A Comprehensive Care Management Program to Prevent ChronicObstructive Pulmonary Disease HospitalizationsA Randomized, Controlled TrialVincent S. Fan, MD, MPH; J. Michael Gaziano, MD, MPH; Robert Lew, PhD; Jean Bourbeau, MD, MSc; Sandra G. Adams, MD, MS;Sarah Leatherman, MS; Soe Soe Thwin, PhD, MS; Grant D. Huang, PhD, MPH; Richard Robbins, MD; Peruvemba S. Sriram, MD;Amir Sharafkhaneh, MD; M. Jeffery Mador, MD; George Sarosi, MD; Ralph J. Panos, MD; Padmashri Rastogi, MD; Todd H. Wagner, PhD;Steven A. Mazzuca, PhD; Colleen Shannon, MPH; Cindy Colling, RPH, MS; Matthew H. Liang, MD, MPH; James K. Stoller, MD, MS;Louis Fiore, MD, MPH; and Dennis E. Niewoehner, MD

Background: Improving a patient’s ability to self-monitor and man-age changes in chronic obstructive pulmonary disease (COPD)symptoms may improve outcomes.

Objective: To determine the efficacy of a comprehensive caremanagement program (CCMP) in reducing the risk for COPDhospitalization.

Design: A randomized, controlled trial comparing CCMP withguideline-based usual care. (ClinicalTrials.gov registration number:NCT00395083)

Setting: 20 Veterans Affairs hospital-based outpatient clinics.

Participants: Patients hospitalized for COPD in the past year.

Intervention: The CCMP included COPD education during 4 indi-vidual sessions and 1 group session, an action plan for identificationand treatment of exacerbations, and scheduled proactive telephonecalls for case management. Patients in both the intervention andusual care groups received a COPD informational booklet; theirprimary care providers received a copy of COPD guidelines andwere advised to manage their patients according to these guide-lines. Patients were randomly assigned, stratifying by site based onrandom, permuted blocks of variable size.

Measurements: The primary outcome was time to first COPDhospitalization. Staff blinded to study group performed telephone-based assessment of COPD exacerbations and hospitalizations, andall hospitalizations were blindly adjudicated. Secondary outcomesincluded non-COPD health care use, all-cause mortality, health-related quality of life, patient satisfaction, disease knowledge, andself-efficacy.

Results: Of the eligible patients, 209 were randomly assigned tothe intervention group and 217 to the usual care group. Citingserious safety concerns, the data monitoring committee terminatedthe intervention before the trial’s planned completion after 426(44%) of the planned total of 960 patients were enrolled. Meanfollow-up was 250 days. When the study was stopped, the 1-yearcumulative incidence of COPD-related hospitalization was 27% inthe intervention group and 24% in the usual care group (hazardratio, 1.13 [95% CI, 0.70 to 1.80]; P � 0.62). There were 28deaths from all causes in the intervention group versus 10 in theusual care group (hazard ratio, 3.00 [CI, 1.46 to 6.17]; P � 0.003).Cause could be assigned in 27 (71%) deaths. Deaths due to COPDaccounted for the largest difference: 10 in the intervention groupversus 3 in the usual care group (hazard ratio, 3.60 [CI, 0.99 to13.08]; P � 0.053).

Limitations: Available data could not fully explain the excess mor-tality in the intervention group. Ability to assess the quality of theeducational sessions provided by the case managers was limited.

Conclusion: A CCMP in patients with severe COPD had not de-creased COPD-related hospitalizations when the trial was stoppedprematurely. The CCMP was associated with unanticipated excessmortality, results that differ markedly from similar previous trials. Adata monitoring committee should be considered in the design ofclinical trials involving behavioral interventions.

Primary Funding Source: Veterans Affairs Cooperative StudyProgram.

Ann Intern Med. 2012;156:673-683. www.annals.orgFor author affiliations, see end of text.

Hospitalizations for exacerbations of chronic obstructivepulmonary disease (COPD) are associated with de-

creases in health-related quality of life, lung function, andlife expectancy and account for more than half of allCOPD-related medical costs (1–5). Successful efforts toreduce COPD hospitalization rates would yield importanthuman and economic benefits.

Implementation of comprehensive care managementprograms (CCMPs) is generally associated with improvedpatient satisfaction; adherence; and disease control in pa-tients with depression, diabetes, arthritis, and congestiveheart failure (6–8). Trials of care management in COPDare few in number and highly variable in terms of patients,interventions, outcomes, duration of follow-up, and qual-ity (9–13). Most previous interventions did not describe

See also:

PrintEditors’ Notes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 674Editorial comment. . . . . . . . . . . . . . . . . . . . . . . . . . 746Related article. . . . . . . . . . . . . . . . . . . . . . . . . . . . . 728Summary for Patients. . . . . . . . . . . . . . . . . . . . . . . I-30

Web-OnlyAppendixAppendix TablesSupplementsConversion of graphics into slides

Annals of Internal Medicine Original Research

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the underlying health behavioral theory or health commu-nication model anticipated to change specific patient be-haviors that improve clinical outcomes. Most systematicreviews have concluded that care management programsprobably reduce overall health care use, but the reductionin COPD hospitalizations has not been consistent and wasnot shown in the largest trial reported to date (13–17).

In this study, we hypothesized that a theory-basedCCMP that included COPD education, an individualizedtreatment action plan for worsening pulmonary symptoms,and telephone case management would reduce the risk forCOPD-related hospitalization in patients with severeCOPD who were at high risk for hospital admission.

METHODS

Design OverviewWe conducted a multisite, randomized, controlled

trial comparing a CCMP with guideline-based usual carefor patients with COPD who were at high risk forhospitalization.

Setting and PatientsPatients in the study had been hospitalized for COPD

in the 12 months before enrollment. Additional inclusioncriteria were a postbronchodilator ratio of FEV1 to FVCbelow 0.70 with an FEV1 below 80% predicted, age olderthan 40 years, current or past history of cigarette smoking(�10 pack-years), at least 1 visit in the past year to either

a primary care or pulmonary clinic at a Veterans Affairs(VA) medical center, no COPD exacerbation in the past 4weeks, ability to speak English, and access to a telephone.Patients were excluded for a primary diagnosis of asthma orany medical conditions that would impair their ability toparticipate in the study or to provide informed consent.The trial commenced with 6 sites in January 2007 andsubsequently expanded to 20 sites.

The institutional review boards at all sites approvedthe study, and all patients gave written informed consent.In accordance with VA Cooperative Studies Program(CSP) procedures, the ethical and scientific aspects of thestudy were evaluated by the CSP Human Rights Commit-tee. A Data and Safety Monitoring Committee (DMC)reviewed the study at least annually.

Randomization and InterventionsThe CSP Coordinating Center in Boston, Massachu-

setts, randomly assigned eligible patients in equal numbersto 2 groups, stratifying patients by site to allow for possibleregional differences in patient characteristics and clinicalpractice patterns. Randomization lists were generated onthe basis of random, permuted blocks of variable size toensure approximate balance over time.

The 2 groups differed on the basis of a complex be-havioral intervention that made blinding impossible.Telephone-based ascertainment of study outcomes (COPDhospitalizations and exacerbations) was performed by cen-tralized research staff blinded to assignment.

CCMP InterventionThe educational intervention was based on the PRECEDE/

PROCEED model of health program planning and evalu-ation (18). Interventions developed with this model ad-dress the key predisposing, reinforcing, and enabling fac-tors that influence health behaviors. We identified keyenvironmental and behavioral factors from prior studiesand clinical experience that might contribute to exacerba-tions of COPD, and we focused on those most likely tohave an effect and to be adopted by patients. The educa-tional program consisted of 4 individual 90-minute weeklysessions. The sessions used an educational booklet devel-oped specifically for this study (19). Topics and educa-tional objectives were a needs assessment followed by anoverview of COPD, including medications and exacerba-tions; self-monitoring of respiratory symptoms and instruc-tions for self-initiation of an antibiotic or prednisone for anexacerbation; learning breathing and coughing techniquesand strategies for energy conservation and reduction ofanxiety; and medication adherence, smoking cessation, nu-trition, and regular exercise at home. The individual les-sons were reinforced during a group session and by tele-phone calls from the case manager once per month for 3months and every 3 months thereafter.

Intervention patients received a written, individualizedaction plan for flare-ups that included prescriptions forprednisone and an antibiotic (chosen in consultation with

Context

Educational and management programs in which patientsare provided with prescriptions and instructions for actionsto initiate at the onset of worsening symptoms have beenreported in some studies to reduce hospitalizations foracute exacerbations of chronic obstructive pulmonarydisease (COPD).

Contribution

This multisite, randomized, controlled trial of an educa-tional and acute care management program was stoppedearly when a safety monitoring board noted more deathsin the intervention group. There was no difference seen inthe number of hospitalizations or the time to initiation oftreatment for an acute COPD exacerbation.

Caution

The cause of the increased mortality and the reason thatintervention patients did not initiate treatment soonercould not be identified with available data.

Implication

Not all educational and care management programs areappropriate for all patients. Safety monitoring boards areimportant for educational and behavioral interventionstudies.

—The Editors

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the primary care physician) with instructions to initiatetreatment within 48 hours after onset of exacerbationsymptoms. On the basis of change in patient symptoms,the written action plan specified whether the patientshould start an antibiotic or prednisone (Supplement 1,available at www.annals.org). At the beginning of thestudy, intervention patients were provided with prescrip-tions that they were expected to fill and refill as needed toalways have medications on hand in case of an exacerba-tion. Patients were also asked to call their case managerafter initiating their action plan and their primary careprovider or 911 if symptoms worsened or failed to respondto treatment. Case managers were instructed to contact thepatient’s primary care provider if an exacerbation occurred.Case managers were also available by telephone during reg-ular work hours to answer questions about the action plan.

With the exception of 2 study coordinators, case man-agement positions were filled by various health-related pro-fessionals (Appendix Table 1, available at www.annals.org). At any point, each site had only 1 case manager whotaught the educational sessions and made proactive casemanagement telephone calls. Before starting the study, allcase managers received a 3-day training course with work-shops covering detailed aspects of the self-managementprogram, and all were supervised by the site investigator.Quality of and adherence to the educational program weremonitored by recording and reviewing 1 of every 4 COPDeducational sessions for each patient. Each audio recordingwas reviewed by a research assistant who completed achecklist to determine the proportion of educational ele-ments that were covered by the case manager. The maxi-mum possible scores for recorded sessions 1 through 4were 31, 19, 17, and 23, respectively.

Guideline-Based Usual CarePrimary care providers for patients in both groups re-

ceived the Global Initiative for Chronic Obstructive LungDisease guidelines and were advised to manage their pa-tients according to published guidelines (20–22). All par-ticipants received a general information booklet forpatients with COPD and had access to an existing VA24-hour help line for any medical questions about theirCOPD.

Outcomes and Follow-upThe primary outcome was time from randomization

to first COPD hospitalization. The goal was to follow allpatients for at least 12 months. Research staff blinded tostudy group contacted patients every 2 months to deter-mine whether they developed symptoms of a COPD exac-erbation, along with details of treatment and health careuse. A COPD exacerbation was defined as an increase in ornew onset of 1 or more respiratory symptoms (cough, spu-tum, wheezing, dyspnea, or chest tightness) persisting forat least 2 days.

Per protocol, 3 blinded pulmonologists reviewed dis-charge summaries and other available information to deter-

mine the primary cause of all hospitalizations and classifiedthem as COPD-related (exacerbation or pneumonia), car-diovascular, or other.

Secondary outcomes included all-cause mortality, num-ber of exacerbations, health-related quality of life, patient sat-isfaction, COPD-related knowledge, and self-efficacy.

Baseline and Follow-up AssessmentsAt baseline and 1-year study visits, we performed post-

bronchodilator spirometry according to American Tho-racic Society criteria and collected medical and sociodemo-graphic data (23). Disease-specific health-related quality oflife was measured with the St. George’s Respiratory Ques-tionnaire (24), which has 76 questions that can be summa-rized in 3 subscales (symptoms, activity, and impacts), eachwith a score ranging from 0 (best) to 100 (worst); theminimum clinically important difference is 4. Generalhealth-related quality of life was measured with the Veter-ans Medical Outcomes Study Short Form-12 (25, 26),which has 12 questions summarized in 2 subscales (physi-cal and mental component summary scales); scores rangefrom 0 (worst) to 100 (best) (27). We measured depressivesymptoms with the 8-item Patient Health Questionnaire,the score of which ranges from 0 (no depressive symptoms)to 24; a score of 10 or higher indicates depression (28).Patient satisfaction was measured with the Seattle Outpa-tient Satisfaction Questionnaire, which has 21 questionsthat are summarized in 2 subscales (humanistic and orga-nizational) and a scoring range of 0 (least satisfied) to 100(most satisfied) (29). A 15-item COPD knowledge ques-tionnaire assessed medication use, management of dyspnea,and exacerbations (Supplement 2, available at www.annals.org). We developed an 8-item questionnaire to measurepatients’ self-efficacy in carrying out the targeted self-management behavior (30, 31) (Supplement 3, available atwww.annals.org).

Statistical AnalysisThe outcome for the primary analysis was time to

event for a first COPD hospitalization. We based the sam-ple size on the test of the primary hypothesis with 90%power to reject the null hypothesis for the log-rank test,based on enrolling 960 patients and losing 7% annuallyand assuming a hazard ratio (HR) of 1.37 (or 0.73). Nointerim analyses were planned. The study began with 6sites to determine whether recruitment goals could be met.After this was achieved, the study was expanded to the full20 sites.

For the primary intention-to-treat analysis, the nullhypothesis was that the COPD hospitalization hazard ratefor intervention did not differ from that for standardizedcare. The log-rank test had a 2-sided alternative hypothesisthat the ratio of the 2 hazard rates was either greater than1.37 or less than 0.73 (1/1.37). The direction of interestwas whether treatment reduced the hospitalization rate by8% annually. This assumes underlying exponential failurerates and a 30% annual hospitalization rate for the control

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group, consistent with COPD data from the VA. Resultsin the opposite direction were regarded as negative results.

The primary analysis had no covariates. The estimatedHR comparing treatments was obtained from the Cox pro-portional hazards model analogous to the log-rank test(32). One-year rates of COPD hospitalization–free survivalwere obtained by the Kaplan–Meier method. Planned ex-ploratory analyses used the Cox proportional hazardsmodel to indicate whether covariates could account forsome of the treatment effect.

The early termination led to several unplanned posthoc analyses focusing on the use of prednisone and antibi-otics. As might be expected, previous studies with similarinterventions have found increased use of medications totreat exacerbations (9, 13). We compared the annual ratesof prednisone and antibiotic treatment for exacerbations ineach group by using data from the first year of follow-up.Because some patients had shorter follow-up times, wecomputed the rates as the number of times the medicationwas taken divided by the total patient-years. We comparedthe number of exacerbation episodes requiring prednisoneand antibiotic use across treatments by using a repeated-measures, unadjusted Poisson model with the generalized

estimating equation method for the number of episodesover time per person. The model provided an estimate ofthe ratio of the Poisson rates. Also, the number of daysfrom onset of an episode to first use of prednisone or anantibiotic was compared across treatments by using amixed-effects model with a single fixed covariate for treat-ment. We compared the number of days over time perpatient, assuming that each patient’s series of monthly ex-acerbation counts were autocorrelated (first-order struc-ture) and weighting the data according to each patient’stime in the study if less than 1 year.

The early termination also led to further Cox modelanalyses of time to death. Appendix Table 2 (available atwww.annals.org) describes various models used to detectthe role of the categorical factor “study site” on time todeath. Also, with respect to time to first COPD hospital-ization, we conducted a futility analysis to assess whatmight have resulted if the trial had continued. We com-puted the probability of rejecting the null hypothesis con-ditional on the data accrued when enrollment stopped.Under the alternative hypothesis (HR, 1/1.37 � 0.73;log[HR], �0.315), we approximated the probability thatfuture data acquired up to the planned termination wouldhave led to rejection of the null hypothesis. We assumedthat the logarithm of the HR was normally distributedwith variance 4/m, where “m” was the accrued number ofevents (33, 34).

Significance levels for exploratory analyses were set at5% for all tests without correction for multiple compari-sons. We used the log-rank test, Kaplan–Meier estimates,and Cox analysis for the time-to-event analyses. We per-formed all analyses by using SAS, version 9.2 (SAS Insti-tute, Cary, North Carolina).

Data and Safety MonitoringIn contrast to behavioral clinical trials in studies

funded by the National Institutes of Health, for which asafety officer is typically sufficient, a DMC is required forall VA CSP trials regardless of the nature of the interven-tion. Because the action plan included self-initiated pred-nisone and antibiotics, the trial’s executive committee (Ap-pendix, available at www.annals.org) supported having aDMC. The DMC monitored patient accrual, outcomes,complications, and protocol adherence. Summary minutesof the proceedings were kept confidential, and decisionswere made during the executive section of the DMC meet-ing without investigators present. As the study sponsor, theVA CSP received recommendations from the DMC. Every6 months, the study biostatistician provided the DMCwith reports on the study status and presented data blindedto treatment assignment.

Role of the Source of FundingThe VA CSP provided guidelines for the overall man-

agement and conduct of the study.

Figure 1. Study flow diagram.

Assessed for eligibility (n = 467)

Enro

llmen

tA

lloca

tion

Ana

lysi

sFo

llow

-up

Allocated to usual care group (n = 217)Received allocated

intervention: 217Did not receive allocated

intervention: 0

Lost to follow-up (n = 0)Discontinued intervention

(n = 10)Declined to continue: 6Developed another

disease: 4

Analyzed (n = 217)Excluded from analysis: 0

Allocated to intervention group (n = 209)Received allocated

intervention: 209Did not receive allocated

intervention: 0

Lost to follow-up (n = 0)Discontinued intervention

(n = 8)Declined to continue: 5Developed another

disease: 3

Analyzed (n = 209)Excluded from analysis: 0

Randomly assigned(n = 426)

Excluded (n = 41)

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RESULTS

The study began enrollment in January 2007. At ascheduled DMC meeting on 15 January 2009, the reportshowed an imbalance in mortality between the 2 studygroups. The DMC requested a log-rank test to comparethe time-to-event rates, and this showed a statistically sig-nificant difference. The DMC then requested a more com-plete analysis.

Deaths were ascertained by staff at the study sites, byreview of VA electronic medical and administrative recordsand by a search of the Social Security Death Index. Exten-sive multivariate analyses failed to identify any factorsalone or combined that could plausibly explain the differ-ence in mortality. Two of the authors who were blinded tostudy group reviewed all available medical information anddid not find anything in the deaths that would not beexpected in frail patients with COPD.

On 27 February 2009, the DMC reviewed these anal-yses and additional data and found no obvious reason forthe discrepancy in mortality. The DMC recommendedthat study enrollment and the intervention be stopped im-mediately and that all patients have all baseline studiesrepeated and be followed in an observational study lasting6 months. When the intervention was stopped, the inves-tigators were told only that there was a discrepancy inserious adverse events because of a concern that unmaskingthe study results might bias the assessment of the follow-upprocedures. Patients were also told that the interventionhad been stopped because of serious adverse events. Wereobtained consent from patients who returned for thefinal study visit recommended by the DMC because of thechange in study procedure.

FindingsWhen the study was stopped, 467 patients had been

screened and 426 enrolled (217 in the usual care group and209 in the intervention group), with a mean follow-up of250 days (Figure 1). The baseline characteristics of thepatients in the 2 groups are presented in Table 1. Wepresent results both up to the termination date of the in-tervention and during the additional 6 months of follow-up. During the entire follow-up period extending to Sep-tember 2009, a total of 8 patients in the intervention groupand 10 in the usual care group either did not attend sched-uled study visits or formally withdrew from the study.

Among patients in the intervention group, 87% com-pleted all 4 individual educational visits and 57% com-pleted the group visit. A review of the recorded sessionsfound that case managers covered 77% to 89% of theeducational items in each session. The ranges of averagescores across sites that provided audio recordings for eachsession were 18.3 to 31 for session 1 (13 sites), 12 to 19 forsession 2 (12 sites), 12.7 to 23 for session 3 (10 sites), and6 to 18 for session 4 (10 sites). There was no statisticallysignificant difference in the average score for each sessionby site. Case managers completed 89% of the 6 scheduled

reinforcement telephone calls during the first year offollow-up. In addition, 26% of all intervention group pa-tients made at least 1 unscheduled call during the first year.

HospitalizationsThrough 1 March 2009, when the intervention was

stopped, 70 patients had the primary outcome of aCOPD-related hospitalization (Figure 2 and Table 2). Atthat time, the 1-year cumulative incidence of COPD-related hospitalization was 27% in the intervention groupand 24% in the usual care group (HR, 1.13 [95% CI, 0.70to 1.80]; P � 0.62). The assumption of proportional haz-ards was not rejected, indicating a good fit of the model tothe data. Differences between treatment groups in the sub-types of COPD-related hospitalizations, in cardiovascular

Table 1. Baseline Characteristics of Study Patients

Characteristic Usual CareGroup(n � 217)

InterventionGroup(n � 209)

Mean age (SD), y 65.8 (8.2) 66.2 (8.4)Male, n (%) 209 (96.3) 204 (97.6)Race, n (%)*

White 191 (88.0) 181 (86.6)African American 20 (9.2) 24 (11.5)American Indian 5 (2.3) 3 (1.4)Asian 1 (0.5) 0Hawaiian/Pacific Islander 0 1 (0.5)

Currently married, n (%) 114 (52.5) 91 (43.5)Education, n (%)

Less than high school 34 (15.7) 33 (15.8)Completed high school 83 (38.2) 69 (33.0)Some college/vocational school 73 (33.6) 78 (37.3)Completed college or beyond 27 (12.4) 29 (13.9)

Current smoker, n (%) 59 (27.2) 59 (28.2)Mean FEV1 (SD), L 1.21 (0.49) 1.20 (0.47)Mean FEV1 (SD), % predicted 37.8 (14.5) 38.2 (14.3)Mean FEV1–FVC ratio (SD) 0.47 (0.12) 0.47 (0.12)Past participation in a pulmonary

rehabilitation program, n (%)31 (14.3) 25 (12.0)

Health care use for COPD in past yearMean emergency/urgent care visits

(SD), n2.7 (2.2) 2.9 (2.3)

�2 hospitalizations, n (%) 82 (37.8) 80 (38.3)Medication use, n (%)

Short-acting inhaled �2-agonist 184 (84.8) 188 (90.0)Short-acting inhaled anticholinergic 88 (40.6) 81 (38.8)Long-acting inhaled �2-agonist 142 (65.4) 120 (57.4)Long-acting inhaled anticholinergic 100 (46.1) 101 (48.3)Inhaled corticosteroid 143 (65.9) 122 (58.4)

Home oxygen use, n (%) 136 (62.7) 120 (57.4)Self-reported comorbid conditions, n (%)

Ischemic heart disease 62 (28.6) 73 (34.9)Congestive heart failure 32 (14.7) 42 (20.1)Atrial fibrillation 15 (6.9) 18 (8.6)Hypertension 131 (60.4) 129 (61.7)Stroke 22 (10.1) 16 (7.7)Peripheral vascular disease 15 (6.9) 24 (11.5)Diabetes mellitus 61 (28.1) 52 (24.9)Chronic renal failure 7 (3.2) 7 (3.4)Cancer (other than skin cancer) 27 (12.4) 22 (10.5)Depression 34 (15.7) 40 (19.1)

COPD � chronic obstructive pulmonary disease.* The chi-square test compared 3 categories: “white,” “African American,” and“other.”

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hospitalizations, or in all-cause hospitalizations were alsonot statistically significant. Inclusion of the categoricalvariable “study site” did not alter the results.

To predict what the result would have been if the trialhad continued, we computed the probability of rejectingthe null hypothesis conditional on the accrued data of 109events when enrollment stopped (35). Under the alterna-

tive hypothesis (HR, 1/1.37 � 0.73; log[HR], �0.315),the probability that future data acquired up to the plannedtermination would have led to rejection of the null hypoth-esis was 0.0002. In other words, if a futility analysis hadbeen planned, this result would have ended the study.

Treatment of COPD ExacerbationsDuring the first 12 months of follow-up, 600 self-

reported COPD exacerbations occurred in the interventiongroup (mean, 4.4 per patient-year) and 610 in the controlgroup (mean, 4.3 per patient-year) (rate ratio, 1.03 [CI,0.97 to 1.10]) (Table 3; Appendix Tables 3 and 4, avail-able at www.annals.org). An average of 2.5 exacerbationsper patient-year were treated with prednisone in the inter-vention group compared with 2.1 in the usual care group(rate ratio, 1.25 [CI, 1.05 to 1.48]; P � 0.011). Fromonset of symptoms, the average delay to prednisone treat-ment was 6.4 days in the intervention group and 7.7 daysin the usual care group (mean difference, �0.57 day [CI,�2.14 to 1.00 days]; P � 0.48). In the intervention group,an average of 2.7 exacerbations per patient-year weretreated with an antibiotic compared with 2.5 in the usualcare group (rate ratio, 1.11 [CI, 0.97 to 1.27]; P � 0.118).The average delay to antibiotic treatment was 7.0 days inthe intervention group and 6.8 days in the usual care group(mean difference, 0.17 day [CI, �1.34 to 1.68 days]; P �0.84). Data on emergency department visits are presentedin Appendix Table 5 (available at www.annals.org).

MortalityWe made concerted efforts to collect information

about the circumstances of all deaths. At the conclusion ofthe follow-up period, site coordinators at the 2 largest re-cruiting sites interviewed family members of deceased pa-tients. In addition, after institutional review board ap-proval, a research coordinator from a central site attemptedto interview relatives and acquaintances of all deceased pa-tients with the aid of a scripted questionnaire. We alsosought additional medical records on all deaths regardlessof group assignment.

We speculated that the educational group might haveused the antibiotic regimen differently or delayed seekingattention because self-treatment may have provided a falsesense of security, causing a delay in seeking care for aCOPD exacerbation or such comorbid conditions as heartfailure. We focused on documenting details of the patient’scourse and medication use in the days before death in thehome or before hospital admission. Four members of thetrial’s Executive Committee, who were blinded to studygroup, independently reviewed medical records and adju-dicated the cause of death as being COPD-related, cardio-vascular, other, or unknown.

Information was sufficient to make a judgment aboutprimary cause in 27 deaths or 71% of all deaths during theintervention period. With few exceptions, we were unsuccess-ful in obtaining detailed information about antibiotic andprednisone use immediately before death or the duration of

Figure 2. Failure curves for chronic obstructive pulmonarydisease hospitalization (top) and mortality (bottom) untiltermination of study intervention, according to studyassignment.

Prob

abili

ty o

f Fa

ilure

Days

Usual care

CCMP

Participants at risk, n

Usual care 209 164 126 100 77 69 51 43

CCMP 217 169 127 102 84 75 61 49

0 60 120 180 240 300 360 420

0.0

0.1

0.2

0.3

0.4

0.5

Prob

abili

ty o

f Fa

ilure

Days

Participants at risk, n

Usual care 209 170 135 106 87 82 67 56

CCMP 217 172 138 113 98 90 77 60

0 60 120 180 240 300 360 420

0.0

0.1

0.2

0.3

0.4

0.5

CCMP � comprehensive care management program.

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symptoms before death or hospitalization. Reasons includedan inability to reach a contact person, substantial delay (some-times as much as 2 years) between date of death and follow-up, and patients living alone and having only intermittentcontact with friends and relatives. Medical records rarelymentioned any specific medications taken before hospi-tal admission.

When the study was terminated, 28 patients in theintervention group and 10 in the usual care group had died(HR, 3.00 [CI, 1.46 to 6.17]; P � 0.003) (Figure 2 andTable 4). Three of these deaths were due to COPD in theusual care group compared with 10 in the interventiongroup, a statistically nonsignificant difference (HR, 3.60[CI, 0.99 to 13.08]; P � 0.053) (Appendix Tables 6 and7, available at www.annals.org, provide further details ofdeaths). During the 6-month follow-up, 11 deaths oc-curred in the usual care group (3 due to COPD) and 15 inthe intervention group (4 due to COPD).

In exploratory Cox model analyses, each baseline fac-tor was tested 1 at a time in separate models, and nonemarkedly altered the treatment effect. In other words, nobaseline factor (including site) seemed to account for themagnitude of the treatment effect. Results were consistentafter adjustment for baseline factors, including age, per-centage of predicted FEV1, current smoking status, homeoxygen use, COPD-specific health-related quality of life asmeasured by the St. George’s Respiratory Questionnaire,multiple hospitalizations, any cardiovascular disease, and

congestive heart failure (adjusted HR, 2.68 [CI, 1.29 to5.60]). In particular, 3 exploratory Cox proportional haz-ards models were run, 2 treating the categorical factor“study site” (the variable that partitions the data for thesandwich estimator) as a fixed effect and 1 as a randomeffect. The HRs for the primary analysis and these 3 mod-els ranged from 3.00 to 3.03 (Appendix Table 2).

Health Status, Depression, COPD-Related Knowledge,Self-Efficacy, and Patient Satisfaction

Among the 209 patients who completed the baselineand 1-year study visits, there were no statistically signifi-cant improvements in COPD-specific or general healthstatus, depressive symptoms, COPD-related knowledge, orpatient satisfaction (Appendix Table 8, available at www.annals.org). A statistically significant improvement wasobserved in patient self-efficacy (that is, self-confidence inmanaging COPD) in the intervention group at 1 year(mean difference of 1-year change in self-efficacy score,0.65 [SD, 2.3] [CI, 0.02 to 1.29]; P � 0.044).

DISCUSSION

In this multisite, randomized, controlled trial, we wereunable to show that a theory-based CCMP reducedCOPD-related hospitalizations. Based on the futility anal-ysis, it is unlikely that a benefit would have been seen inCOPD hospitalizations if the trial had continued to itsplanned completion. The trial was stopped because all-

Table 2. Hazard Ratios for Hospitalization at Termination of Treatment, by Category of Disease

Reason for Hospitalization Usual Care Group (n � 217) Intervention Group (n � 209) Hazard Ratio(95% CI)

P Value*

Hospitalizations, n P(hosp) (95% CI) Hospitalizations, n P(hosp) (95% CI)

All categories 55 0.36 (0.28–0.46) 54 0.37 (0.28–0.46) 1.05 (0.72–1.53) 0.80COPD-related 34 0.24 (0.17–0.37) 36 0.27 (0.20–0.37) 1.13 (0.70–1.80) 0.62

Exacerbation 26 0.18 (0.12–0.27) 27 0.19 (0.13–0.28) 1.11 (0.64–1.89) 0.72Exacerbation/pneumonia 4 0.04 (0.01–0.10) 6 0.06 (0.02–0.13) 1.61 (0.45–5.69) 0.46Pneumonia 4 0.04 (0.01–0.10) 3 0.04 (0.01–0.13) 0.80 (0.18–3.57) 0.77

Cardiovascular 8 0.04 (0.01–0.09) 15 0.11 (0.06–0.19) 2.06 (0.87–4.86) 0.099Cardiac 5 0.03 (0.01–0.09) 11 0.08 (0.04–0.16) 2.43 (0.84–6.97) 0.101Cerebrovascular 0 – 7 0.01 (0.00–0.08) – –Peripheral vascular 3 0.01 (0.00–0.04) 3 0.02 (0.00–0.06) 1.09 (0.22–5.39) 0.92

Other 24 0.16 (0.11–0.24) 23 0.16 (0.10–0.24) 1.06 (0.59–1.86) 0.86

COPD � chronic obstructive pulmonary disease; P(hosp) � product-limit estimate of hospitalization at 1 y based on treating each category in isolation as opposed tocompeting risks.* Log-rank test P value.

Table 3. Treatment of Exacerbations During the First Year of Follow-up

Mean Variable Usual Care Group(n � 217)

Intervention Group(n � 209)

Rate Ratio(95% CI)

Difference (95% CI) P Value

Exacerbations per person-year (SD) 4.3 (2.3) 4.4 (2.4) 1.03 (0.97 to 1.10) – 0.32Prednisone treatments per person-year (SD) 2.1 (2.2) 2.5 (2.1) 1.25 (1.05 to 1.48) – 0.011Antibiotic treatments per person-year (SD) 2.5 (2.1) 2.7 (2.1) 1.11 (0.97 to 1.27) – 0.118Days before receiving prednisone (SD) 7.7 (10.2) 6.4 (6.8) – �0.57 (�2.14 to 1.00) 0.48Days before receiving antibiotic (SD) 6.8 (7.8) 7.0 (7.5) – 0.17 (�1.34 to 1.68) 0.84

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cause mortality was higher in the intervention group thanin the usual care group. We could not demonstrate animprovement in COPD knowledge. There was a modeststatistically significant difference in the rate of use of pred-nisone per exacerbation, but not of antibiotics, and thedifferences in the timing of either prednisone or antibioticuse were not statistically significant.

Our findings differ from 2 previous trials that evalu-ated similar interventions in similar COPD populations.At 7 hospitals in Quebec, Canada, Bourbeau and col-leagues (9) conducted a randomized trial of a CCMP in181 patients with COPD, all of whom had been hospital-ized in the previous year. The intervention included 7 to 8weekly educational sessions in the patient’s home, an ac-tion plan, and a case manager who made monthly calls fora year. During the 1-year follow-up, they found a 40%reduction in COPD hospitalizations in the interventiongroup, with 9 (9.5%) deaths in the usual care group and 5(5.2%) deaths in the intervention group.

Rice and colleagues (13) evaluated a CCMP in 743patients with COPD at 5 VA medical centers in 1 admin-istrative region. Eligibility included a COPD-related hos-pital admission or emergency department visit, prednisoneuse for COPD in the previous year, or current home oxy-gen use. As with the Bourbeau trial, the intervention in-cluded an action plan and a case manager who mademonthly telephone calls for a year. The intervention dif-fered principally in that the initial educational programwas condensed to a single 1- to 1.5-hour on-site session.The investigators found a 41% reduction in the compositeprimary outcome of COPD-related hospitalizations oremergency department visits in the intervention group over1 year but a statistically nonsignificant reduction in hospi-talization. Forty-eight (12.9%) deaths occurred in theusual care group versus 36 (9.7%) in the interventiongroup.

Aside from chance, attempts to explain the divergentresults in our trial should consider characteristics of thepatients or the intervention. Comparison of publishedbaseline characteristics among these 3 trials provides noobvious clues, but subtle differences cannot be excluded.

The interventions in the 3 trials were similar but variedconsiderably in the intensity of the initial educational pro-gram. This would seem not to be an important factor,because the number of sessions in our trial fell midwaybetween those of the Bourbeau trial and those of the Ricetrial. Our educational program was shorter than that of theBourbeau trial; was done at the hospital rather than athome; and was less focused on such patient behaviors assmoking cessation, diet, and exercise. The intervention inthe Rice trial was shorter than in our trial, was conductedin a group setting, and focused mostly on the action plan.One potentially important difference may have been thenumber of reinforcement telephone calls from case manag-ers; these were scheduled monthly for 1 year in the Bour-beau and Rice trials, whereas in our study calls were madeon a monthly basis only for the first 3 months and every 3months thereafter.

An action plan has been identified as a critical elementfor improving symptom recovery and reducing hospitaliza-tions in COPD self-management programs (36, 37). Ob-servational studies show that patients with COPD do notseek medical care for most exacerbations, that delays of upto a week after onset of symptoms are not uncommonwhen they do seek care, and that delays in seeking care areassociated with worse clinical outcomes (38–42). Wehoped that successful implementation of an action planwould lead to a substantial increase in the use of antibioticsand prednisone and less delay in initiating treatment.

In our study, prednisone use increased modestly in theintervention group during exacerbations (9%). There wereno statistically significant differences in antibiotic use. Incontrast, in Rice and colleagues’ successful trial, prednisoneuse and antibiotic use in the intervention group increasedby 262% and 191%, respectively (13). Although patientsin the intervention group were instructed to start treatmentwithin 48 hours of worsening symptoms, we observed thattreatment was begun approximately 1 week after onset ofsymptoms in the intervention group, similar to controlpatients. Although test scores for self-efficacy improved inthe intervention group compared with the control group,there was no sustained improvement in COPD-related

Table 4. Hazard Ratios for Mortality at Termination of Treatment, by Cause of Death

Reason forDeath

Usual Care Group (n � 217) Intervention Group (n � 209) Hazard Ratio(95% CI)

P Value*

Deaths, n P(death) (95% CI) Deaths, n P(death) (95% CI)

All reasons 10 0.07 (0.05–0.14) 28 0.17 (0.11–0.25) 3.00 (1.46–6.17) 0.003COPD 3 0.03 (0.01–0.09) 10 0.07 (0.03–0.13) 3.60 (0.99–13.08) 0.053Cardiovascular 2 0.01 (0.00–0.08) 3 0.01 (0.00–0.04) 1.62 (0.27–9.72) 0.60Other† 2 0.01 (0.00–0.04) 7 0.06 (0.03–0.13) 3.78 (0.78–18.17) 0.096Unknown 3 0.02 (0.01–0.08) 8 0.05 (0.02–0.11) 2.81 (0.74–10.56) 0.128

COPD � chronic obstructive pulmonary disease; P(death) � cause-specific product-limit estimate of death at 1 y based on treating each reason in isolation as opposed tocompeting risks.* Log-rank test P value.† Other causes of death in the usual care group were lung cancer (n � 1) and cholangitis (n � 1). Other causes of death in the intervention group were liver failure (n �1), colitis (n � 2), diabetes mellitus (n � 2), and trauma (n � 2).

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knowledge. It is believed that behavior change requiresboth a sufficient understanding of the problem and theself-confidence to address it effectively, but our data sug-gest that the 2 factors are not dependent on one another.

We cannot explain the unexpected increase in mortal-ity observed in the intervention group, but we believe thatthe threats to internal validity, such as biased group assign-ment or biased outcome assessment, were not contributors.Patients were randomly allocated to study group, all out-comes were collected by centralized staff blinded to studygroup, and all hospitalizations were adjudicated by a com-mittee that was also blinded to study group. Nearly allpatients in the intervention group completed the individ-ual educational sessions. Chance, imbalance between the 2groups in unmeasured confounding factors, the effect ofthe intervention itself, or a combination of these are possibleexplanations for the between-group difference in mortality.

Efforts to deconstruct the causes and circumstances ofindividual deaths by examination of the medical docu-ments were successful for only 71% of the cases during theintervention period. Excess deaths in the interventiongroup involved several causes (Table 4 and Appendix Ta-ble 6), with COPD accounting for the largest difference:10 deaths in the intervention group versus 3 in the usualcare group (HR, 3.60 [CI, 0.99 to 13.08]). Inability todetermine a specific cause of death in a high proportion ofcases, possible misclassification of death by the adjudica-tion procedure, and the complex intervention make it dif-ficult to clearly delineate potential explanations for thestudy’s observations. Severe acute exacerbations of chronicCOPD are life-threatening, and the 1-year mortality rate is21% from date of discharge from a VA hospital (43). Theoverall mortality in our study is consistent with what mightbe expected in the general population of veterans withCOPD discharged from hospitalization after a flare-up.

Examining baseline measures of COPD severity or co-morbid conditions did not provide any insight into theincreased risk for death. Cardiovascular diseases and un-married status were more common in the interventiongroup; however, we do not know whether these factorswere sufficiently important to explain the increased risk formortality. Previously, we addressed the possibility of delaysin seeking medical attention among those in the interven-tion group. Comparing these factors across CCMP study pop-ulations may help provide further insight into any differences.

Some limitations require discussion. The conclusionsmay not be generalizable to other populations because ourpatients were predominantly male and followed in VAmedical centers. Our patients may differ from those re-cruited to previous studies; however, major differences arenot evident from published baseline characteristics, andour patients came from diverse backgrounds at 20 sites.Although we checked the completeness of the educationalelements, we were not able to scrutinize their accuracy orassess the manner in which they were delivered, which mayhave contributed to the study findings.

This study underscores the critical role of the DMC inensuring the safety of study patients and questioning cur-rent clinical trial practices. Its function in terminatingstudies, particularly when unexpected and often unex-plained adverse events occur, is one of the most vexingjudgments in the conduct of trials and must be done in anenvironment that maintains scientific integrity and safetyat its core. Currently, DMCs are not typically convened forbehavioral and educational intervention studies because ofthe small overall perceived risk. Studies often involve onlya safety officer without planned interim reports. The mor-tality signal was observed in a scheduled meeting that fol-lowed VA CSP standard operating procedures and wouldhave been missed if the monitoring had not occurred rou-tinely. Regardless of the cause of the disparity, the out-comes suggest that it should not be assumed that there areminimal safety concerns in behavioral or educationalinterventions.

In summary, a randomized clinical trial of the effec-tiveness of a CCMP in reducing hospitalizations in patientswith severe COPD was terminated by its DMC beforecompletion and was inconclusive. The self-managementintervention failed to yield a structural behavioral change,in that patients in the intervention group did not initiatetheir action plan for worsening respiratory symptoms anysooner than the patients in the control group, as was in-tended. The intervention group had an unexpected excessmortality that we could not satisfactorily explain, even withadditional data collection. Whatever the reason, our find-ings suggest that self-management or intensive manage-ment protocols may not be appropriate for all subsets ofpatients with COPD.

From the Veterans Affairs Puget Sound Health Care System, Seattle,Washington; Veterans Affairs Boston Healthcare System and Brighamand Women’s Hospital, Boston, Massachusetts; Montreal Chest Insti-tute, Montreal, Quebec, Canada; South Texas Veterans Health CareSystem, San Antonio, Texas; Department of Veterans Affairs Coopera-tive Studies Program, Washington, DC; Phoenix Veterans Affairs Med-ical Center, Phoenix, Arizona; North Florida/South Georgia VeteransHealth System, Gainesville, Florida; Michael E. DeBakey Veterans Af-fairs Medical Center, Houston, Texas; Veterans Affairs Western NewYork Healthcare System, Buffalo, New York; Cincinnati Veterans AffairsMedical Center, Cincinnati, Ohio; Dallas Veterans Affairs Medical Cen-ter, Dallas, Texas; Veterans Affairs Palo Alto Healthcare System, MenloPark, California; Richard L. Roudebush Veterans Affairs Medical Centerand Indiana University School of Medicine, Indianapolis, Indiana; Vet-erans Affairs Cooperative Studies Program Clinical Research PharmacyCoordinating Center, Albuquerque, New Mexico; Minneapolis VeteransAffairs Healthcare System, Minneapolis, Minnesota; and The ClevelandClinic, Cleveland, Ohio.

Disclaimer: The views expressed in this article are those of the authorsand do not necessarily represent the views of the Department of VeteransAffairs. Vincent S. Fan, MD, MPH; J. Michael Gaziano, MD, MPH;and Dennis E. Niewoehner, MD, had full access to all of the data in thestudy and take responsibility for the integrity of the data and the accu-racy of the data analysis.

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Financial Support: By the Cooperative Studies Program (CSP #560),Veterans Affairs Office of Research and Development.

Potential Conflicts of Interest: Disclosures can be viewed at www.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum�M11-1426.

Reproducible Research Statement: Study protocol: Available from thedata coordinating center at the Massachusetts Veterans EpidemiologyResearch and Information Center (MAVERIC) (e-mail, MAVERIC-Info@va.gov). Statistical code: Available from Dr. Lew (e-mail, robert.lew2@va.gov). Data set: Not available.

Requests for Single Reprints: Vincent S. Fan, MD, MPH, HealthServices Research and Development Center of Excellence, Veterans Af-fairs Puget Sound Health Care System, 1600 South Columbian Way,Seattle, WA 98108; e-mail, vincent.fan@va.gov.

Current author addresses and author contributions are available at www.annals.org.

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13. Rice KL, Dewan N, Bloomfield HE, Grill J, Schult TM, Nelson DB, et al.Disease management program for chronic obstructive pulmonary disease: a ran-domized controlled trial. Am J Respir Crit Care Med. 2010;182:890-6. [PMID:20075385]14. Taylor SJ, Candy B, Bryar RM, Ramsay J, Vrijhoef HJ, Esmond G, et al.Effectiveness of innovations in nurse led chronic disease management for patientswith chronic obstructive pulmonary disease: systematic review of evidence. BMJ.2005;331:485. [PMID: 16093253]15. Effing T, Monninkhof EM, van der Valk PD, van der Palen J, van Her-waarden CL, Partidge MR, et al. Self-management education for patients withchronic obstructive pulmonary disease. Cochrane Database Syst Rev. 2007:CD002990. [PMID: 17943778]16. Peytremann-Bridevaux I, Staeger P, Bridevaux PO, Ghali WA, Burnand B.Effectiveness of chronic obstructive pulmonary disease-management programs:systematic review and meta-analysis. Am J Med. 2008;121:433-443.e4. [PMID:18456040]17. Adams SG, Smith PK, Allan PF, Anzueto A, Pugh JA, Cornell JE. System-atic review of the chronic care model in chronic obstructive pulmonary diseaseprevention and management. Arch Intern Med. 2007;167:551-61. [PMID:17389286]18. Green LW, Kreuter MW. Health Program Planning: An Educational andEcological Approach. 4th ed. New York: McGraw Hill; 2005.19. Bourbeau J, Nault D. Self-management strategies in chronic obstructivepulmonary disease. Clin Chest Med. 2007;28:617-28, vii. [PMID: 17720048]20. The Management of COPD Working Group. VA/DoD Clinical PracticeGuideline for Management of Outpatient Chronic Obstructive Pulmonary Dis-ease. Washington, DC: U.S. Department of Veterans Affairs/U.S. Department ofDefense; 2007.21. Celli BR, MacNee W; ATS/ERS Task Force. Standards for the diagnosisand treatment of patients with COPD: a summary of the ATS/ERS positionpaper. Eur Respir J. 2004;23:932-46. [PMID: 15219010]22. Rabe KF, Hurd S, Anzueto A, Barnes PJ, Buist SA, Calverley P, et al;Global Initiative for Chronic Obstructive Lung Disease. Global strategy for thediagnosis, management, and prevention of chronic obstructive pulmonary dis-ease: GOLD executive summary. Am J Respir Crit Care Med. 2007;176:532-55.[PMID: 17507545]23. Standardization of Spirometry, 1994 Update. American Thoracic Society.Am J Respir Crit Care Med. 1995;152:1107-36. [PMID: 7663792]24. Jones PW, Quirk FH, Baveystock CM, Littlejohns P. A self-complete mea-sure of health status for chronic airflow limitation. The St. George’s RespiratoryQuestionnaire. Am Rev Respir Dis. 1992;145:1321-7. [PMID: 1595997]25. Ware J Jr, Kosinski M, Keller SD. A 12-Item Short-Form Health Survey:construction of scales and preliminary tests of reliability and validity. Med Care.1996;34:220-33. [PMID: 8628042]26. Kazis LE, Miller DR, Clark JA, Skinner KM, Lee A, Ren XS, et al. Im-proving the response choices on the veterans SF-36 health survey role functioningscales: results from the Veterans Health Study. J Ambul Care Manage. 2004;27:263-80. [PMID: 15287216]27. Ware JE, Kosinski M, Keller SD. SF-36: Physical and Mental Health Sum-mary Scales: A User’s Manual. Boston: The Health Institute, New England Med-ical Center; 1994.28. Corson K, Gerrity MS, Dobscha SK. Screening for depression and suicidal-ity in a VA primary care setting: 2 items are better than 1 item. Am J ManagCare. 2004;10:839-45. [PMID: 15609737]29. Fan VS, Burman M, McDonell MB, Fihn SD. Continuity of care and otherdeterminants of patient satisfaction with primary care. J Gen Intern Med. 2005;20:226-33. [PMID: 15836525]30. Bandura A. Self-efficacy: toward a unifying theory of behavioral change.Psychol Rev. 1977;84:191-215. [PMID: 847061]31. Bandura A. Social cognitive theory: an agentic perspective. Annu Rev Psy-chol. 2001;52:1-26. [PMID: 11148297]32. Kalbfleisch JD, Prentice RL. The Statistical Analysis of Failure Time Data.Hoboken, NJ: Wiley-Interscience; 2002.33. Jennison C, Turnbull BW. Group Sequential Methods with Applications toClinical Trials. Boca Raton, FL: Chapman and Hall/CRC; 2000.34. Spiegelhalter DJ, Abrams KR, Myles JP. Bayesian Approaches toClinical Trials and Health-Care Evaluation. Chichester, United King-dom: J Wiley; 2004.35. Tsiatis AA. The asymptotic joint distribution of the efficient scores test forthe proportional hazards model calculated over time. Biometrika. 1981;68:311-5.

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36. Bischoff EW, Hamd DH, Sedeno M, Benedetti A, Schermer TR, BernardS, et al. Effects of written action plan adherence on COPD exacerbation recovery.Thorax. 2011;66:26-31. [PMID: 21037270]37. Sedeno MF, Nault D, Hamd DH, Bourbeau J. A self-management educa-tion program including an action plan for acute COPD exacerbations. COPD.2009;6:352-8. [PMID: 19863364]38. Langsetmo L, Platt RW, Ernst P, Bourbeau J. Underreporting exacerbationof chronic obstructive pulmonary disease in a longitudinal cohort. Am J RespirCrit Care Med. 2008;177:396-401. [PMID: 18048806]39. Seemungal TA, Donaldson GC, Bhowmik A, Jeffries DJ, Wedzicha JA.Time course and recovery of exacerbations in patients with chronic obstructivepulmonary disease. Am J Respir Crit Care Med. 2000;161:1608-13. [PMID:10806163]

40. Camargo CA Jr, Ginde AA, Clark S, Cartwright CP, Falsey AR, Niewoeh-ner DE. Viral pathogens in acute exacerbations of chronic obstructive pulmonarydisease. Intern Emerg Med. 2008;3:355-9. [PMID: 18825480]41. Wilkinson TM, Donaldson GC, Hurst JR, Seemungal TA, Wedzicha JA.Early therapy improves outcomes of exacerbations of chronic obstructive pulmo-nary disease. Am J Respir Crit Care Med. 2004;169:1298-303. [PMID:14990395]42. Chandra D, Tsai CL, Camargo CA Jr. Acute exacerbations of COPD: delayin presentation and the risk of hospitalization. COPD. 2009;6:95-103. [PMID:19378222]43. McGhan R, Radcliff T, Fish R, Sutherland ER, Welsh C, Make B. Predic-tors of rehospitalization and death after a severe exacerbation of COPD. Chest.2007;132:1748-55. [PMID: 17890477]

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Current Author Addresses: Dr. Fan: Veterans Affairs Puget SoundHealth Care System, 1100 Olive Way, Suite 1400, Seattle, WA 98101.Drs. Gaziano, Lew, Thwin, and Fiore; Ms. Leatherman; and Ms. Shan-non: Veterans Affairs Boston Healthcare System, 150 South HuntingtonAvenue, Boston, MA 02130.Dr. Bourbeau: Montreal Chest Institute, 3650 St-Urbain, Montreal,Quebec H2X 2P4, Canada.Dr. Adams: South Texas Veterans Health Care System, 7400 MertonMinter, San Antonio, TX 78229.Dr. Huang: Department of Veterans Affairs Cooperative Studies Pro-gram, 810 Vermont Avenue NW, MS-10P9CS, Washington, DC20420.Dr. Robbins: Phoenix Veterans Affairs Medical Center, 650 East IndianSchool Road, Phoenix, AZ 85012.Dr. Sriram: North Florida/South Georgia Veterans Health System, 1601SW Archer Road, Gainesville, FL 32608.Dr. Sharafkhaneh: Michael E. DeBakey Veterans Affairs Medical Center,2002 Holcombe Boulevard, Houston, TX 77030.Dr. Mador: Veterans Affairs Western New York Healthcare System,3495 Bailey Avenue, Buffalo, NY 14215.Drs. Sarosi and Niewoehner: Minneapolis Veterans Affairs HealthcareSystem, 1 Veterans Drive, Minneapolis, MN 55417.Dr. Panos: Cincinnati Veterans Affairs Medical Center, 3200 VineStreet, Cincinnati, OH 45220.Dr. Rastogi: Dallas Veterans Affairs Medical Center, 4500 South Lan-caster Road, Mail Code IIIE, Dallas, TX 75216.Dr. Wagner: Veterans Affairs Palo Alto Healthcare System, 795 WillowRoad, 152-MPD, Menlo Park, CA 94025.Dr. Mazzuca: Indiana University School of Medicine, Long Hospital,Room 545, 1110 West Michigan Street, Indianapolis, IN 46202-5100.Ms. Colling: Veterans Affairs Cooperative Studies Program Clinical Re-search Pharmacy Coordinating Center, 2401 Centre Avenue SE, Albu-querque, NM 87106-4180.Dr. Liang: Department of Medicine, Brigham and Women’s Hospital,75 Francis Street, PBB3, Boston, MA 02115.Dr. Stoller: The Cleveland Clinic, 9500 Euclid Avenue, NA22, Cleve-land, OH 44195.

Author Contributions: Conception and design: V.S. Fan, J.M. Gaziano,R. Lew, J. Bourbeau, S.G. Adams, G.D. Huang, T.H. Wagner, S.A.Mazzuca, M.H. Liang, J.K. Stoller, L. Fiore, D.E. Niewoehner.Analysis and interpretation of the data: V.S. Fan, J.M. Gaziano, R. Lew,J. Bourbeau, S. Leatherman, S.S. Thwin, G.D. Huang, T.H. Wagner,S.A. Mazzuca, M.H. Liang, J.K. Stoller, D.E. Niewoehner.Drafting of the article: V.S. Fan, R. Lew, G.D. Huang, R.J. Panos, T.H.Wagner, S.A. Mazzuca, J.K. Stoller, D.E. Niewoehner.Critical revision of the article for important intellectual content: V.S.Fan, J.M. Gaziano, R. Lew, J. Bourbeau, S.G. Adams, G.D. Huang, A.Sharafkhaneh, M.J. Mador, S.A. Mazzuca, M.H. Liang, L. Fiore, D.E.Niewoehner.Final approval of the article: V.S. Fan, J.M. Gaziano, R. Lew, J. Bour-beau, S.G. Adams, G.D. Huang, P.S. Sriram, A. Sharafkhaneh, M.J.Mador, G. Sarosi, R.J. Panos, T.H. Wagner, S.A. Mazzuca, C. Shannon,M.H. Liang, J.K. Stoller, L. Fiore, D.E. Niewoehner.Provision of study materials or patients: V.S. Fan, J.M. Gaziano, S.G.Adams, R. Robbins, P.S. Sriram, A. Sharafkhaneh, M.J. Mador, G.Sarosi, R.J. Panos, P. Rastogi, L. Fiore.Statistical expertise: R. Lew, S. Leatherman, S.S. Thwin.Obtaining of funding: V.S. Fan, J.M. Gaziano, R. Robbins, P. Rastogi,T.H. Wagner, L. Fiore, D.E. Niewoehner.Administrative, technical, or logistic support: J.M. Gaziano, R. Lew,S.G. Adams, T.H. Wagner, C. Shannon, C. Colling, M.H. Liang, L.Fiore.

Collection and assembly of data: V.S. Fan, J.M. Gaziano, S.G. Adams,P.S. Sriram, A. Sharafkhaneh, M.J. Mador, G. Sarosi, R.J. Panos, P.Rastogi, T.H. Wagner, C. Colling, D.E. Niewoehner.

APPENDIX: STUDY COMMITTEES AND CLINICAL CENTERS

Co-chairs: Vincent S. Fan, MD, MPH; Dennis E. Niewoeh-ner, MD.

Planning Committee: Jean Bourbeau, MD, MSc; Seth Co-hen, MPH; Cindy Colling, RPH, MS; Theodore Colton, MD;Daniel Deykin, MD; Vincent S. Fan, MD, MPH; Louis Fiore,MD, MPH; J. Michael Gaziano, MD, MPH; Lawrence W.Green, MPH, DrPH; Grant D. Huang, PhD, MPH; RobertLew, PhD; Matthew H. Liang, MD, MPH; Steven Mazzuca,PhD; Dennis E. Niewoehner, MD; Colleen Shannon, MPH;Mark Smith, PhD; James K. Stoller, MD, MS.

Executive Committee: Sandra G. Adams, MD, MS; JeanBourbeau, MD, MSc; Cindy Colling, RPH, MS; Vincent S. Fan,MD, MPH; J. Michael Gaziano, MD, MPH; Grant D. Huang,PhD, MPH; Robert Lew, PhD; Matthew H. Liang, MD, MPH;Steven Mazzuca, PhD; Dennis E. Niewoehner, MD; James K.Stoller, MD, MS; Todd H. Wagner, PhD.

Data Monitoring Committee: Benjamin Cleveland Amick III,PhD; R. Graham Barr, MD, DrPH; Martin Larson, ScD; CarolK. Redmond, ScD; Edwin K. Silverman, MD, PhD; RichardZuWallack, MD.

Human Rights Committee, West Haven, Connecticut: HeatherAllore, PhD; Donald G. Beckwith; William Farrell; Richard C.Feldman, JD; Stanislav Kasl, PhD; Richard Marottoli, MD; Ra-jni Mehta, MPH; James C. Niederman, MD; Edward B. PerryJr., MD; Sister Frances Randall; Reverend Michael Zeman.

Adjudication Committee: Dennis E. Niewoehner, MD; Kath-ryn Rice, MD; Erik Swensen, MD.

VA Cooperative Studies Program Central Office: Grant D.Huang, PhD, MPH; Timothy O’Leary, MD, PhD.

Massachusetts Veterans Epidemiology Research and InformationCenter (MAVERIC) & CSP Coordinating Center, Boston, Massa-chusetts: Mary Brophy, MD, MPH; Ryan Ferguson, MPH; LouisFiore, MD, MPH; J. Michael Gaziano, MD, MPH; Sarah Lea-therman, MS; Robert Lew, PhD; Gregory Muldoon; GeorgetteNichols, MA; Sabrina Russell, MBA; Colleen Shannon, MPH;Victor Tam.

Clinical Centers: Atlanta VA Medical Center, Decatur, Geor-gia: Ryan Moore; Rafael Perez, MD. Bay Pines VA HealthcareSystem, Bay Pines, Florida: Claudia Cote, MD; Michele Morris-sey; Hafida Nedach; Kelly Paradis. Brooklyn Campus of the VANew York Harbor Healthcare System, Brooklyn, New York: ValarieBrutus; Miriam Cohen, ARNP; Bethanne Wenzel. CincinnatiVA Medical Center, Cincinnati, Ohio: Laura Lach; Ralph J. Pa-nos, MD. Hunter Holmes McGuire VA Medical Center, Richmond,Virginia: Michael Godschalk, MD; Deborah Haynes. Kansas CityVA Medical Center, Kansas City, Missouri: Cheryl Perkins; MarkPlautz, MD; Peter Weigmann. Lexington VA Medical Center, Lex-ington, Kentucky: Rey Cortez; Dennis Doherty, MD. Michael E.DeBakey VA Medical Center, Houston, Texas: Joseph Chandy;Amir Sharafkhaneh, MD. New Mexico VA Health Care System,

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Albuquerque, New Mexico: Gregory Foteio, MD; ChristopherZima. North Florida/South Georgia Veterans Health System,Gainesville, Florida: Valorea McLaurin; Peruvemba S. Sriram,MD. Oklahoma City VA Medical Center, Oklahoma City, Okla-homa: Mikel Beavin; Jean Keddissi, MD. Phoenix VA Health CareSystem, Phoenix, Arizona: Patricia Jacobs; Richard Robbins, MD.Providence VA Medical Center, Providence, Rhode Island: LindaNici, MD; Toni Panciera. Richard L. Roudebush VA Medical Cen-ter, Indianapolis, Indiana: Chadi Hage, MD; Carolyn Magnes;George Sarosi, MD. Robert J. Dole VA Medical Center, Wichita,

Kansas: Nancy Coupland; Jing W. Liu, MD. Southern ArizonaHealthcare System, Tucson, Arizona: Michael Habib, MD; TomVincent. South Texas Veterans Health Care System, Audie L. Mur-phy Division, San Antonio, Texas: Sandra G. Adams, MD, MS;Paul McCartor. VA Loma Linda Healthcare System, Loma Linda,California: James Anholm, MD; Laura Carnahan; Kathleen Ell-strom; Lennard Specht, MD. VA North Texas Health Care Sys-tem, Dallas, Texas: Cassie Lusk; Padmashri Rastogi, MD. VAWestern New York Healthcare System at Buffalo, Buffalo, NewYork: Karen Eschberger; Elongia Farrell; M. Jeffery Mador, MD.

Appendix Table 1. Patient Allocations According to Site andCare Manager Qualifications

Site Usual CareGroup, n (%)

InterventionGroup, n (%)

Total Care ManagerQualification

1 4 (57.1) 3 (42.9) 7 RT2 4 (50.0) 4 (50.0) 8 RT3 32 (50.0) 32 (50.0) 64 SC/MD*4 16 (51.6) 15 (48.4) 31 RN/RN*5 13 (52.0) 12 (48.0) 25 RT6 9 (50.0) 9 (50.0) 18 CMA7 19 (50.0) 19 (50.0) 38 RT8 18 (50.0) 18 (50.0) 36 RT9 15 (51.7) 14 (48.3) 29 SC10 7 (53.9) 6 (46.2) 13 NP11 2 (66.7) 1 (33.3) 3 RN12 6 (50.0) 6 (50.0) 12 RN13 2 (66.7) 1 (33.3) 3 MD14 4 (40.0) 6 (60.0) 10 RN15 30 (50.9) 29 (49.2) 59 RT16 4 (50.0) 4 (50.0) 8 RN17 6 (54.6) 5 (45.5) 11 PA18 20 (50.0) 20 (50.0) 40 RT19 3 (50.0) 3 (50.0) 6 PA20 3 (60.0) 2 (40.0) 5 RT

Total 217 209 426 –

CMA � certified medical assistant; MD � medical doctor; NP � nurse practi-tioner; PA � physician assistant; RN � registered nurse; RT � respiratory ther-apist; SC � study coordinator.* Change of case manager during trial.

Appendix Table 2. Cox Proportional Hazards Models WithTreatment Predicting the Outcome of Death, Controlling forthe Categorical Factor “Study Site”*

Cox Model Covariates Hazard Ratio forTreatment (95% CI)

P Valuefor Site

Primary analysis None 3.00 (1.46–6.17) –Usual Cox Site fixed 3.03 (1.47–6.23) 1.00Cox/frailty† Site fixed 3.00 (1.46–6.18) 0.94Cox/sandwich‡ Site random 3.00 (1.88–4.79) –

* The table shows little variation in the estimated hazard ratio for treatment. Theapproximation to the Huber sandwich estimator unexpectedly narrowed the CI,indicating some inconsistency with underlying variance assumptions. See www.stat.berkeley.edu/�census/mlesan.pdf.† The Cox frailty model used the “coxph” function in the R language survivalpackage written by Terry Therneau (most recent version released 1 October 2011).See http://cran.r-project.org/web/packages/survival/index.html.‡ Analysis performed by using the “PHREG” procedure in SAS, version 9.2 (SASInstitute, Cary, North Carolina). The aggregate option was used to invoke thesandwich estimator.

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Appendix Table 4. Antibiotic Treatment of Exacerbations, by Site and Study Group

Site Patients With >1 Treatment, n (%) Total Treatments, n Mean Days to Total Treatments

Usual CareGroup

InterventionGroup

Usual CareGroup

InterventionGroup

Usual CareGroup

InterventionGroup

1 1 (50.0) 1 (50.0) 1 2 10.0 4.02 4 (57.1) 3 (42.9) 9 6 2.6 5.83 21 (52.5) 19 (47.5) 55 57 9.6 7.64 6 (40.0) 9 (60.0) 12 28 8.3 3.55 6 (40.0) 9 (60.0) 13 18 11.5 5.86 5 (55.6) 4 (44.4) 13 13 2.7 7.57 13 (44.8) 16 (55.2) 37 49 7.1 13.08 13 (50.0) 13 (50.0) 25 32 5.6 5.59 8 (40.0) 12 (60.0) 17 24 3.4 9.310 7 (58.3) 5 (41.7) 13 11 9.9 3.411 0 0 0 0 – –12 4 (50.0) 4 (50.0) 5 6 2.1 14.313 1 (100.0) 0 1 0 26.0 0.014 2 (40.0) 3 (60.0) 4 9 2.2 10.715 26 (60.5) 17 (39.5) 77 54 5.0 4.116 3 (60.0) 2 (40.0) 4 10 9.7 4.217 2 (33.3) 4 (66.7) 2 9 3.5 5.318 16 (53.3) 14 (46.7) 51 35 7.7 5.119 3 (60.0) 2 (40.0) 6 6 7.3 3.820 3 (60.0) 2 (40.0) 5 2 3.0 5.0

Appendix Table 3. Prednisone Treatment of Exacerbations, by Site and Study Group

Site Patients With >1 Treatment, n (%) Total Treatments, n Mean Days to Total Treatments

Usual CareGroup

InterventionGroup

Usual CareGroup

InterventionGroup

Usual CareGroup

InterventionGroup

1 1 (50.0) 1 (50.0) 1 1 10.0 1.02 3 (42.9) 4 (57.1) 6 7 2.9 4.03 16 (43.2) 21 (56.8) 45 53 9.6 7.24 4 (30.8) 9 (69.2) 10 26 7.4 5.55 3 (25.0) 9 (75.0) 6 21 19.7 6.86 5 (55.6) 4 (44.4) 13 10 2.8 8.87 13 (46.4) 15 (53.6) 35 49 7.1 7.68 9 (42.9) 12 (57.1) 19 29 7.3 5.29 5 (35.7) 9 (64.3) 15 13 2.3 9.610 6 (66.7) 3 (33.3) 13 6 16.7 4.011 0 0 0 0 – –12 5 (55.6) 4 (44.4) 7 8 3.7 5.913 0 0 0 0 – –14 1 (16.7) 5 (83.3) 4 11 1.5 3.615 16 (45.7) 19 (54.3) 66 53 5.2 4.116 3 (60.0) 2 (40.0) 4 10 9.7 2.917 3 (50.0) 3 (50.0) 3 7 7.0 7.018 13 (48.1) 14 (51.9) 44 31 10.3 8.119 2 (50.0) 2 (50.0) 4 8 7.5 8.620 3 (60.0) 2 (40.0) 5 2 1.7 5.0

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Appendix Table 5. Patients With at Least 1 EmergencyDepartment Visit and Total Number of EmergencyDepartment Visits at Each Site Reported During BimonthlyTelephone Calls at 1-Year Follow-up, by Site and Treatment

Site Usual Care Group Intervention Group

Patients, n Events, n Patients, n Events, n

1 1 1 2 22 2 2 2 33 17 30 12 204 5 9 9 145 6 10 6 126 6 9 2 67 12 30 11 208 10 20 9 169 9 15 8 1310 4 7 3 611 0 0 0 012 3 4 3 313 1 1 0 014 2 3 4 1015 16 20 14 2116 4 4 2 917 3 3 2 318 14 27 8 1319 1 2 0 020 3 6 2 2

Total 119 203 99 173

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Appendix Table 6. Details of Mortality

Group HospitalDeath

Comments Adjudicated Causeof Death

Usual care group duringintervention period

Yes Respiratory failure with pneumonia due to Pseudomonas COPD/pneumonia

No “End-stage COPD,” according to death certificate; died in hospice COPDUnknown No information obtainable UnknownNo Home hospice care for end-stage heart failure, COPD, and diabetes; died at home with no

further details obtainableUnknown

Unknown Death found in Social Security Death Index; no other information UnknownYes Admitted to hospital with cholangitis and died of sepsis and multiple organ failure CholangitisYes Presented to hospital with hypercapnic respiratory failure and died COPDYes Admitted to hospital with acute myocardial infarction and heart failure; intubated because of

cardiorespiratory failure and diedCardiovascular

Unknown Known diagnosis of lung cancer and was receiving chemotherapy; detailed circumstances ofdeath are not known

Lung cancer

Yes According to wife, patient died of a heart attack Cardiovascular

Intervention group duringintervention period

No Hospitalized for COPD; discharged to hospice and died a week later COPD

No Hospitalized for repair of abdominal aortic aneurysm; postoperative complications developedbut patient was eventually discharged; died a month later at home

Cardiovascular

Yes Intubated and mechanically ventilated for COPD exacerbation; developed C. difficile colitis anddied

COPD

No Died at home with “end-stage COPD,” according to relative; no further details available COPDYes Nursing home resident; hospitalized and died of C. difficile colitis ColitisYes Died in hospital with diagnosis of pneumonia and COPD COPD/pneumoniaNo Died at home of liver failure, according to family member Liver failureYes Admitted to hospital and died of acute hypercapnic respiratory failure COPDNo No information obtainable UnknownYes Admitted to hospital and died of COPD; had been receiving home hospice care COPDNo Telephone message from family member stating that patient had died at home; no details

providedUnknown

Unknown Death found in Social Security Death Index UnknownNo Patient died at home under unclear circumstances UnknownUnknown Notification of death by family member; no details provided UnknownNo Blood glucose level at home found to be 39.2 mmol/L (706 mg/dL); patient unwilling to be

hospitalized and died at home; no mention of increased respiratory symptomsDiabetes mellitus

Yes Patient fell, developed large retroperitoneal hematoma, and died of series of complications TraumaUnknown Patient had been admitted to hospital for severe COPD exacerbation; died within several weeks

after discharge but exact circumstances of death not knownCOPD

Yes Died of severe COPD exacerbation and pneumonia in hospital COPD/pneumoniaYes Death record from non-VA hospital states death was due to hypoglycemia from diabetes

therapyDiabetes mellitus

Yes Treated with amoxicillin–clavulanate by hospice for several days and then admitted to hospitalwith abdominal pain and bloating; found to have C. difficile colitis and died in hospital

Colitis

No Patient was observed to have collapsed suddenly in parking lot and died CardiovascularUnknown No information obtainable UnknownUnknown Death certificate lists cause of death as “acute respiratory failure and COPD”; no further details COPDNo Died in motor vehicle accident TraumaNo Took multiple courses of antibiotics and prednisone over several weeks before death; patient

became very dyspneic at home; taken to emergency department by EMS where he died withdiagnosis of COPD

COPD

Yes Admitted to hospital with ruptured abdominal aneurysm and died during surgery CardiovascularUnknown No information obtainable UnknownUnknown No information obtainable Unknown

Usual care group duringfollow-up period

Yes Hospitalized for ischemic bowel; developed respiratory failure and C. difficile colitis after bowelresection and died

Cardiovascular

Yes Receiving chemotherapy for widely metastatic small-cell lung cancer Lung cancerUnknown No information obtainable UnknownYes Admitted to hospital and died 9 days later of “cardiopulmonary arrest”; underlying cause not

evident from available hospital notesUnknown

No Patient diagnosed with COPD exacerbation in emergency department, given prednisone, anddischarged to home; died at home 2 days later

COPD

Yes Supratherapeutic INR (for heart valve) with multiple bleeding complications CardiovascularYes Hospitalized twice within short period for COPD and respiratory failure; active treatment

withdrawn on second admission; sick for 3 days before last admission and took no antibioticsor prednisone

COPD/pneumonia

No No additional information obtainable UnknownUnknown No information obtainable UnknownYes Admitted to hospital with severe exacerbation and died of respiratory failure and sepsis COPD/pneumoniaNo Died in hospice but no details obtainable Unknown

Continued on following page

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Appendix Table 6—Continued

Group HospitalDeath

Comments Adjudicated Causeof Death

Intervention group duringfollow-up period

No No additional information obtainable Unknown

No No additional information obtainable UnknownYes Admitted to hospital and died of respiratory failure COPDUnknown Unknown UnknownNo Fall at home TraumaUnknown No information obtainable UnknownYes Admitted to hospital with acute respiratory failure and status changed to hospice care; receiving

prednisone before going to hospitalCOPD

Yes Documented sudden cardiac arrest with anoxic brain injury resulting in death 6 months later CardiovascularUnknown No information obtainable UnknownNo According to daughter, patient died at home of unknown cause; she stated that he had not

had increased respiratory symptoms before deathUnknown

Yes Found unresponsive in home by family; EMS found asystole; died 4 days later in hospital CardiovascularYes Patient with known lung cancer and enlarging hilar mass admitted for worsening of dyspnea in

previous 2 weeks; died of respiratory failureLung cancer

Yes Several exacerbations in months before death; died in hospital with COPD exacerbation COPDUnknown Admitted to hospital with cough and fever; diagnosed with pneumonia and intubated for

respiratory failure; discharged from hospital but died 10 days later under unknowncircumstances

COPD/pneumonia

Unknown No information obtainable Unknown

C. difficile � Clostridium difficile; COPD � chronic obstructive pulmonary disease; EMS � emergency medical services; INR � international normalized ratio; VA �Veterans Affairs.

Appendix Table 7. Patient Deaths Before 1 March 2009, by Site and Study Group

Site Usual Care Group Intervention Group Total, n

No, n (%) Yes, n (%) No, n (%) Yes, n (%)

1 4 (57.1) 0 3 (42.9) 0 72 4 (50.0) 0 4 (50.0) 0 83 28 (52.8) 4 (36.4) 25 (47.2) 7 (63.6) 644 14 (53.9) 2 (40.0) 12 (46.2) 3 (60.0) 315 13 (54.2) 0 11 (45.8) 1 (100.0) 256 9 (50.0) 0 9 (50.0) 0 187 19 (50.0) 0 19 (50.0) 0 388 17 (54.8) 1 (20.0) 14 (45.2) 4 (80.0) 369 15 (55.6) 0 12 (44.4) 2 (100.0) 2910 7 (58.3) 0 5 (41.7) 1 (100.0) 1311 2 (66.7) 0 1 (33.3) 0 312 6 (50.0) 0 6 (50.0) 0 1213 2 (66.7) 0 1 (33.3) 0 314 4 (40.0) 0 6 (60.0) 0 1015 28 (56.0) 2 (22.2) 22 (44.0) 7 (77.8) 5916 4 (50.0) 0 4 (50.0) 0 817 6 (60.0) 0 4 (40.0) 1 (100.0) 1118 19 (51.4) 1 (33.3) 18 (48.7) 2 (66.7) 4019 3 (50.0) 0 3 (50.0) 0 620 3 (60.0) 0 2 (40.0) 0 5

Total 207 10 181 28 426

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Appendix Table 8. Assessment of General Health Status, Depression, COPD-Related Knowledge, Patient Satisfaction, and PatientSelf-Efficacy*

Measure Baseline 1 Year Change Difference(Usual Care � Intervention)

P Value

St. George’s Respiratory QuestionnaireSymptoms

Usual care group (n � 108) 53.2 (11.2) 54.9 (12.1) 1.62 (14.7) �3.18 (14.8) 0.123Intervention group (n � 101) 53.3 (13.3) 51.7 (14.6) �1.56 (14.9) – –

ActivityUsual care group 74.1 (19.2) 72.8 (20.4) �1.31 (18.2) 1.06 (19.3) 0.69Intervention group 73.3 (17.8) 73.1 (20.9) �0.25 (20.4) – –

ImpactUsual care group† 41.6 (16.3) 38.7 (15.6) �2.94 (13.2) 1.02 (12.7) 0.56Intervention group 40.5 (12.2) 38.6 (14.8) �1.92 (12.2) – –

TotalUsual care group 53.5 (13.3) 51.8 (13.3) �1.67 (11.5) 0.31 (11.4) 0.84Intervention group 52.6 (10.6) 51.3 (13.3) �1.36 (11.2) – –

SF-12Physical component summary

Usual care group 31.0 (7.5) 30.9 (8.4) �0.09 (7.7) 1.19 (7.1) 0.23Intervention group 28.9 (7.9) 30.0 (7.8) 1.10 (6.4) – –

Mental component summaryUsual care group 49.8 (10.8) 49.4 (10.8) �0.46 (9.8) 1.49 (10.3) 0.30Intervention group 49.2 (11.0) 50.2 (10.7) 1.03 (10.8) – –

Patient satisfactionHumanistic scale

Usual care group 77.09 (23.44) 77.36 (23.64) 0.27 (24.37) 4.25 (22.34) 0.167Intervention group† 76.50 (24.74) 81.02 (20.59) 4.52 (19.88) – –

Organizational scaleUsual care group 72.94 (21.83) 72.58 (21.00) �0.36 (18.07) 1.89 (18.07) 0.45Intervention group 71.61 (21.77) 73.14 (21.06) 1.53 (18.07) – –

Depression (PHQ-8)Usual care group 5.76 (5.7) 5.03 (5.1) �0.73 (4.9) �0.54 (5.1) 0.44Intervention group† 5.69 (5.2) 4.41 (4.3) �1.28 (5.3) – –

KnowledgeUsual care group 8.44 (1.7) 8.65 (2.0) 0.21 (1.8) 0.11 (2.0) 0.71Intervention group 8.35 (1.8) 8.67 (1.8) 0.32 (2.2) – –

Self-efficacyUsual care group† 7.72 (1.9) 8.18 (1.8) 0.47 (2.3) 0.65 (2.3) 0.044Intervention group† 7.56 (2.1) 8.69 (1.7) 1.12 (2.3) – –

COPD � chronic obstructive pulmonary disease; HRQOL � health-related quality of life; PHQ-8 � Patient Health Questionnaire-8; SF-12 � Short Form-12.* Values are reported as means (SDs).† Change from baseline to 1 year is significant (P � 0.05).

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