are available, including

metered-dose inhalers, dry powderinhalers, and nebulizers.

caregivers acknowledge Benefits

of nebulization

In the first survey, 400 caregivers ofpatients with COPD who are currentlyusing nebulized therapy were inter-viewed over the telephone. “Themajority of caregivers recognized thebenefits of nebulization therapy andits positive impact on the quality of lifeof their friend or family member with

© C










Pharmacologic approaches to thetreatment of chronic obstructive

pulmonary disease (COPD) are evolv-ing rapidly. Thinking outside of thecurrent comfort zone will be required iftreatment of COPD is to be improved,said respiratory experts during a sym-posium sponsored by Forest Lab -oratories at Chest 2010.Current pharmacotherapies do not

change the natural history of COPD,and many patients remain sympto-matic despite the available therapies,said Nicola Hanania, MD, MS, Directorof the Asthma Clinical Research Center,Baylor College of Medicine, Houston,TX. Furthermore, inadequate adher-ence to inhaled therapy is a majorcause of poor clinical outcomes in thetreatment of COPD, he added.

This supplement was made possibleby funding from Sunovion, Inc.

HealtH economics

Burden of COPD . . . . . . . . . . . . . . . . . . . S3Treatment complexity affectsresource utilization . . . . . . . . . . . . . . . . S4

inHalation systems

Selecting inhalation device for COPD . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S6Updates on aerosol delivery . . . . S7

emerging tHerapies

Investigational anticholinergic . . S9Novel PDE 4 inhibitor . . . . . . . . . . . . . S9Indacaterol shows promise . . . . S10

copD management

Systemic effects of COPD and comorbidities . . . . . . . . . . . . . . . . . S11Heading off exacerbations is crucial . . . . . . . . . . . . . . . . . . . . . . . . . . . . S12The risk of first acute exacerbation . . . . . . . . . . . . . . . . . . . . . . . S12

proviDers’ perspective

COPD: What’s state-of-the-art, what’s in the future? . . . . . . . . . . . . . . . S13

payers’ perspective

COPD and associated costs . . . S14


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PublisherNicholas [email protected] PublisherMaurice [email protected] DirectorDalia [email protected] EditorLara J. [email protected] AssistantJessica A. SmithSenior Production ManagerLynn HamiltonBusiness ManagerBlanche MarchittoQuality Control DirectorBarbara MarinoEditor-in-ChiefRobert E. Henry609-902-1644Contact Information:For reprints, subscription information, and editorialqueries, please contact: [email protected]: 732-992-1892F: 732-992-1881

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COPD is characterized by progres-sive airflow limitation that is notfully reversible. Almost 13 millionpeople in the United States werediagnosed with COPD in 2006, butthe overall prevalence of COPD inthe United States has been estimatedat 24 million, indicating substantialunderdiagnosis.3,4

As such, better recognition andmanagement of COPD and its exacer-bations are required to reduce theclinical and economic burden of thischronic, progressing disease. Currenttherapies focus almost solely on air-way obstruction and consist mainlyof bronchodilators.

Despite the efficacy of current phar-macotherapies in controlling symp-toms, they do not change the naturalhistory of the disease, and manypatients remain symptomatic.

At the 2010 annual meeting of theAmerican College of Chest Physicians(Chest 2010), new and emerging ther-apies for COPD and state-of-the-artmanagement of the disease werehighlighted in more than 20 scientificplenary sessions, symposia, paneldiscussions, oral abstract sessions,and poster sessions.

Potential future therapies also re -ceived special emphasis, given the scope,morbidity, and mortality of COPD.

The State of COPD Therapy

As discussed in this publication,new beta-agonists, anticholinergics,and combination therapies are underdevelopment to better address themultifactorial nature of COPD andenhance patient adherence to medica-tion regimens.

New therapies for COPD currentlyin development and presented inthis supplement address otheraspects of COPD, such as inflamma-tion, mu cociliary dysfunction, andairway scarring and remodeling.

Many of the novel agents beingdeveloped are once-daily therapies,an important advance in patientacceptance and adherence.

Delivery Systems Can Affect

Treatment Efficacy, Patient


Several methods of aerosol drug de -livery are available, and improvementsto their design are improving the effi-ciency of drug delivery (page S7).

Inefficient delivery of drug to thelungs is a problem with current pres-surized metered-dose inhalers (MDIs)and dry powder inhalers, and pressur-ized MDIs have the added drawbackof requiring coordination be tweentheir actuation and breath inhalationfor optimal efficacy (page S6).

Nebulized therapy (page S7) ismaking inroads, because nebulizersrequire no such coordination betweenactuation and inhalation and can beused effectively in patients with lowpeak inspiratory flow rates.

The 2 classes in development thatmay provide unexpected benefits inCOPD are phosphodiesterase (PDE)4 inhibitors and peroxisome prolif-erator-activated receptor agonists(pages S9-S10).

Importance of COPD


Our understanding of COPD exac-erbations is evolving, as new dataindicate the serious impact of an acuteexacerbation on mortality. More thanone third of patients with COPD willdie within 4 years of a first acute exac-erbation (page S12). In one studyreported here, an acute exacerbationwas typically preceded by 10 days ofworsening symptoms and worseningpulmonary function (page S11).

Preventing exacerbations in COPDis therefore essential for limiting thedecline in lung function that canlead to exacerbations (page S12).Long-acting bronchodilators andinhaled corticosteroids have beenshown to de crease the rate of exacer-bations in COPD.

Theoretically, antibiotics wouldhave a positive impact in this regard,because bacterial infection is animportant risk factor in COPD exacer-

bations; preliminary evidence indeedshows that cyclical antibiotics mayreduce the risk of exacerbation, as dis-cussed by Dr Hanania (page S13).

A new agent—roflumilast, a PDE 4inhibitor—is in late-phase develop-ment in the United States but isalready ap proved in Europe; in clini-cal trials, roflumilast reduced therate of moderate or severe exacerba-tions of COPD (page S9).

COPD Therapies Must Address

an Inflammatory State

Comorbidities are abundant withCOPD, and treatments have differen-tial effects on some of the many sys-temic manifestations of COPD (pageS11). The inflammation that character-izes COPD may represent a general-ized inflammatory state, and thisinflammation may initiate or worsencomorbid conditions.

Some of the diseases that oftencoexist with COPD are cardiovascu-lar disease (ischemic heart disease,heart failure), skeletal muscle weak-ness and osteoporosis, depressionand anxiety disorders, anemia, andobstructive sleep apnea.

Treatment of COPD inflammationmay therefore concomitantly treat sys-temic inflammation and associatedcomorbidities. For instance, inhaledcorticosteroids appear to decrease therisk of heart attack in patients withCOPD. Some therapies that may serveto calm the inflammatory state ofCOPD are broad-spectrum anti-inflammatory treatments. �

References1. Centers for Disease Control and Prevention.Strokes drops to fourth leading cause of death in2008. Press Release. December 9, 2010. AccessedJanuary 4, 2011. 2. Centers for Disease Control and Prevention.National Center for Health Statistics, Accessed January 4, 2011.3. Pleis JR, Lethbridge-Cejku M. Summary healthstatistics for U.S. adults: National Health InterviewSurvey, 2005. Vital Health Stat 10. 2006;232:1-153.4. Yawn BP. Differential assessment and manage-ment of asthma vs chronic obstructive pulmonarydisease. Medscape J Med. 2009;11:20.

Chest 2010 Explores State-of-the-ArtManagement of COPD... Continued from cover


Important Resources for COPD

GOLD (Global Initiative for Chronic Obstructive Lung Disease) guidelines:

TORCH (Towards a Revolution in COPD Health)

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of COPD for at least 1 year. Meanpack-years of cigarettes smoked was45.6; mean COPD duration, 8.2 years;and mean postbronchodilator intoforced expiratory volume in 1 second(FEV1), 58% predicted.The researchers reviewed patient

charts and conducted patient surveysto gather information on healthcareresource utilization related to COPDmaintenance and exacerbations. Inaddition, patients completed theEuroQol 5 Dimensions (EQ-5D) ques-tionnaire on enrollment.The average annual COPD-related

cost per patient was $4147 (Table 1).The annual cost per patient increasedwith increasing COPD severity—measured by the Global Initiative forChronic Obstructive Lung Disease(GOLD) staging criteria—from $3525per patient for those with GOLDstage I disease severity to $6141 perpatient for those with GOLD stage IVseverity. The frequency of exacerbations by

COPD severity is outlined in Table 2.A total of 98 patients (34%) had 157

combined exacerbations. “Forty per-cent of annual COPD-related cost wasdue to exacerbations, and the percent-age of the exacerbation cost contribut-ing to the total cost of COPDincreased with disease severity,” theresearchers noted.

The mean cost per exacerbationwas $3035, of which $2786 was directcosts and $249 was indirect costs (ie,the cost of patient’s and caregiver’smissed time from work). Treatmentsfor exacerbations included medica-tions and outpatient care, 19 visits to

the emergency department, and 40hospitalizations.The mean scores for EQ-5D and the

EQ visual analog scale (VAS) were 0.74and 68.25, respectively. Although the

EQ-5D and EQ VAS scores were as so ci-ated with COPD-related total costs andmaintenance costs, the scores were notcorrelated with the FEV1 percent pre-dicted or the exacerbation costs. �

Total Annual COPD Costs Top $4000... Continued from cover

Table 2 Annual Frequency of Exacerbations per Patient, by COPD Severity

Disease severity category

Patients with 1 exacerbation/yr, %

Patients with ≥2 exacerbations/yr, %

GOLD I 11 14

GOLD II 15 14

GOLD III 29 14

GOLD IV 18 46

COPD indicates chronic obstructive pulmonary disease; GOLD, Global Initiativefor Chronic Obstructive Lung Disease.

Table 1 Annual COPD-Related Cost per Patient, by Disease Severity

COPD severitycategory

Exacerbation-related cost, $ Maintenance cost, $ Total cost, $

GOLD I 698 2041 2739

GOLD II 1354 2171 3525

GOLD III 2414 2984 5398

GOLD IV 2631 3510 6141

All patients 1673 2474 4147

COPD indicates chronic obstructive pulmonary disease; GOLD, Global Initiativefor Chronic Obstructive Lung Disease.

“There are substantial cost,exacerbation frequency, andimpairment in quality of life inall stages of COPD. Theresults of this study highlightthe importance of earlydetection of the subjects atrisk of COPD exacerbations.”—M. Reza Maleki-Yazdi, MD, FRCPC

Burden of COPD on Older Employees Is SubstantialBy Wayne Kuznar

Work productivity and quality oflife are significantly worse in

workers aged ≥65 years with chronicobstructive pulmonary disease (COPD)compared with those without COPD,according to survey data presented atChest 2010.Researchers examined the health

outcomes of 3358 older employees(aged ≥65 years) using the US 2009National Health and Wellness Survey,an online cross-sectional survey. Ofthese employees, 297 self-reported adiagnosis of COPD and 3061 did not.Outcomes measured included

health-related quality of life (QOL),healthcare resource use, and workproductivity and activity, measuredby absenteeism, presenteeism, overallwork loss, and activity impairment.After adjusting for demographic and

health history variables, older workerswith COPD had significantly lowerscores on the mental component sum-mary measure of health-related QOL

(mean scores: 52.05 for patients withCOPD vs 53.37 for those without;range 0-100, with higher scores indicat-ing better health). The physical compo-nent score was also lower in patientswith COPD (mean: 40.29 for those withCOPD vs 47.19 for those without).

In addition, older workers withCOPD had higher levels of presen-teeism, defined as the percentage ofhealth-related impairment while atwork in the past 7 days.

Overall work loss and activityimpairment were also significantlyworse for older workers with COPDthan those without the disease (Table).“These results highlight the sub-

stantial burden of COPD in the elder-ly US workforce, particularly as it

relates to on-the-job productivity, aneffect not often documented in the lit-erature,” the researchers observed.The research team was led by MarcodaCosta DiBonaventura, PhD, Health

Sciences Practice, Kantar Health,New York City.

There were no significant differ-ences in the number of emergencydepartment visits, hospitalizations, ortraditional healthcare provider visitsbetween the 2 groups.“Effective programs and policies

may be necessary to better manageCOPD in the US workforce, particu-larly in the elderly population,” theresearchers suggested. �

Older workers with COPDhad higher levels ofpresenteeism and had more work loss and activity impairment than those without the disease.

Table Impact of COPD on Older Employees (Age ≥65)

Productivity measures(mean)

Employees with COPD, %(N = 297)

Employees without COPD, % (N = 3061)

Presenteeism 12.60 8.71

Work loss 19.26 10.00

Activity impairment 23.93 13.69

COPD indicates chronic obstructive pulmonary disease.

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Health Economics

An examination of a large data-base of employers, health plans,

and public organizations revealedthat persistence and adherence totherapy are greater and resource uti-lization and costs are less with the useof single long-acting inhalers com-pared with multiple long-actinginhalers in the treatment of chronicobstructive pulmonary disease (COPD),according to Andrew P. Yu, PhD, ofAnalysis Group, a consulting groupin Boston, MA.Dr Yu and colleagues examined a

commercial medical claims databaseof 23,494 patients with COPD plus ≥2medical claims. A matched-pair analy-sis was conducted of patients whoused single inhalers versus those whoused multiple inhalers. The patientswere followed for 12 months.Treatment discontinuation was de -

fined as an interruption in prescriptiondrug claims that lasted for ≥30 days.Adherence to inhaler treatment wasestimated based on the proportion ofdays covered.

Adherence: Multiple versus Single


Multiple-inhaler users were lessadherent to their medication regimenthan users of a single inhaler—79.2%of multiple-inhaler users were notadherent (defined as less than 80% ofstudy medication use) compared with71.5% of single-inhaler users. After controlling for potential con-

founders, the proportion of days cov-ered was 8.6% greater for single-

inhaler users, who were 34% morelikely to be adherent than the multiple-inhaler users.Over the 12 months, 86.7% of the

multiple-inhaler users discontinued ≥1of their index inhaler medicationscompared with 78.6% of the single-inhaler users (Table 1). After adjust- ing for confounders, multiple-inhalerusers were 40% more likely to discon-tinue treatment.Higher adherence to COPD medica-

tion is strongly associated with a lowerrisk for mortality and hospitalizationfor COPD exacerbations, Dr Yu noted.The lower adherence to multiple-inhaler use may also be responsible forincreased healthcare resource utiliza-tion in this group, he said.

Resource Utilization, Cost

Another analysis of the same data-base showed an increase in the numberof healthcare visits for multiple-inhalerusers (Table 2), resulting in higherhealthcare costs for multiple-inhalerusers versus single-inhaler users.After adjusting for potential con-

founders, multiple-inhaler users had64% more inpatient admissions forCOPD, 20% more inpatient days, 27%more COPD-related emergency de -part ment visits, 10% more urgent carevisits, and 6% more outpatient visitscompared with single-inhaler users.Incremental all-cause healthcare

costs were higher for the multiple-inhaler users compared with the costsof single-inhaler users. Comparedwith single-inhaler users, total health-care costs for the 12 months of the

study were $3319 greater for multi-ple-inhaler users; their medical costswere $1586 higher, and their pharma-cy costs were $1776 higher. Similarly, incremental costs for

COPD-related healthcare costs werehigher for multiple-inhaler users. Theconvenience of a single inhaler couldexplain the better adherence rate inthis group, Dr Yu said.This study was an observational

study; therefore, although the re -search ers controlled for proxies of dis-ease severity to reduce bias, “multiple-inhaler users may still have had a littlemore severe disease to begin with,which could have affected exacerba-tion rates and outcomes,” said Dr Yu.He noted that for now, the most con-venient inhaler regimen that controlsdisease may be the best option. �

Compared with single-inhalerusers, total 12-month costswere $3319 greater formultiple-inhaler users.

Table 1 12-Month Treatment Discontinuation Rates: Multiple- versus Single-Inhaler Users

Treatment discontinuationSingle

inhaler, %Multiple

inhalers, %Adjusted

hazard ratio

All patients 78.6 86.7 1.40

Well-controlled patients 76.7 86.1 1.44

Poorly controlled patients 82.1 88.4 1.40

Table 2 Annual Healthcare Resource Utilization: Multiple- versus Single-Inhaler Users

Resource utilizationSingle inhaler


Adjusted incidencerate ratio

Inpatient admissions 0.32 0.36 1.15

Inpatient days 2.09 2.43 1.20

Emergency department visits 1.15 1.00 0.93

Urgent care visits 3.24 3.43 1.10

Outpatient visits 43.84 45.57 1.06

Other medical service visits 9.63 10.66 1.12

Launched at Chest 2010, a newCOPD Alliance is focusing on a

national education campaign to raisethe awareness of primary care physi-cians of chronic obstructive pul-monary disease (COPD) and bringabout significant change in the diag-nosis and treatment of this progress-ing, chronic disease.The COPD Alliance is composed

of several national societies—theAmerican College of Chest Physi -cians, the American Academy of

Nurse Practitioners, the AmericanAcademy of Family Physicians, theAmerican College of OsteopathicFamily Physicians, and the AmericanCollege of Osteopathic Internists(representing about 200,000 primarycare and specialty physicians). The need for the campaign is

obvious considering that only about50% of the 24 million Americanswith COPD have been diagnosed.Accord ing to Brian W. Carlin, MD,Chair of the COPD Alliance, thetotal cost of COPD in 2010 is expect-

ed to be $49.9 billion, whichincludes $29.5 billion in directhealthcare expenditures and $20.4billion in indirect costs. The alliance will ask primary care

physicians to integrate the routineuse of validated screening measuresfor patients at risk for the develop-ment of COPD, to use spirometry toconfirm the diagnosis, and to useevidence-based therapy in the man-agement of COPD patients, DrCarlin said.The COPD Alliance has launched

a website ( thatgrants access to free COPD tools; itwill serve as an electronic toolkit tosupport the efforts of healthcareproviders, patients, and caregivers.Outreach and promotional strategieswill be used to reach members.In 2011, each society in the

alliance will develop and delivereducational strategies specificallytailored to its membership. Clini - cians in training will also be target-ed, Dr Carlin said, because fewtraining programs offer compre-hensive training in COPD manage-ment for residents or fellows.As part of its strategy, the alliance

will keep current tools available, suchas the COPD Population Screener, theTobacco Dependence Treatment Tool -kit, the GOLD (Global Initiative forChronic Obstructive Lung Disease)re commendations for diagnosing andtreating COPD, and case-basedCOPD video vignettes.—WK �

COPD Alliance Aims for BetterRecognition and Care of COPD

Although only about 50% of the 24 million Americanswith COPD have beendiagnosed, the total cost ofthe disease in 2010 isexpected to be $49.9 billion.

COPD Treatment Complexity Affects Adherence, Resource UtilizationBy Wayne Kuznar

Andrew P. Yu, PhD

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Expect Widespread Adoption of P4P as Healthcare Spending IncreasesBy Wayne Kuznar

Although pay-for-performance (P4P)is an intimidating concept for

many clinicians, it is rapidly workingits way into healthcare delivery,according to speakers at a panel dis-cussion at Chest 2010. P4P relies onthe use of evidence-based medicine,which can be defined as “the integra-tion of the best research evidence withclinical expertise and patient values,”said Michael H. Baumann, MD, MS,Chief Quality Officer and Professor ofMedicine, Division of Pulmonary,Critical Care and Sleep Medicine,University of Mississippi, Jackson.Performance measures are a hot

topic as a result of the projectedincrease in health expenditures in theUnited States. Health spending was16.6% of the gross domestic product(GDP) in 2008, up from 15.3% in 2002,and is projected to be 19.6% of theGDP in 2019. The wide variationbetween health costs and outcomeshas fueled government scrutiny andthe adoption of performance measuresas a way to improve patient outcomesand quality of care.The recommendations generated

from evidence-based medicine areoften turned into performance meas-ures, Dr Baumann said. Performancemeasures are a tool to evaluate theextent to which the actions of a health-

care provider conform to practiceguidelines or standards of quality. Itcan also be considered a value againstwhich the performance of an individ-ual, group, or hospital can be com-pared, or benchmarked.The components of a “good” per-

formance measure, as defined by theNational Quality Forum, include sci-entific acceptability (it produces con-sistent or credible results whenimplemented), usability (the intend-ed audience understands the resultsand can use them for decisions), andfeasibility (the data are obtained innormal workflow).P4P, also known as value-based

performance, is based on criticalmeasures by which a physician’s per-formance is compared with clinicalbenchmarks. The individual’s per-formance level then determines his orher reimbursement.“Pay-for-performance is already

out there,” Dr Baumann said. Forexample, the Centers for Medicare &Medicaid Services (CMS) is running aPremier Hospital Quality IncentiveDemonstration (HQID), in which hos-pitals receive incentive paymentsbased on performance, improvementin performance, and attaining median-level composite quality scores.Hospitals participating in HQID

raised their overall quality by an aver-age of 18.3% over 5 years, based ondelivery of standardized care meas-ures in 6 clinical areas.CMS also produces a “Hospital

Compare” website—a consumer-ori-ented website that provides informa-

tion on how well hospitals providedrecommended care to patients, DrBaumann noted.The challenges for performance

measurement include the time lag inadopting data to keep up with newtherapies, said Jun Chiong, MD,Director of the Advanced Heart Fail -ure Program and Associate Professorof Medicine, Pharmacology andOutcomes Science, Loma LindaUniversity, CA.In the case of heart failure and other

diseases, correct dosing of an indicatedmedication is crucial to optimal out-comes, so performance measuresshould go beyond “just the percentageof patients on a given drug,” DrChiong said. He also asked whetherhospital stay is a valid performancemeasure, or if outcomes downstreamshould be included in a measure.In ranking hospitals’ performance,

being small has an advantage, DrChiong said. In a study of perfor -mance measures for acute heart attackfrom more than 3700 US hospitals,large-volume hospitals were found tohave better aggregate performancemeasures (ie, use of beta-blockertreatment) but were less likely to beidentified as a top hospital because ofthe unequal denominators (numberof cases). �

“Pay-for-performance isalready out there”; it relies onevidence-based medicine,which can be defined as “theintegration of the bestresearch evidence with clinicalexpertise and patient values.”

—Michael H. Baumann, MD, MS

COPD,” said lead investigator AmirSharafkhaneh, MD, PhD, DABSM,Associate Professor of Medicine,Section of Pulmonary, Critical Care,and Sleep Medicine, Baylor College ofMedicine, Houston, TX. Among the caregivers, 92% ex -

pressed satisfaction with nebulizedtreatment, 80% rated a nebulizer as bet-ter than using only an inhaler, and 12%reported that using a nebulizer was notdifferent from using an inhaler.When asked about their views of

nebulization therapy, more than 80%of the caregivers agreed that nebu-lization made it easier to help care fora friend or family member, that thebenefits outweigh any difficulties orinconvenience, and that the overallquality of life of their friend or family

member had improved since begin-ning nebulization.

The most positive aspect of nebuliza-tion, cited by 65% of the caregivers, wasits ability to allow the patient to breatheeasier and/or to open up the airways.

Patients Describe Similar Benefits

A similar survey of 400 patients

with COPD who received nebulizedtherapy yielded nearly identical

results: 80% of them rated nebulizedtherapy as better than using only aninhaler, and 12% said that they foundit no different from an inhaler. Theoverall patient satisfaction rate withnebulized therapy was 89%.More than 80% of the patients

agreed that the benefits of nebuliza-tion outweighed any difficulties orinconvenience, that nebulizationmade it easier for their caregivers tohelp care for them, and that the over-all quality of their lives hadimproved since starting using a neb-ulizer. Furthermore, 60% of thepatients said that they wished theycould have started nebulized thera-py sooner.“Overall, these data do not support

the current negative perception thatnebulization may be too cumbersomefor the patient and/or the caregiver,”Dr Sharafkhaneh concluded. “Clini -cians should consider patient-report-ed benefits and preferences whenchoosing a system to deliver inhaledmedications for COPD.” �

More than 80% of the patients agreed that the benefits of nebulization outweighed any difficulties or inconvenience.“Clinicians should consider patient-reported benefits and preferences when choosing a system to deliver inhaled medications.”

—Amir Sharafkhaneh, MD, PhD, DABSM

Patients with COPD and Their Caregivers Are Satisfied... Continued from cover

Inhalation Systems

See also pages S6-S7.

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Inhalation Systems

Peak inspiratory flow rate (PIFR) isan important consideration in the

selection of an inhalation device in themanagement of chronic obstructivepulmonary disease (COPD), saidNicola A. Hanania, MD, MS, Director ofthe Asthma Clinical Research Center,and Associate Professor of Medicine,Sec tion of Pulmonary and Critical CareMedicine, Baylor College of Medicine,Houston, at a symposium sponsoredby Sunovion, Inc, held at Chest 2010.Patients with low PIFR may obtain

greater therapeutic benefit from neb-ulized therapy, because unlike drypowder inhalers, nebulizers haveminimal resistance and PIFR require-ments for effective use.

PIFR is defined as the maximumamount of air that can be inhaled overthe course of 1 deep breath, and ismeasured in L/min. A low PIFR,which is more common in olderpatients and those with more severeCOPD, may result in inadequate drugdeposition in the lungs when using drypowder inhalers, thus compromising

drug efficacy, Dr Hanania explained.“Why should internal resistance and

PIFR matter? For the drug to work, ithas to be deposited where you wantit,” Dr Hanania said. A low PIFR—defined as <30 L/min

—results in greater drug deposition inthe mouth and throat than in thelungs. Lung function is another impor-tant measure of effective drug delivery,and low PIFR correlates with poorerlung function, he said.Although metered-dose inhalers

(MDIs) also have minimal resistanceand PIFR requirements, MDIs requirecoordination between actuation of thedevice and the inhalation for effectivedrug delivery. Patients must inhalewith a slow, deep breath and then holdtheir breath when using an MDI. “When choosing a delivery system,

you want something the patient canaccept. You have to choose the rightdrug and the right delivery system,”Dr Hanania said.Coordination between device actua-

tion and inspiration is not necessary fora nebulizer, he said, “and a nebulizer iseffective with regular tidal breathing;deep breaths are not required.”As nebulizers have become more

portable, they have become more pop-ular with patients. Approximately 25%of patients with COPD use nebulizedtherapy to manage their disease,according to Dr Hanania. In a survey of patients with COPD,

the advantages of nebulizer therapy

were considered to outweigh anypotential disadvantages of nebulizertherapy. The advantages cited were:• An increased feeling of well-being• Better symptom control• Increased confidence• Greater independence.

The GOLD (Global Initiative forChronic Obstructive Lung Disease)guidelines recommend intermittentshort-acting beta-agonist therapy forpatients with mild COPD, stepping upto the addition of ≥1 long-acting beta-agonists (LABAs) with moderate orworse disease. The addition of inhaledcorticosteroids is recommended forsevere or very severe disease. The 2 LABAs currently available in

the nebulized format are arformoteroltartrate (Brovana) and formoterolfumarate (Symbicort).Formoterol is a racemic mixture of

the (R,R)- and (S,S)-isomers. Arfor -moterol contains only the (R,R)-iso-mer and is 1000 times more potent atreceptor sites than formoterol, DrHanania said.Arformoterol is approved for the

treatment of COPD, to be dosed every12 hours. In 12-week comparisonswith placebo in patients with COPD,the improvement in forced expiratoryvolume in 1 second (FEV1) from base-line was significantly greater witharformoterol (15 µg) compared withplacebo at the end of the 12-hour dos-ing interval. The mean FEV1 improve-ment from baseline was also superiorwith arformoterol versus placebo overthe 12-hour dosing interval.Shortness of breath was also re -

duced with arformoterol, as measuredby the transitional dyspnea index(TDI) score. The mean improvement inTDI was 2.0 units with arformoterolcompared with 1.1 units for placebo,Dr Hanania said.Use of arformoterol was also associ-

ated with a reduction in the use ofshort-acting bronchodilators, he said.Daily rescue albuterol was reduced by37% from baseline in arformoterol-treated patients compared with a 2%reduction in placebo recipients, anddaily use of supplemental ipratropi-um was also reduced by 37% witharformoterol and by 9% with placebo.The percentage of patients reportingad verse events was similar betweenarformoterol and placebo. �

“Why should internalresistance and PIFR matter?For the drug to work, it has to be deposited whereyou want it.”

—Nicola A. Hanania, MD, MS

Selecting an Inhalation Device for COPD Should Consider Peak Flow Rates, Patient SatisfactionBy Wayne Kuznar

“Whenchoosing adelivery system,you wantsomething thepatient can

accept. You have to choosethe right drug and the rightdelivery system.”

—Nicola A. Hanania, MD, MS

In a comparison of 4 inhalers used inthe treatment of chronic obstructivepulmonary disease (COPD), patientspreferred the Genuair for its per-ceived ease of use. The Genuair alsoranked highest in overall success rate,which was defined as patients’ abilityto successfully open, prepare, close,and clean the inhaler.Chris Hass, Usability Consultant,

Bentley University Design andUsability Center, Waltham, MA, andcolleagues compared the Genuair,Diskus, HandiHaler, and Respimatinhalers in 48 patients (mean age, 63.5years) who had COPD, chronic bron-chitis, or emphysema. The patients had 1 to 5 years’ expe-

rience with other inhalers before

being enrolled in the study. Becausethe study focused on ease of userather than on efficacy of the medica-tion, no medication was used.

During 90-minute sessions, theresearchers observed the patients asthey assembled and activated the

inhalers. The patients were asked toopen the inhaler packaging, prepare adose, mimic inhalation, close theinhaler, and clean the device. Theresearchers recorded errors in any ofthe processes, and between inhalerexaminations they interviewed the pa -tients about their inhaler experiences.Patients also rated individual and

overall device attributes on a 1-to-5scale (worst to best). The ratingsfocused on key inhaler use steps andsatisfaction with the inhalers. Patientsthen ranked the inhalers in order ofoverall preference.The majority of the patients (94%-

100%) were able to open all theinhalers. Dose preparation was donesuccessfully by 73% of patients with

HandiHaler, by 69% of patients withGenuair, by 69% of patients withDiskus, and by 23% of patients withRespimat. Successful cleaning wasachieved with Genuair, Respimat,and Diskus most of the time (98%-100%) but only 52% of the time withHandiHaler, Mr Hass said.Success with all inhaler steps was

accomplished by 69% of patients withGenuair, by 67% with Diskus, by 35%with HandiHaler, and by 23% withRespimat.The Genuair inhaler received the

highest satisfaction rating in all thecategories assessed—overall satisfac-tion, manipulation measures, inter-face measures, and all measures forinhaler.—WK �

Performance, Preference Vary for COPD Inhalers

The Genuair inhaler receivedthe highest satisfaction ratingby patients in all categories—overall satisfaction,manipulation measures,interface measures, and allmeasures for inhaler.

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Inhalation Systems

Almost two thirds of patients andclinicians do not know the prop-

er inhaler technique to get the maxi-mal benefit of drug treatment forchronic obstructive pulmonary disease(COPD). A panel discussion focusedon current and future aerosol drugdelivery at Chest 2010.The effectiveness of aerosolized

drug delivery depends on the patient,the properties of the propellant andthe drug, and the type of inhaler.Inhalers have as many as 17 steps fortypical use and some types requiresynchronization between inspirationof breath and aerosol actuation or aconstant breathing pattern, saidJames Fink, PhD, Adjunct Professor,Georgia State University, Atlanta, andan independent consultant to thebiotechnology industry.Even with perfect inhalation tech-

nique, however, deposition of parti-cles can be limited by airway geome-try, which is altered by the presence ofCOPD and other airway diseases.Inhalers can be classified as pressur-

ized metered-dose inhalers (MDIs),dry powder inhalers, or jet or ultra-sonic nebulizers. The major drawback of convention-

al pressurized MDIs and dry powderinhalers is inefficient delivery of drugto the lungs; only about 10% to 40% ofthe drug reaches the lungs. Several design changes have been

made to inhalers to promote more effi-cient drug delivery, including produc-tion of particles within the extra-finerange to target the deep lung, saidMyrna B. Dolovich, PEng, AssociateClinical Professor, Division of Respirol -ogy, McMaster University, Canada.

Pressurized Metered-Dose


Spacers are now used with manypressurized MDIs to collect large par-ticles that would normally be deposit-ed in the mouth or the back of thethroat. Although spacers have littleeffect on the concentration of drugdeposited in the lungs, they reducethe total amount of the drug deposit-ed in the body. (Lung penetration isdetermined by the size of drug parti-cles in the aerosol; only particlesbetween 1 µm and 5 µm in diameterreach the airway.)Newer pressurized MDIs have

breath-synchronized devices to controlinhalation. Actuators have recentlybeen introduced that will improve theefficacy and efficiency of pressurizedMDIs by increasing the respirable frac-

tion of drug delivered, which will alsoserve to reduce side effects.Ozone-damaging chlorofluoro-

carbons (CFCs) must be phased out ofmedical devices per the MontrealProtocol obligations, and are beingreplaced by hydrofluoroalkaline pro-pellants. The Modulite is a CFC-freeMDI with beclomethasone dipropi-onate as its constituent. Parti cle sizeis smaller to achieve greater lungpenetration and the aerosol is slowermoving compared with CFC pressur-ized MDIs, to make it easier forpatients to coordinate the breath.

The Modulite platform wasmatched to its CFC counterparts on amicrogram-for-microgram basis (usingsalbutamol pressurized MDIs andsome corticosteroid pressurized MDIs),so no dosage modification is neededwhen switching from a CFC to ahydrofluoroalkaline formulation, Pro -fessor Dolovich said.Breath-actuated pressurized MDIs

have been developed to overcome theproblem of poor coordination betweenpressurized MDI actuation and inhala-tion. Higher pulmonary dispositionhas been achieved with the MaxairAutohaler, a breath-actuated pressur-ized MDI, in patients who had poorcoordination with a conventional CFCpressurized MDI, she said.In another study, the onset of bron-

chodilation was similar between for-moterol/beclomethasone Moduliteand formoterol/budesonide Turbu -haler (another breath-actuated pres-surized MDI), and greater than withformoterol alone in patients withCOPD, Professor Dolovich stated.


The use of nebulizer therapy hasbeen increasing. Nebulizers are typi-cally used by patients who have diffi-culty operating pressurized MDIs ordry powder inhalers, because of poorhand–lung coordination. Con vention al nebulizers continu-

ously release a drug throughout therespiratory cycle, so that as much astwo thirds of the drug is wasted dur-ing expiration. They allow delivery ofindividual drug doses over a longerperiod than can be achieved with pres-surized MDIs or dry powder inhalers,but to use a conventional nebulizermost efficiently, patients must be ableto adapt to the device and have a reg-ular breathing pattern.Vibrating mesh nebulizers are a more

recent development; they have a high-er lung deposition, negligible residualvolumes, and a faster rate of nebuliza-tion compared with jet nebulizers.“Position of the nebulizer has been

found to influence drug delivery,”Professor Dolovich said. In a study ofthe effect of nebulizer type and posi-tion on drug delivery, it was found thatplacement of the nebulizer before thehumidifier increased drug deliverywith vibrating mesh nebulizers and jetnebulizers, and that drug delivery withthe vibrating mesh nebulizer was morethan double that with the jet nebulizerat all positions.Adaptive aerosol delivery systems

have been designed to detect and con-stantly adapt to a patient’s variablebreathing patterns. Software-drivenmonitoring and control systems moni-tor inspiratory flow and breathing fre-quency. The technology enables meas-urement of the volume of drug

delivered per aerosol pulse, whichensures that the total preprogrammeddose is delivered.

Dry Powder Inhalers

Dry powder inhalers are breath-actuated devices, and therefore do notrequire patient coordination, which isan advantage over pressurized MDIs.Newer designs for dry powderinhalers incorporate battery-drivenimpellers and vibrating piezoelectriccrystals that reduce the need forpatients to generate a high inspiratoryflow rate, as with conventional drypowder inhalers.Drug delivery into the lungs with

dry powder inhalers is 10% to 37%;recent improvements in design per-mit the dose dispensed to be inde-pendent of inspiratory flow rate, at 30L/min to 90 L/min. Variations in thedesign and performance of dry pow-der inhalers may make them not read-ily interchangeable. �

New Developments in Aerosol Delivery Aim to Improve Therapeutic EfficacyBy Wayne Kuznar

The major drawback ofconventional pressurizedMDIs and dry powderinhalers is inefficient deliveryof drug to the lungs; onlyabout 10% to 40% of thedrug reaches the lungs.

“Position of thenebulizer hasbeen found toinfluence drugdelivery.”

—Myrna B. Dolovich, PEng

Patients with chronic obstructivepulmonary disease (COPD) pre-fer the Breezhaler single-dose drypowder inhaler over the HandiHalerfor continued daily use. Their prefer-ence stems from ease of use and con-fidence that the medication is takencorrectly using the Breezhaler, ac -cording to a poster presented byKenneth R. Chapman, MD, MSc,Director, Asthma & Airway Centre,University Health Network, TorontoWestern Hospital, Canada. “These initial impressions, after a

relatively short familiarization peri-

od, may be important to continuedsuccessful use, since a patient maybe more adherent when using aninhaler that they like and find easyto use,” Dr Chapman and colleaguesobserved.They studied 82 patients (aged ≥40

years) with mild-to-severe COPDand a smoking history of at least 10pack-years who required treatmentwith inhaled medication. Patients were randomized to either

the Breezhaler or the HandiHalerwith placebo capsules once daily for7 days in addition to usual treatment,

Dry Powder InhalersCompared for Correct Use,Ease of Handling: Breezhaler versus HandiHaler

Continued on page S8

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Emerging Therapies

Emerging Drugs for COPD Target Lung Function... Continued from cover

“COPD is a systemic disease and amulticomponent disease,” Dr Hananiasaid. Novel targets of therapy wouldreduce local and systemic inflammation,and potentially regenerate the lung.

Ultra–Long-Acting Bronchodilators

Bronchodilators remain the corner-stone of treatment and act to controlsymptoms; long-acting bronchodila-tors represent an advance over short-acting bronchodilators in improvinglung function (as measured by forcedexpiratory volume in 1 second [FEV1]),said Mario Cazzola, MD, Professor ofRespiratory Medicine, University ofRome Tor Vergata, Italy.“Since it has been difficult to dis-

cover novel classes of bronchodilatordrugs, the logical approach has beento improve the existing bronchodila-tors,” Dr Cazzola said.A once-daily bronchodilator would

further improve compliance over thecurrent long-acting agents. Other cri-teria for a new bronchodilator wouldinclude a fast onset of action anddrug delivery through an efficientand convenient device (ie, a breath-actuated device with effective feed-back to indicate successful inhalation),Dr Cazzola said. Several ultra–long-

acting beta-agonists (LABAs) are cur-rently under development for COPD.

Indacaterol is one candidate as anultra-LABA. In preclinical models,indacaterol demonstrated a rapidonset of action that correlated with

high intrinsic efficacy and a 24-hourduration of action. Its 24-hour duration of bronchodi-

lation may be a result of its retentionin the raft domain of the lipid mem-brane, Dr Cazzola ex plained. Lipidrafts are areas of cell membraneswhere beta2-receptors are held to -gether in close contact with signalingmolecules and effectors.In clinical trials of adult patients

with COPD, 12 weeks of therapy withindacaterol proved to be superior totiotropium, formoterol, and to salme-terol in trough FEV1 levels comparedwith placebo. Indacaterol was also superior to its

comparators on measures of health-related quality of life, symptoms ofbreathlessness, and percentage of dayswithout the use of rescue medication,and it was associated with an increasein the time to a first exacerbation dur-ing 1 year compared with placebo.

Carmoterol is another ultra-LABAunder investigation. After 14 days oftreatment, a 4-µg dose of carmoterolincreased peak FEV1 by a mean ofapproximately 110 mL (placebo-adjusted), compared with an increaseof 80 mL with salmeterol.Yet another investigational agent in

this class, vilanterol trifenatate, pro-duced dose-dependent increases intrough FEV1 as high as 160 mL com-pared with placebo.

Olodaterol is not as advanced in itsdevelopment; in preclinical studies, itdemonstrated a fast onset of and a longduration of action, Dr Cazzola said.

Attacking Inflammation

Ideal future options for COPDshould address the multiple compo-nents of the disease, which include,among others, mucous hypersecretion,mucosal damage, inflammation, andloss of alveolar attachments, accordingto Dr Hanania. Ideally, new therapieswould blunt proinflammatory cells,modify disease progression, be com-patible with other therapies, and besimple to administer.In addition to improved treatment,

“we should not forget the delivery sys-tem,” Dr Hanania said. More effectiveanti-inflammatory therapy is needed,he said. Phosphodiesterase (PDE) 4inhibitors have anti-inflammatoryaction in COPD, and there is strongscientific rationale for their use inCOPD, said Dr Hanania. Most PDE 4 inhibitors in develop-

ment are administered systemically,but some inhaled formulations are inthe works, he said.

Roflumilast is the oral PDE 4 in -hibitor that is furthest along in develop-

ment; it inhibits PDE 4 activity in proin-flammatory cells and is approved foruse in the European Union but not yetin North America. Roflumilast has been shown to

reduce the rate of moderate-to-severeCOPD exacerbations before or duringthe use of bronchodilator agents. Whenused in combination with a long-act-ing bronchodilator or long-actingmuscarinic antagonist in patientswith moderate-to-severe COPD, it hasalso demonstrated an improvementin lung function.Some inhaled macrolide antibiotics

are currently being investigated for thetreatment of COPD, according to DrHanania. The macrolide antibioticerythromycin may also act as an anti-inflammatory agent to reduce thenumber of exacerbations in COPD,and studies with macrolides are ongo-ing, he said.

Relaxing Smooth Muscles

Long-acting antimuscarinic agentsalso are in development, some in com-bination with ultra–long-acting bron-chodilators, and combinations ofinhaled corticosteroids and ultra–long-acting bronchodilators are being testedclinically, Dr Cazzola said.

Aclidinium bromide is a new mus-carinic antagonist in development. Atwice-daily inhaled agent deliveredvia a dry powder inhaler, it is beinginvestigated for maintenance treat-ment of COPD. In placebo-controlled studies it pro-

vided long-lasting bronchodilationand was associated with improve-ments in FEV1 and other measures oflung function. It has a faster rate ofonset of the smooth-muscle–relaxingactivity than tiotrop ium bromide,the current muscarinic antagonist onthe market.

Targeting Oxidative Stress

Because oxidative stress is knownto occur in COPD, agents that targetreactive oxygen species—the superox-ide dismutase inhibitors—hold pro -m ise in the treatment of COPD, saidIrfan Rahman, MSc, PhD, AssociatePro fessor of Environmental Medicine,Lung Biology and Disease Program,Univer sity of Rochester MedicalCenter, NY. Antioxidant therapy may affect

important outcomes in COPD, suchas helping to overcome steroid resist-ance, mucous hypersecretion, andinflammation. Antioxidants may havea role in combination with anti-inflammatory agents, bronchodila-tors, and other COPD treatments, DrRahman said. �

“Since it has been difficult todiscover novel classes ofbronchodilator drugs, thelogical approach has been toimprove the existingbronchodilators.”

—Mario Cazzola, MD

and then were switched to the oppo-site inhaler.On day 1, patients read written in -

structions for use of the inhaler andhad 30 minutes to practice. Patients’ability to perform each of the 21steps required for correct use of the

Breez haler, as well as the 19 stepsrequired for the HandiHaler, wererecorded by 2 trained assessors. Foreach device, 2 steps were deemedessential for correct use. Patientsthen received training and a demon-stration of correct device use. Theywere assessed again on day 7. Afterthe end of the second treatment

period, they completed a preferencequestionnaire. Most patients completed each han-

dling step for both inhalers correctlyafter 7 days (78%-100% for Breez -haler; 81%-100% for HandiHaler).For most steps, the proportion ofpatients correctly performing thestep improved from day 1 to day 7.Patient training had a greater effect

on use of the HandiHaler than on useof the Breezhaler, Dr Chapman said.For the critical step of fully releasingthe button before inhalation, theBreezhaler score was similarly highon both days (93% and 96%, respec-tively), whereas the HandiHalerscore changed 11 points, from 88% onday 1 to 99% on day 7.Overall, patients preferred the

Breezhaler (61%) over the Handi -Haler (31%). The Breezhaler waspreferred for ease of opening andclosing the cap and mouthpiece,closing the mouthpiece after insert-ing the capsule, and holding theinhaler during use. It was also pre-ferred for simplicity of use and forconfidence in successful intake ofthe medication.—WK �

Dry Powder Inhalers... Continued from page S7

In this study, the Breezhalerwas preferred for ease ofopening and closing the capand mouthpiece, closing themouthpiece after insertingthe capsule, and holding theinhaler during use.

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Emerging Therapies

Twice-daily treatment with acli-dinium, an investigational long-acting muscarinic antagonist in

phase 3 development, results in sus-tained bronchodilation and improve-ment in lung function in patients withchronic obstructive pulmonary disease(COPD), according to the results of 2randomized, controlled clinical trialspresented at Chest 2010.

Aclidinium Improves COPD


The first was a placebo-controlled,double-blind, 12-week study of 561patients with moderate-to-severe, sta-ble COPD who were randomized toaclidinium, 200 µg or 400 µg twicedaily, or placebo. Patients could con-tinue using salbutamol and inhaled,oral, or parenteral corticosteroids (upto 10 mg/day or 20 mg every otherday) as needed. A total of 467 patientscompleted the study.According to the investigators, led

by Edward Kerwin, MD, at theClinical Research Institute in Medford,OR, “Cholinergic tone is the major

reversible component of airflow ob -struction; thus, therapy with anti-cholinergics can be effective in thetreatment of COPD.”The change from baseline in trough

forced expiratory volume in 1 second(FEV1) at week 12 was 86 mL greater inthe patients randomized to aclidinium200 µg and 124 mL greater in thoserandomized to aclidinium 400 µg com-pared with placebo.The change in peak FEV1 from base-

line to week 12 was 146 mL greater inthe aclidinium 200-µg group com-pared with placebo, and 192 mLgreater in the aclidinium 400-µggroup compared with placebo.Both doses of aclidinium were asso-

ciated with significantly better im -provement compared with placebo inscores on the St. George’s Respira toryQuestionnaire (a standardized, self-completed questionnaire for measur-ing impaired health and perceivedwell-being in airways disease) and inthe transitional dyspnea index.Both doses of aclidinium were well-

tolerated. The incidence of treatment-

emergent serious adverse events was2.2% in the placebo group, 4.3% in theaclidinium 200-µg group, and 3.2% inthe aclidinium 400-µg group.

Aclidinium Safe and Effective for


In the second randomized, double-blind study, German investigatorscompared the safety and efficacy ofaclidinium 400 µg twice daily withplacebo and with tiotropium 18 µgonce daily in 30 patients with moder-ate-to-severe COPD. Patients weretreated for 15 days with their assigned

therapy and then crossed over toanother therapy, until they completed15 days in each of the 3 arms, with awashout period of 9 to 15 daysbetween treatments.The normalized FEV1 area under the

curve for 12 hours immediately aftermorning dose administration on day15 was increased significantly withaclidinium or tiotropium comparedwith placebo. The researchers reportedthat optimal bronchodilation wasachieved as early as the first day oftreatment.The bronchodilatory effect of acli-

dinium and tiotropium versus placebowas sustained over 24 hours on day 15.The average use of rescue medica-

tions declined significantly frombaseline in the aclidinium (–1.48puffs) and tiotropium (–0.79 puffs)groups compared with those receiv-ing a placebo (–0.53 puffs).In addition, aclidinium—but not

tiotropium—significantly reducedthe scores for breathlessness, cough,and nighttime symptoms comparedwith placebo. �

Investigational Anticholinergic Achieves Early BronchodilationCholinergic Tone the Main Reversible Factor in Airflow ObstructionBy Wayne Kuznar

Both doses of aclidinium—200 µg and 400 µg twicedaily—were associated withsignificantly greaterimprovement compared withplacebo. Adverse events werefewer with the higher dose.

Roflumilast, an oral selectivephosphodiesterase (PDE) 4inhibitor reduced the rate of

moderate or severe exacerbations com- pared with placebo in patients withchronic obstructive pulmonary di sease(COPD), said Nicola A. Hanania, MD,MS, Director of the Asthma ClinicalResearch Center, Baylor College ofMedicine, Houston, TX. The effects of roflumilast were more

pronounced in patients who had a his-tory of frequent exacerbations and inthose with more severe disease, basedon a pooled analysis of 2 year-longstudies presented at Chest 2010.“Reduction of the rate of COPD

exacerbations may improve overallpatient outcomes and result in a reduc-tion of the healthcare burden,” DrHanania said.Because exacerbations are inflamma-

tory events, and PDE 4 may affect mul-tiple inflammatory cells in the lung, aPDE 4 inhibitor could be expected toreduce the number and severity ofCOPD exacerbations, he said. “Roflu -milast targets key proinflammatory

mediators underlying the pathogenesisof COPD and associated exacerba-tions,” Dr Hanania said. Frequent exac-erbations (≥2 annually) occur in up to50% of patients with COPD, depend-ing on their disease severity.

Dr Hanania and colleagues lookedat the exacerbation rate and time toexacerbations in 1538 patients withsevere COPD and a history of exacer-bations who were enrolled in 1 of 2multicenter, placebo-controlled trialsin which they were randomized toroflumilast or placebo for 52 weeks.An exacerbation was defined as new

or worsening COPD symptoms thatrequired oral or parenteral glucocorti-coids or hospitalization. The results ofthese trials showed that:• The rate of moderate or severe exac-erbations was reduced by 17% withroflumilast compared with placebo

• The time to a first or second moder-ate or severe exacerbation wasextended in roflumilast recipientsby 11% and 21%, respectively

• The rate of moderate or severe exac-erbations in the roflumilast groupsdeclined by 18.7% in patients withsevere COPD and by 19.7% in thosewith very severe COPD

• Among patients with 2 or moreexacerbations before enrollment inthe study, roflumilast reduced theexacerbation rate by 22% comparedwith placebo, and in those withfewer than 2 exacerbations beforestudy entry, it reduced the exacerba-tion rate by 16%

• Some 27.7% of placebo patientsexperienced ≥2 moderate or severeexacerbations during the study com-pared with 21.4% of the roflumilast

groups. The benefit of roflumilast onthis end point was observed regard-less of disease severity, although theeffects were more pronounced inpatients with a history of frequentexacerbations and in those withmore severe disease.“Roflumilast has minimal bron-

chodilatory effects; it’s not a bron-chodilator,” Dr Hanania said. “We’renot going to see improvements inFEV1 [forced expiratory volume in 1second] of 100 mL with roflumilast.”Instead, its benefits can be attributedto its anti-inflammatory activity. Assuch, he envisions that roflumilast willbe used as add-on therapy to long-act-ing bronchodilators, but it remains tobe seen whether it will be used beforeor after initiation of inhaled cortico -steroids as add-on therapy.Side effects of roflumilast include

nausea and other gastrointestinal sideeffects, as well as weight loss, butnone of these have caused with-drawals from clinical studies. Themechanism behind weight loss is stillbeing explored.—WK �

Novel PDE 4 Inhibitor Cuts COPD ExacerbationsAnti-Inflammatory Effects Are Crucial in This Disease

“Reduction of the rate ofCOPD exacerbations mayimprove overall patientoutcomes and result in areduction of the healthcareburden.”

—Nicola A. Hanania, MD, MS

See also pages S10, S15.

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Emerging Therapies

When used concomitantly withinhaled corticosteroids, roflu-

milast—the phosphodiesterase (PDE)4 inhibitor currently under review bythe US Food and Drug Admin -istration—further improves lungfunction, reduces the rate of exacerba-tions, and has an additive therapeuticeffect in patients with chronic ob -structive pulmonary disease (COPD),said Stephen I. Rennard, MD, Pro -fessor of Internal Medicine, Divisionof Pulmonary, Critical Care, Sleep &Allergy, University of Nebraska,Omaha. He and his colleaguesassessed data from 2 trials in the ro - flumilast development program thatallowed for concurrent inhaled corti-costeroid use.

Roflumilast Reduces


Of the 2686 patients enrolled in the2 studies, roflumilast was used withinhaled corticosteroids in 1622patients. Prebronchodilator forcedexpiratory volume in 1 second (FEV1)

levels improved by 53 mL comparedwith placebo in the group receivingroflumilast plus inhaled cortico -steroids, and by 49 mL comparedwith placebo in those not usinginhaled corticosteroids.Roflumilast was better at reducing

exacerbations in patients who werealso taking inhaled corticosteroids.The mean rate of COPD exacerbations

was reduced by 19% with roflumilastcompared with placebo with concomi-tant inhaled corticosteroid use, and by8% without inhaled corticosteroids.Dr Rennard said that concurrent

treatment with inhaled corticosteroidsidentified patients who had moreexacerbations and worse lung functionat study entry. These patients alsowere more responsive to roflumilast,which suggests potential synergy ofthe 2 medication classes.

Useful Addition to COPD


A separate pooled analysis of 2placebo-controlled clinical trials ofroflumilast in 3091 patients withCOPD demonstrated that roflumilastimproved lung function in patientswith or without use of an inhaled cor-ticosteroid pretreatment, reportedAndrew McIvor, MD, MSc, FirestoneInstitute for Respiratory Health atMcMaster University, Canada.“This analysis looked at patients who

were pretreated with inhaled steroids,”he said. “Sometimes, when inhaledsteroids are withdrawn, you see anincrease in the exacerbation rate.”Among the patients randomized to

roflumilast who were pretreated withinhaled corticosteroids, prebroncho -

dilator FEV1 increased by 37 mL over52 weeks compared with a decline of10 mL in the placebo groups.Similar benefits with roflumilast

treatment compared with placebo wereobserved in patients who were nottreated with inhaled corticosteroids.“I certainly feel that it [roflumilast]

will be a very useful addition to thearmamentarium of our patients. It’svery effective, and over 90% ofpatients have no problem with it.With PDE 4 inhibitors, some patientswill get gastrointestinal intolerance,but there’s no need to monitor bloodlevels and there are no drug–druginteractions,” Dr McIvor said.“Our study showed that roflumilast

acted as an anti-inflammatory agent,perhaps with a different mode ofaction,” he continued. “I’m not sayingthat we’re going to stop Advair [fluti-casone/salmeterol] in our patients, butwe might be able to reduce the dosefrom Advair 500/50 to Advair 100/50,and use roflumilast, because it’s tack-ling a different aspect. Patients are stillhaving exacerbations with triple thera-py, so roflumilast perhaps meets anunmet need.” �

Concurrent treatment withinhaled corticosteroidsidentified patients who hadmore exacerbations andworse lung function at studyentry, according to Dr Rennard.

“Our study showed thatroflumilast acted as an anti-inflammatory agent, perhaps with a different mode of action.”

—Andrew McIvor, MD, MSc

Roflumilast Improves Lung Function Independent of Inhaled CorticosteroidsRespiratory Experts Embrace Potential New PDE 4 InhibitorBy Wayne Kuznar

Stephen I. Rennard, MD

The ultra–long-acting beta-agonist(LABA) indacaterol holds promisefor the treatment of chronic obstruc-tive pulmonary disease (COPD), saidMario Cazzola, MD, Professor ofRespiratory Medicine, University ofRome Tor Vergata, Italy. In preclinicaland early clinical studies, indacateroldemonstrated a fast onset of actionand 24-hour bronchodilation. Indacaterol has already been

approved in the European Union,but the US Food and Drug Adminis -tration has requested additional databefore again considering it for thetreatment of COPD.The high intrinsic activity of inda-

caterol may allow for faster activationof beta-receptor, permitting fast onsetof action. In a study of 89 patientswith COPD, single doses of inda-caterol (150 µg and 300 µg) had anonset of action that was similar to thatof salbutamol and faster than that ofsalmeterol-fluticasone (Balint B, et al.Int J Chron Obstruct Pulmon Dis. 2010;5:311-318).Indacaterol’s interaction with lipid

rafts may explain its 24-hour bron-

chodilation, Dr Cazzola said. In onestudy (Lombardi D, et al. Eur J PharmSci. 2009;38:533-547), indacaterol hadequivalent interaction with lipids tosalmeterol but had a 2-fold higheraffinity for raft microdomains.

In the INERGIZE COPD phase 3clinical trials released by Novartis in2009, indacaterol proved superior tocurrent comparators (ie, tiotropium,formoterol, salmeterol) in improve-ments over placebo in trough forcedexpiratory volume in 1 second at 12weeks of treatment, Dr Cazzola said.Its effect on quality of life and breath-lessness was also superior to thesesame comparators. Indacaterol alsoincreased the percentage of days

without rescue medication more thanthese other agents.In a 1-year comparison of once-

daily indacaterol with twice-dailyformoterol and placebo (Dahl R, etal. Thorax. 2010;65:473-479), inda-caterol improved the BODE (bodymass index, obstruction, dyspnea,exercise) index at week 12 and week52 compared with placebo. TheBODE index correlates with the riskof exacerbations.In this same study, indacaterol

increased the time to first exacerbationover 52 weeks compared with place-bo. Indacaterol has a favorable cardio-vascular safety profile, with minimalchanges in the corrected QT intervalobserved over 52 weeks, he said.Cough is a frequent adverse event

with indacaterol; 17% to 20% ofpatients in this study experienced asporadic, short-lasting cough within15 seconds after inhalation of inda-caterol. In other clinical trials, only6.8% of patients reported cough as anadverse event, and no patients dis-continued the study because ofcough, Dr Cazzola noted. �

Single doses of indacaterolhad an onset of action thatwas similar to that ofsalbutamol and faster than that of salmeterol-fluticasone.

Ultra-LABA Indacaterol Shows Promise: Fast Onset, 24-Hour Bronchodilation, Favorable Safety

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COPD Management

Impending chronic obstructive pul-monary disease (COPD) exacerba-tions are heralded by 10 days ofworsening COPD symptoms, wors-ening pulmonary function, andincreased daytime rescue medicationuse, said Donald P. Tashkin, MD,Director, Pulmonary Function Lab -oratory, Uni versity of California atLos Angeles. Dr Tashkin evaluated the changes

in symptoms and pulmonary func-tion during the 10 days preceding aninitial COPD exacerbation in 1964patients with moderate-to-very-severe COPD. To be eligible, patientscould not have had an exacerbationwithin 1 month of their pre-enroll-ment screening. COPD exacerbations

were defined as those requiring oralcorticosteroids or hospitalization.Patients were being treated with

twice-daily budesonide/formoterolpressurized metered-dose inhaler(MDI) 320/9 µg, budesonide/for-moterol pressurized MDI 160/9 µg,formoterol dry powder inhaler 9 µg,or placebo.Patients recorded dyspnea, cough,

and sputum scores; peak expiratoryflow; and nighttime rescue medicationuse (inhalations/night) in a diary.Mean changes from baseline in thosevariables were assessed during the 10days preceding the patient’s first exac-erbation. A total of 669 had ≥1 exacer-bations. Patients with exacerbationshad more severe disease and worse

lung function at baseline.“There were slight increases in spu-

tum, dyspnea, and cough starting 10days prior to exacerbations,” DrTashkin said.

The mean change in dyspnea scoreoverall during the 10 days wasapproximately 0.40 units, whichexceeded the predefined criteria for

a minimal important difference (0.2-unit difference). No matter which treatment the

patient received, the mean changes inscores indicating dyspnea, cough,and sputum accelerated at day 5before the exacerbation.“There was a small change in peak

flow in the run off to exacerbation,” hesaid. “The trajectories were similarwith all drugs.” Morning peak expira-tory flow (all treatment groups com-bined) dropped by 9.4 L/min starting10 days before the exacerbation.An increase in the use of rescue

medications occurred, especially in the5 days closest to the exacerbation, witha similar pattern of increase across alltreatment groups.—WK �

Worsening Symptoms, Lung Function PrecedeCOPD Exacerbations

“There were slight increasesin sputum, dyspnea, andcough starting 10 days priorto exacerbations.”

—Donald P. Tashkin, MD

Systemic Effects of COPD Linked to Many Comorbidities,Affect Treatment Decisions, Increase Costs By Wayne Kuznar

Chronic obstructive pulmonarydisease (COPD) is often accom-

panied by other conditions that canpotentiate its morbidity, leading tohospitalizations and increased health-care costs. The systemic effects ofCOPD were examined at a Meet theProfessor session at Chest 2010.

Systemic Manifestations Guide

Treatment Decisions

“Airflow obstruction has profoundeffects on cardiac function and gasexchange, with systemic conse-quences,” said Paolo Palange, MD,Associate Professor of Internal Med -icine, University of Rome, Italy.COPD inflammation may initiate

or worsen comorbid conditions,including ischemic heart disease,heart failure, osteoporosis, depres-sion, and diabetes.The systemic manifestations of

COPD have been explained by 2hypotheses:1.There is systemic spillover of theinflammatory and respiratory eventsoccurring in the lungs of patientswith COPD

2.COPD is the expression of a sys-temic inflammatory state, withmultiple organ compromise.These hypotheses have important

implications on treatment pathways,Dr Palange said. If one subscribes tothe first hypothesis, therapy shouldbe centered in the lungs. If the secondhypothesis is more accurate, however,

therapy should shift toward the sys-temic inflammatory state. “Treatment of COPD inflammation

may concomitantly treat systemic in -flammation and associated comorbidi-ties,” Dr Palange said. Broad-spectrumanti-inflammatory treatments—phos-phodiesterase in hibitors, per oxisomeproliferator-activated re ceptor ago-nists—may therefore provide unex-pected benefits in patients with COPD.

Cardiovascular disease (CVD) iscommon in patients with COPD, andevidence suggests that anti-inflam-matory treatments for COPD can alsoreduce CVD risk. Patients with COPDhave a 2- to 3-fold higher risk for CVDmortality compared with those with-out COPD.Low-dose inhaled corticosteroids

have been shown to decrease the riskof acute heart attack in patients withCOPD. Dr Palange speculated thatacute reductions in the inflammatorymarker C-reactive protein (CRP) withinhaled corticosteroids may partiallyexplain reductions in CVD risk with

these agents when used in patientswith COPD.In contrast, beta-agonists may have

deleterious effects in patients withheart failure and COPD. This excessrisk, however, appears to be confinedto short-acting beta-agonists, where asthe long-acting beta-agonists (LABAs)appear to have an acceptable safetyprofile; however, LABAs also shouldbe used with caution in patients whoalso have CVD.In an observational study, patients

with COPD who were being treatedwith statins had a near halving ofmortality compared with those nottreated with statins, and statin thera-py in combination with inhaled corti-costeroids was associated with alower rate of mortality than eithertherapy alone.Skeletal muscle weakness is one of

the main systemic effects of COPD. Itleads to reduced exercise capacityindependent of disease severity,worsening health status, increasedmortality, and higher healthcareresource utilization.Pulmonary rehabilitation improves

the skeletal muscle dysfunction ofpatients with COPD, improves exer-cise capacity, and accelerates thespeed of reoxygenation of skeletalmuscle, Dr Palange noted.Osteoporosis is another serious

comorbidity in patients with COPD.Although therapy with inhaled corti-costeroids had been thought to be a

factor in the development of osteo-porosis in patients with COPD, therewere no significant changes in therates of osteoporosis or osteopenia inmen or women with COPD after treat-ment with inhaled cortico steroids inthe TORCH (Towards a Revolution inCOPD Health) study.Anxiety disorders and depression

in patients with COPD appear morefrequently in women than in men.Women also have greater psychologi-cal distress and worse perceived con-trol of COPD symptoms.Anemia and obstructive sleep

apnea syndrome are 2 other diseasesthat appear frequently in patientswith COPD. Anemia with COPD isrelated to dyspnea, worse exercisecapacity, and worse 3-year survival.

Evolving COPD Biomarkers

The search for systemic biomarkersto predict COPD worsening contin-ues. CRP “may be the best biomark-er,” Dr Palange said. Other biomarkers with promise

include an imbalance of leptin/adiponectin, surfactant protein D,and plasma proadrenomedullin. The coexistence of metabolic syn-

drome in patients with COPD is oneobstacle in the search for biomark- ers to predict COPD exacerbation,because the metabolic syndrome itselfis a proinflammatory state associatedwith the release of many inflamma-tory proteins and molecules. �

“Treatment of COPDinflammation mayconcomitantly treat systemicinflammation and associatedcomorbidities.”

—Paolo Palange, MD

See also page S12.

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Preventing exacerbations in chronicobstructive pulmonary disease

(COPD) is crucial to limit the decline inlung function that can lead to hospital-izations and poor outcomes. Methodsto prevent exacerbations, with anemphasis on newer therapies, were thefocus of a symposium presented byNicola A. Hanania, MD, MS, and MarioCazzola, MD.Patients with COPD who have exac-

erbations experience faster declines inlung function and worsening lunginflammation compared with thosewithout exacerbations, said Dr Hanania,Director of the Asthma Clini calResearch Center, and Associate Profes -sor of Medicine, Section of Pul monaryand Critical Care Medicine, BaylorCollege of Medicine, Houston, TX. Exacerbations are also associated

with poorer quality of life and anincreased risk of mortality in the yearsafter a hospitalization. According to DrHanania, patients at high risk for exac-erbation include those with: • A more severe airway obstruction• Chronic bronchial mucous hyper-secretion

• A longer duration of COPD• Productive cough and wheeze• Bacterial colonization. A reliable predictor of future exacer-

bation is a history of exacerbation.Influenza vaccination is a simple

way to prevent exacerbations. In flu -en za vaccination has been shown in arandomized clinical trial to reduceexacerbations, “due to a reduction inexacerbations ≥3 weeks after vacci- nation and due to influenza,” DrHanania said.Nonpharmaceutical strategies in -

clude pulmonary rehabilitation, whichis underutilized in the United States,and education to self-manage COPD,which has been shown to reduce theincidence of short- and long-termhospitalization and reduce healthcareutilization.A 12-week, home-based program of

pulmonary rehabilitation was effectivein improving exercise tolerance, dysp-nea, and quality of life in houseboundpatients with COPD. At 6 months,patients undergoing pulmonary reha-bilitation had a significantly shorteraverage length of stay at readmissionto the hospital with exacerbations.Long-acting bronchodilators de -

crease the rate of exacerbations, as evi-denced by findings from the UPLIFT(Understanding Potential Long-TermImpacts on Function with Tiotropium)study, in which the addition of tiotropi-um to a baseline COPD treatment regi-men reduced exacerbations (median

delay to first exacerbation of 16.7months vs 12.5 months for placebo).Inhaled corticosteroids have also

been proved to reduce exacerbationrisk. Fluticasone demonstrated clearefficacy in this regard, Dr Hanania said,and in the TORCH (Towards aRevolution in COPD Health) trial, thecombination of a long-acting beta- agonist and an inhaled corticosteroiddecreased the number of exacerbations.In patients with severe COPD, tripletherapy with tiotropium, fluticasone,and salmeterol may reduce hospitaliza-tion risk, as observed in the CanadianOptimal Therapy of COPD trial.

The data behind mucolytics withrespect to exacerbation risk are mixed.In the PEACE study, oral carbocisteinedecreased exacerbation risk by aboutone third compared with placebo, butresults from the BRONCUS (BronchitisRandomized on NAC Cost-UtilityStudy) showed no beneficial effect ofacetylcysteine on exacerbations. The

conflicting data may possibly beexplained by the different patient pop-ulations enrolled in the studies and thedifferent pharmacologic properties ofthe 2 mucolytics, said Dr Cazzola,Professor of Respiratory Medicine,University of Rome Tor Vergata, Italy.“The BRONCUS study recruited

less severe patients, with a forced expi-ratory volume in 1 second [FEV1] pre-dicted of 57% in BRONCUS patientscompared with 43% in the PEACEstudy,” Dr Cazzola said.Furthermore, more patients in

BRONCUS than in the PEACE studywere being treated with inhaled corti-costeroids (70% vs 17%), which mighthave diluted the findings in BRON-CUS. In addition, the PEACE studywas conducted in Chinese patients,whereas BRONCUS enrolled whitepatients, and there may be pharmaco-genetic differences between these 2ethnic groups, Dr Cazzola said.With respect to the 2 mucolytics stud-

ied, the action of carbocisteine is uniqueand may, in part, depend on inhibitionof viral adherence to the airway.Because bacterial infection is one of

the most important risk factors inCOPD exacerbations, it has been pro-

posed that antibiotics could reducerisk. Cyclical moxifloxacin (5 daysevery 8 weeks) was shown to decreaseexacerbations compared with placebo.A polyvalent mechanical bacterial

lysate (the first 10 days of 3 consecu-tive months) added to regular treat-ment with salmeterol/fluticasonereduced the total number of exacerba-tions, the rate of exacerbations perpatient per year, the number of exacer-bations that required treatment withoral corticosteroids, and the total rateof hospitalizations in a study of 63patients with COPD, Dr Cazzola said.While waiting for new families of

antibiotics to be developed, currentantimicrobial strategy may need to bechanged, he said. This may includeadministration of inhaled or nebulizedantibiotics, which would require amotivated patient and is expensive.Another option is to use antibioticswith different mechanisms of action incombination to reduce the possibledevelopment of resistance, but “thisapproach will increase costs and possi-ble side effects.”Emerging therapies with some suc-

cess at preventing exacerbations areindacaterol, which increased the medi-an time to a first exacerbation over 52weeks compared with placebo; acli-dinium, which improved the time to afirst moderate-to-severe exacerbationin 2 clinical studies; and roflumilast,which was effective in reducing exac-erbations with 1 year of treatment inpatients with severe COPD. �

COPD Management

Heading Off Exacerbations in COPD Is CrucialBy Wayne Kuznar

The risks for COPDexacerbation include having amore severe airwayobstruction, chronic bronchialmucous hypersecretion, a longer duration of COPD,productive cough and wheeze,and bacterial colonization.

Nicola A. HananiaMario Cazzola

More than one third of patientswith a first acute exacerbation

of chronic obstructive pulmonary dis-ease (COPD) died within 4 years in arecent small study presented byKamil Klenha, MD, and colleaguesfrom the Regional Hospital Tabor inthe Czech Republic.The study included 80 patients

with a first acute COPD exacerbationwho met the GOLD (Global Initiativefor Chronic Obstructive Lung Disease)criteria for hospitalization. The pa -tients were treated in a nonintensivecare unit ward; the cause of exacerba-tion was infectious in 57.5% of thepatients and noninfectious in 42.5%.Patients were treated according to

current recommendations and weremonitored every 3 to 6 months in thehospital’s outpatient clinic. By year 4

of follow-up, 35% of the group haddied—7 patients during the firstyear, 8 during the second year, 7 dur-ing the third year, and 6 during thefourth year.

The mortality in this case series wasnot as high as in other series, some ofwhich are as high as 59%; this likelyreflects the absence of patients withthe most severe disease, because no

patients required treatment in anintensive care unit ward, according tothe researchers. Significant predictorsof mortality were: • Older age• Worsening lung function as deter-mined by a lower forced expiratoryvolume in 1 second

• Frequent acute exacerbations• A history of smoking. Current smokers, as well as those

who quit <10 years earlier, had 3.8times the risk for death comparedwith lifelong nonsmokers or thosewho quit ≥10 years earlier.Hypoxemia and/or hypercapnia

were associated with a more thandoubling of the risk for mortality. The researchers concluded that

their data confirm the seriousness ofan acute exacerbation.—WK �

Significant predictors ofmortality were older age,worsening lung function,frequent acuteexacerbations, and a history of smoking.

First Acute COPD Exacerbation a SignificantRisk for Death within 4 Years

See also Emerging Therapies,pages S8-S10.

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Providers’ Perspective

COPD: What’s State-of-the-Art, What’s in the Future?An interview with Nicola A. Hanania, MD, MS Director of the Asthma Clinical Research Center, and Associate Professor of Medicine, Section of Pulmonary and Critical Care Medicine, Baylor College of Medicine, Houston.

At the 2010 meeting of the Amer -ican College of Chest Physicians,

American Health & Drug Benefitsasked Dr Hanania to weigh in on thecurrent and emerging therapies forchronic obstructive pulmonary dis-ease (COPD).

What is the current state ofCOPD therapy, and why arenewer options needed?

We have therapy for COPD that canimprove symptoms, exercise tolerance,and quality of life (QOL). The concernis that despite available therapy, manypatients with COPD continue to havesymptoms and exacerbations thatrequire emergency department visitsand even hospitalization.

Current therapy does not modifythe cause of the disease, and this hasbeen shown in 2 large trials—UPLIFT(Understanding Potential Long-TermImpacts on Function with Tiotropium)and TORCH (Towards a Revolution inCOPD Health), which showed thatalthough the current therapies—including long-acting bronchodilatorsand the long-acting bronchodilator/inhaled corticosteroid combination—can improve frequency of exacerba-tions and improve QOL, they have alimited effect on the declining lungfunction that occurs over time withCOPD, which is a major problem.

Also, available therapies have aminimal effect on mortality. COPD isnow the third (up from fourth untilrecently) leading cause of death in theUnited States.1,2 In addition, someCOPD medications have dose-depen-dent side effects.

Finally, cost is also an issue for cur-rent therapies. Many patients cannotafford using them, because they areexpensive.

Has there been any breakthroughin COPD treatment in the pastfew years?

The biggest breakthrough is thatguidelines written for COPD considerit a treatable disease. For many yearswe approached COPD as a diseasethat happens in smokers, and that wecould not do much for them. We had anihilistic attitude about treatment; wedid not believe that treatment couldimprove outcome.

Since the past few years, with therelease of the landmark trials (UPLIFTand TORCH), we know that treatmentdoes improve outcomes, but there isstill a way to go. There is still the needfor more intervention.

Where do we stand with deliverysystems?

Some patients, especially elderlypatients, have problems with certaindelivery systems. Currently, mostCOPD medications are deliveredthrough the inhaled route. The inhalerdevices are not all the same. Some areeasier to use than others. We havemetered-dose inhalers, dry powderinhalers, and nebulizers. In somepatient populations, one delivery sys-tem may be better than the other. Inaddition to what drug we give thepatient, it is important to keep in mindthat the choice of delivery systemplays a major role in the acceptance ofthe medication, as well as adherence.

Can you discuss some of the neweragents in development?

There are 4 areas of new drugs ornew interventions. One is the develop-ment of drugs similar to what we havenow, except in a simpler platform,such as once-daily drugs and combi-nation therapies. Many companies aredeveloping once-daily long-actingbronchodilators, including once-dailylong-acting beta-agonists (LABAs),once-daily long-acting anticholinergic(antimuscarinic) agents (LAMAs), anda combination of these 2—what wecall a LABA/LAMA combination.

Some manufacturers are looking at acombination of a once-daily LABA/inhaled corticosteroid. The agents wehave now are twice daily. The emerg-ing drugs will be much of the sameagents we have today, but with once-daily inhaled delivery system.

Many of them are in phase 3 trials.

The most advanced is indacaterol,which is a once-daily LABA. It isapproved in Europe and in somecountries in South America, but not inthe United States. Others are in phase2 or starting phase 3 trials, includingvilanterol, olodaterol, and carmoterol.

The others are LAMAs. Probablythe most advanced is aclidinium. Itcan be once daily or twice daily. Theproblem with aclidinium is that itmay not be as long-acting as tiotropi-um, but there are other options.

The second avenue is to look atnovel therapeutic targets. COPD is aninflammatory disease, and multiplepathways of inflammation can be tar-geted. The most advanced group ofdrugs in this field is the phospho di-esterase (PDE) 4 inhibitors. Roflu -milast is approved in the EuropeanUnion but not yet in the UnitedStates. It is still under review by theFood and Drug Administration (FDA)and may be approved early in 2011. Itis an oral agent with once-daily dos-ing, which is an advantage.

Roflumilast has anti-inflammatoryactivity, but it is not a bronchodilator.It has decreased exacerbations inmost of the clinical studies as a stand-alone therapy, but it is more impres-sive when added to long-acting bron-chodilators. It will have to be studiedas stand-alone therapy to get FDAapproval, but in my mind, it will beused as an add-on therapy. The effectis very significant when added tolong-acting bronchodilators.

Several drugs that target mediatorsof inflammation are being studied.Many of these studies so far have

been disappointingly negative. Forexample, anti–interleukin-8 has beenlooked at, as well as leukotriene B4inhibitors and anti–tumor necrosisfactor-alpha inhibitors.

Several mitogen-activated protein(MAP) kinase inhibitors are in phase 2trials; MAP kinase may play a role inchronic inflammation. The problemwith these agents is potential toxicity.They are given systemically (bymouth), so inhaled versions willprobably need to be developed toreduce systemic exposure.

Drugs such as antioxidants andsynthetic protease inhibitors arepotentially beneficial, but it is tooearly to tell how effective they will be.Some of them are targeting thiol (anextra- and intracellular antioxidant inthe lungs) and inflammation of thealveoli. Retinoids are also being test-ed right now, but they are very earlyin development.

The third group of interest includesdrugs that we use for other comor-bidities, which may have an effect onCOPD. There is some interest instatins in COPD; they may reduceexacerbations. They have anti-inflam-matory effects and were shown inobservational studies to decreaseexacerbations and even mortality.STATCOPE (Prospective RandomizedPlacebo-Controlled Trial of Sim va -statin in the Prevention of COPDExacerbations) is a large multicenterstudy that will investigate simva - statin in COPD.

Another group is prophylactic anti -biotics. Inhaled antibiotics are in earlydevelopment in COPD to preventexacerbations. Inhaled levofloxacinand ciprofloxacin are 2 such antibioticsin the fluoroquinolone class.

By which mechanism wouldantibiotics be acting in COPD?

These are antibacterial agents—bronchial bacterial colonization is aproblem in COPD that could con-tribute to progression of airway dis-ease and decline in lung function, butbacterial colonization is also associat-ed with airway inflammation, andantibiotics may also have anti-inflam-matory effects.

Macrolides are another group ofantibiotics being investigated inCOPD; erythromycin has been shownto decrease exacerbations. A largemacrolide study (with erythromycinover 1 year) has just been completed,but the data will only be presented atthe 2011 meeting of the AmericanThoracic Society.

The biggest breakthrough is that guidelines written for COPDconsider it a treatable disease. We know that treatment doesimprove outcomes, but there is still a way to go.

Continued on page S15

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Payers’ Perspective

Although not discussed as often asdiabetes, heart disease, or even

oncology, chronic obstructive pul-monary disease (COPD) is a signifi-cant, challenging disease state formanaged care organizations in 2011.According to a study presented at theAmerican Thoracic Society’s 2006annual meeting, the US medical costsrelated to COPD are expected to totalapproximately $832.9 billion between2006 and 2026.1

Approximately 12 million Americanshave COPD, which is second only toheart disease as a disability forcingemployees to quit working.2As recent-ly reported by the Centers for DiseaseControl and Prevention, COPD is nowthe third most common cause of mor-tality in the United States,3,4 accountingfor more than 120,000 annual deaths.1

The mortality rate from COPD hasincreased more than 60% over thepast 20 years, with more than 95% ofall COPD-related deaths being thoseaged >55 years.2 COPD affects morewomen than men, but the mortalityrates are approximately the same forboth sexes.2

The mortality rates for COPD aregreater in whites than nonwhites andalso greater in blue-collar workersthan white-collar workers.2 These aresobering statistics about a serious anddisabling illness that is often under-diagnosed and undertreated. In 2006it was estimated that close to 13 mil-lion Americans had been diagnosedwith COPD, but 24 million peoplehad the disease, indicating substantialunderdiagnosis.5,6

This report highlights data related toCOPD presented at the 2010 annualmeeting of the American College ofChest Physicians (ACCP 2010), with afocus on new and emerging therapies,as well as data presented at ACCP2010 that show that the cost of care forCOPD escalates based on GOLD(Global Initiative for Chronic Obstruc -tive Lung Disease) severity criteria. According to the study by M. Reza

Maleki-Yazdi, MD, FRCPC, FCCP, andcolleagues discussed in this publica-tion, almost half of the cost of care forCOPD is related to exacerbations ofthe disease. This study shows that theaverage annual COPD-related cost perpatient is $4147 in Canada, and thatthe cost rises to $6141 for those withGOLD stage 4 COPD. Of that $6141,$2631 results from exacerbations of theillness, and $3510 is maintenance cost,according to this study. A study presented at ACCP 2010 by

Andrew P. Yu, PhD, and discussed in

this supplement, is based on real-world information that is derivedfrom a robust claims database withnearly 23,500 patients with COPD.From this study we learn that in -creased patient adherence to COPDtherapies is strongly associated withreduced mortality and hospitalizationrisks for patients with COPD. We also learn that the use of a more

complex routine of multiple inhalerscompared with single inhalers resultsin lower adherence to medication, andthis lower adherence is associated witha total healthcare cost increase of $3319for these patients. Clearly these are negative cost

implications related to the severity ofdisease and medication nonadher-ence. One can certainly hypothesizethat the combination of severe dis-ease, which is likely to need morecomplex care, and the associated non-adherence seen with more complexcare, may have a negative cost impacton the healthcare system.This publication also presents infor-

mation about new therapies in thepipeline for the treatment of COPD.The cornerstones of therapy for thiscondition remain bronchodilation andreduction of inflammation. To thatend, ultra–long-acting beta-agonists,such as indacaterol, carmoterol,vilanterol, or olodaterol, may soonoffer clinicians and payers alternativesto currently available bronchodilators.Roflumilast (Daxas), an oral phospho-diesterase 4 inhibitor, shows promisein reducing inflammation in patientswith COPD. However, it remains to bedetermined if any of these newer

agents will offer clinical advantagesover existing therapies.So where do we go from here? We

know that health plans and physiciansmust work together to help improveoutcomes and control the cost of thisprogressive and debilitating disease.New medications and new guidelinesalone are not enough to change clinicaloutcomes and “bend the cost curve.” Asystemwide approach involving allstakeholders is necessary to improveoutcomes in this patient population. Successful health plans may there-

fore need to consider the followingapproaches to managing COPD:� Improving diagnosis• Does the health plan have pro -cesses in place to ensure thatmembers with COPD are properlydiagnosed?

• The plan must also be able todemonstrate to their employersthat diagnosing patients with pre-viously undiagnosed COPD willhave a major impact on future costs

� Improving treatment• Does the health plan have pro -cesses in place to ensure that itsmembers are receiving recom-mended treatments according toguidelines? As we have learnedin this supplement, optimal carefor those already diagnosed canresult in substantial improve-ments in symptoms and qualityof life, as well as reductions inmedical expenses

� Improving outcomes• Plans with disease managementprograms for COPD must be ableto demonstrate that the educationand adherence support providedto patients with COPD ultimatelyresults in decreases in hospitaliza-tions, emergency department vis-its, admissions to the intensivecare unit, unscheduled office vis-its, and acute exacerbations; if thiscannot be shown, the programsneed to be assessed and re designedto achieve these end points

�Working with employers• Prevention at the worksite: smoke-free work environments and care-ful adherence to occupationalsafety procedures can reduceexposure to environmental pollu-tants that increase the risk ofCOPD or worsen symptoms forthose with the disease

• Education: campaigns to increaseemployee awareness of the symp-toms of COPD (eg, shortness ofbreath is not a normal part of get-ting older and should be broughtto the attention of a physician) andthe impact of smoking, which canimprove early detection of COPD

• COPD screening: programs toencourage lung function testingfor those at high risk for COPDwill improve early detection

• Patient programs: smoking cessa-tion programs can help reduce theincidence of COPD. Once an em -ployee has been diagnosed withCOPD, one-on-one case manage-ment programs can be effective.

Several important conclusions arerelevant to the health plan perspectiveconcerning the management of COPD.First, the number of patients withCOPD is still growing as a result of theaging of the population and the signif-icant time it takes to see the effect ofreduced rates of smoking on theprevalence of COPD. Second, the costof caring for individuals with COPD islikely to increase as this patient groupincreases. Therefore, it is imperative tomanage guidelines and use the mosteffective treatments available. Third, itis important that we have new treat-ment options in the quest to bettermanage patients with COPD.And yet, pharmaceutical innovation

alone will not result in better manage-ment of COPD. In addition to newtreatment options, we must betterunderstand how to help patientsimprove their medication adherence.Finally, helping physicians to managethese patients according to well-estab-lished guidelines will continue to be amajor challenge. To adequately manage patients with

COPD and to control the clinical andeconomic consequences of this dis-ease, an equal amount of effort needsto be invested in finding new treat-ments, managing patients to estab-lished guidelines, educating physi-cians, working with employers, andbetter understanding how to motivatepatients to comply with care routines.Only by involving all stakeholders inthis process will we be able to improveclinical outcomes and control cost-effectively in patients with COPD. �

References1. Medical News Today. COPD will cost U.S. over$800 billion over next 20 years. May 30, January 8, 2011.2. The Merck Manual. Chronic obstructive pulmonarydisease. Accessed January 11, 2011.3. Centers for Disease Control and Prevention.Strokes drops to fourth leading cause of death in2008. Press Release. December 9, 2010. AccessedJanuary 4, 2011. 4. Centers for Disease Control and Prevention.National Center for Health Statistics, Accessed January 4, 2011.5. Pleis JR, Lethbridge-Cejku M. Summary healthstatistics for U.S. adults: National Health InterviewSurvey, 2005. Vital Health Stat 10. 2006;232:1-153.6. Yawn BP. Differential assessment and managementof asthma vs chronic obstructive pulmonary disease.Medscape J Med. 2009;11:20.

According to a 2006 study, the US medical costs relatedto COPD are estimated toamount to $832.9 billionbetween 2006 and 2026.

COPD and Its Associated CostsGary M. Owens, MDPresident, Gary Owens Associates, Philadelphia, PA

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Anew, highly selective intravenous(IV) beta-agonist in develop-

ment—MN-221 (bedoradrine sul-fate)—improves lung function in pa -tients with stable, moderate-to-severechronic obstructive pulmonary disease(COPD), according to a dose-rangingstudy presented at the meeting.In development for the treatment of

acute exacerbations of asthma andCOPD, MN-221 has higher selectivityfor the beta2-receptors than the cur-rently used beta-agonists (ie, albuterol,levalbuterol, terbutaline), which sug-gests that the cardiac-stimulatingaction on beta1-receptors may bereduced with this investigationalagent. Therefore, MN-221 may reducebronchospasm, while minimizing car-diovascular complications.James Pearle, MD, and colleagues at

California Research Medical Group inFullerton, examined 3 dose levels ofMN-221 (300 µg, 600 µg, and 1200 µgIV) in 16 patients with stable, moder-ate-to-severe COPD. The patients wererandomized to receive either MN-221or placebo in a 3:1 ratio—half of the

dose was given over 15 minutes, fol-lowed by the remaining dose over 45minutes, for a total 1-hour infusion.Lung function improved with all 3

doses; the improvement was signifi-cant compared with placebo at the600-µg and 1200-µg doses. The forced

expiratory volume in 1 second (FEV1)increases from baseline were 9.2%with the 300-µg dose (not a significantdifference), 16.2% with the 600-µgdose (P = .02), and 21.5% with the1200-µg dose (P = .025). In compari-son, FEV1 declined by 4% in patientsreceiving placebo infusion.The researchers noted that MN-221

at doses of 600 µg and 1200 µgimproved lung function for at least 6hours compared with placebo.�

Novel Selective Beta-AgonistImproves Lung Function inCOPD: Preliminary AnalysisBy Wayne Kuznar

Some studies suggest that cyclic oralantibiotics may be effective. One studyshowed that giving moxifloxacin for 5days every 8 weeks on a cyclic basis de -creases exacerbations compared with pla - cebo, but we are not ready to pre scribeantibiotics to everybody with COPD.Beta-blockers also look like they

may have an effect on COPD, but it istoo early to know. In one recent study,beta-blockers were associated withreductions in mortality and risk ofexacerbations in COPD.

What is the fourth interventionbeing investigated?The fourth area is nonpharmacolog-

ic interventions, such as bronchoscop-ic avenues for patients with emphyse-ma. One trial involved putting valvesin the upper lobes of patients withemphysema. Lung volume reductionsurgery is also being performed forpatients with end-stage disease (severeemphysema in the upper lobes).

What do you envision 3 or 4 yearsfrom now?This is a very slow-moving field,

which is a bit frustrating. New drugsare expensive to research, and the USFood and Drug Administration hasput in many safety issues, which isimportant but slows approval.

A few years from now, we will like-ly have 1 or 2 of the LABAs available.The PDE 4 inhibitor roflumilast willprobably come on board in 2011, but Ido not think we will move far for-ward. Five years down the road wewill likely see more of the novelagents on the market. The key question is, how will long-

acting bronchodilators compete withthe drugs we have now? Many of thecurrent agents will go off patent andwill be cheap. They may have to begiven twice daily, but if they are cheap-er, they may still be preferred, becausepatients may not be able to afford thelong-acting medications. That is a con-cern now. This is a competitive field,and the long-acting bronchodilatorswill have to differentiate themselves.People will also have to look at aneasier way of delivery. Nebulized delivery is emerging—

in the United States at least—so theremay be more combination therapiesin a nebulized platform. �


1.Centers for Disease Control and Prevention. Strokedrops to fourth leading cause of death in 2008. PressRelease. December 9, 2010. Accessed January 4, 2011.2. Centers for Disease Control and Prevention.National Center for Health Statistics, Accessed January 4, 2011.

What’s State-of-the-Art... Continued from page S13

Coming in AprilACAAI 2010: Payers’ Perspectives

Updates on Current Therapies for Allergic Rhinitis from the 2010 Annual Meeting of the

American College of Allergy, Asthma & Immunology

See also pages S8-S10.Providers’ Perspective Emerging Therapies

Lung function improved withall 3 doses; the improvementwas significant comparedwith placebo at the 600-µgand 1200-µg doses.

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©2011 Engage Healthcare Communications, LLC

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