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Characteristics at the time of oxygen initiation associated with its adherence: Findings from the COPD Long-term Oxygen Treatment Trial

Open ArchivePublished:February 13, 2019DOI:https://doi.org/10.1016/j.rmed.2019.02.004

      Highlights

      • Readiness, confidence, and importance to use LTOT are associated with adherence.
      • Early oxygen adherence predicts later adherence.
      • Characteristics associated with high adherence differ initally and over time.
      • Adherence characteristics differ in continuous versus intermittent oxygen groups.

      Abstract

      Rationale

      Characteristics associated with adherence to long-term oxygen therapy (LTOT) in COPD remain unclear.

      Objectives

      To identify patient characteristics at the time of oxygen initiation associated with its adherence.

      Methods

      We conducted a secondary analysis of data from 359 COPD participants assigned to oxygen in the Long-term Oxygen Treatment Trial. Participants were prescribed continuous (n = 214) or intermittent (n = 145) oxygen based on desaturation patterns at study entry. At the time of initial prescription, participants rated their perceived readiness, confidence, and importance to use oxygen on a 0–10 scale (0 = not at all, 10 = very much). During follow-up, they self-reported average hours per day of use (adherence). Adherence was averaged over short-term (0–30 days), medium-term (months 9–12), and long-term (month 13 to last follow-up) intervals. Multivariable logistic regression models explored characteristics associated with high adherence (≥16 h/day [continuous] or ≥8 h/day [intermittent]) during each time interval.

      Results

      Participant readiness, confidence, and importance at the time of oxygen initiation were associated with high short- and medium-term adherence. For each unit increase in baseline readiness, the odds of high short-term adherence increased by 21% (odds ratio [OR] 1.21, 95% confidence interval [CI] 1.05–1.40) and 94% (OR 1.94, 95% CI 1.45–2.59) in the continuous and intermittent groups, respectively. In both groups, high adherence in the medium-term was associated with high adherence in the long-term (continuous, OR 12.49, 95% CI 4.90–31.79; intermittent, OR 38.08, 95% CI 6.96–208.20).

      Conclusions

      Readiness, confidence, and importance to use LTOT at initiation, and early high adherence, are significantly associated with long-term oxygen adherence.

      Keywords

      Abbreviations list

      BD
      bronchodilator
      CI
      confidence interval
      COPD
      chronic obstructive pulmonary disease
      FEV1
      forced expiratory volume in 1 s
      FVC
      forced vital capacity
      LOTT
      Long-term Oxygen Treatment Trial
      LTOT
      long-term oxygen therapy
      MMRC
      modified Medical Research Council
      OR
      odds ratio
      SD
      standard deviation
      SGRQ
      St. George's Respiratory Questionnaire

      1. Introduction

      Although long-term oxygen therapy (LTOT) prolongs life in patients with chronic obstructive pulmonary disease (COPD) who have severe resting hypoxemia [
      Nocturnal Oxygen Therapy Trial Group
      Continuous or nocturnal oxygen therapy in hypoxemic chronic obstructive lung disease: a clinical trial.
      ,
      From the global strategy for the diagnosis, management and prevention of COPD, global initiative for chronic obstructive lung disease (GOLD) 2017.
      ], adherence to treatment has been reported to be as low as 45–70% [
      • Katsenos S.
      • Constantopoulos S.H.
      Long-term oxygen therapy in COPD: factors affecting and ways of improving patient compliance.
      ,
      • Cullen D.L.
      Long term oxygen therapy adherence and COPD: what we don't know.
      ]. Many factors—physiological, psychosocial, and oxygen treatment-related—determine adherence to LTOT. Reasons for low adherence, previously assessed in patients already using LTOT, include cumbersome and unreliable equipment, no perceived benefit, embarrassment and stigma, and lack of social support [
      • Katsenos S.
      • Constantopoulos S.H.
      Long-term oxygen therapy in COPD: factors affecting and ways of improving patient compliance.
      ,
      • Cullen D.L.
      Long term oxygen therapy adherence and COPD: what we don't know.
      ,
      • Pe´ pin J.L.
      • Barjhoux C.E.
      • Deschaux C.
      • Brambilla C.
      Long-term oxygen therapy at home: compliance with medical prescription and effective use of therapy.
      ,
      • Peckham D.G.
      • McGibbon K.
      • Tonkinson J.
      • Plimbley G.
      • Pantin C.
      Improvement in patient compliance with long-term oxygen therapy following formal assessment with training.
      ,
      • Arnold E.
      • Bruton A.
      • Donovan-Hall M.
      • Fenwick A.
      • Dibb B.
      • Walker E.
      Ambulatory oxygen: why do COPD patients not use their portable systems as prescribed? A qualitative study.
      ,
      • Earnest M.A.
      Explaining adherence to supplemental oxygen therapy.
      ,
      • Evans T.W.
      • Waterhouse J.
      • Howard P.
      Clinical experience with the oxygen concentrator.
      ,
      • Granados A.
      • Escarrabill J.
      • Borràs J.M.
      • Rodríguez-Roisín R.
      The importance of process variables analysis in the assessment of long-term oxygen therapy by concentrator.
      ,
      • Howard P.
      • Waterhouse J.C.
      • Billings C.G.
      Compliance with long-term oxygen therapy by concentrator.
      ,
      • Restrick L.J.
      • Paul E.A.
      • Braid G.M.
      • Cullinan P.
      • Moore-Gillon J.
      • Wedzicha J.A.
      Assessment and follow up of patients prescribed long term oxygen treatment.
      ,
      • Verduri A.
      • Ballerin L.
      • Simoni M.
      • Cellini M.
      • Vagnoni E.
      • Roversi P.
      • Papi A.
      • Clini E.
      • Fabbri L.M.
      • Potena A.
      Poor adherence to guidelines for long-term oxygen therapy (LTOT) in two Italian university hospitals.
      ,
      • Walshaw M.J.
      • Lim R.
      • Evans C.C.
      • Hind C.R.K.
      Factors influencing the compliance of patients using oxygen concentrators for long-term home oxygen therapy.
      ].
      Bandura's Social Cognitive Theory states that understanding and addressing both efficacy and outcome expectations are required for behavior change [
      • Rosenstock I.M.
      • Strecher V.J.
      • Becker M.H.
      Social learning theory and the health belief model.
      ]. Specifically, believing that one is capable of using the oxygen (efficacy expectation) and knowing the importance of wearing oxygen (outcome expectation) are needed to effect the behavior changes of using and adhering to LTOT [
      • Rosenstock I.M.
      • Strecher V.J.
      • Becker M.H.
      Social learning theory and the health belief model.
      ]. In clinical practice at the time of LTOT initiation, provider counseling focuses on outcome expectations (importance), and little is known about patient efficacy expectations [
      • Cullen D.L.
      Long term oxygen therapy adherence and COPD: what we don't know.
      ,
      • Croxton Tl
      • Bailey W.C.
      Long-term oxygen treatment in chronic obstructive pulmonary disease: recommendations for future research - an NHLBI workshop report.
      ,
      • Lacasse Y.
      • Tan A.M.
      • Maltais F.
      • Krishnan J.A.
      Home oxygen in chronic obstructive pulmonary disease.
      ]. It is not uncommon that oxygen is prescribed and delivered to the home with no formal assessment of the patient's self-efficacy (readiness and confidence) to use oxygen. In a survey of oxygen users, approximately one-third of patients felt “very” or “somewhat” unprepared to operate oxygen equipment [
      • Jacobs S.S.
      • Lindell K.O.
      • Collins E.G.
      • Garvey C.M.
      • Hernandez C.
      • McLaughlin S.
      • Schneidman A.M.
      • Meek P.M.
      Patient perceptions of the adequacy of supplemental oxygen therapy: results of the American Thoracic Society nursing assembly oxygen working group survey.
      ]. Furthermore, there is a paucity of information about differences in adherence to LTOT in patients recently prescribed continuous (24 h/day) or intermittent oxygen (e.g., with exertion and during sleep), and factors associated with adherence in these two groups at various points in time after initiating LTOT (e.g., first 30 days vs. after the first 12 months) [
      • Cullen D.L.
      Long term oxygen therapy adherence and COPD: what we don't know.
      ,
      • Croxton Tl
      • Bailey W.C.
      Long-term oxygen treatment in chronic obstructive pulmonary disease: recommendations for future research - an NHLBI workshop report.
      ,
      • Lacasse Y.
      • Tan A.M.
      • Maltais F.
      • Krishnan J.A.
      Home oxygen in chronic obstructive pulmonary disease.
      ].
      In the Long-term Oxygen Treatment Trial (LOTT), participants with COPD and moderate resting hypoxemia or normal resting saturation and moderate hypoxemia during exercise were randomly assigned to no supplemental oxygen or to supplemental oxygen [
      • Albert R.K.
      • Au D.H.
      • Blackford A.L.
      • Casaburi R.
      • Cooper Jr., J.A.
      • Criner G.J.
      • Diaz P.
      • Fuhlbrigge A.L.
      • Gay S.E.
      • Kanner R.E.
      • MacIntyre N.
      • Martinez F.J.
      • Panos R.J.
      • Piantadosi S.
      • Sciurba F.
      • Shade D.
      • Stibolt T.
      • Stoller J.K.
      • Wise R.
      • Yusen R.D.
      • Tonascia J.
      • Sternberg A.L.
      • Bailey W.
      Long-term Oxygen Treatment Trial Research Group
      A randomized trial of long-term oxygen for COPD with moderate desaturation.
      ,
      • Yusen R.D.
      • Criner G.J.
      • Sternberg A.L.
      • Au D.H.
      • Fuhlbrigge A.L.
      • Albert R.K.
      • Casaburi R.
      • Stoller J.K.
      • Harrington K.F.
      • Cooper Jr., J.A.D.
      • Diaz P.
      • Gay S.
      • Kanner R.
      • MacIntyre N.
      • Martinez F.J.
      • Piantadosi S.
      • Sciurba F.
      • Shade D.
      • Stibolt T.
      • Tonascia J.
      • Wise R.
      • Bailey W.C.
      LOTT Research Group
      The Long-term Oxygen Treatment Trial (LOTT) for chronic obstructive pulmonary disease: rationale, design, and lessons learned.
      ]. Participants assigned to supplemental oxygen received it either continuously or intermittently with exercise and sleep based on resting and exercise desaturation patterns at trial entry. They also received an adherence intervention to promote oxygen use, which included regular participant self-assessments of readiness, confidence, and importance to use oxygen. The LOTT did not find a benefit of supplemental oxygen for these specific participants with COPD [
      • Albert R.K.
      • Au D.H.
      • Blackford A.L.
      • Casaburi R.
      • Cooper Jr., J.A.
      • Criner G.J.
      • Diaz P.
      • Fuhlbrigge A.L.
      • Gay S.E.
      • Kanner R.E.
      • MacIntyre N.
      • Martinez F.J.
      • Panos R.J.
      • Piantadosi S.
      • Sciurba F.
      • Shade D.
      • Stibolt T.
      • Stoller J.K.
      • Wise R.
      • Yusen R.D.
      • Tonascia J.
      • Sternberg A.L.
      • Bailey W.
      Long-term Oxygen Treatment Trial Research Group
      A randomized trial of long-term oxygen for COPD with moderate desaturation.
      ]. Nevertheless, the participants started on oxygen as part of LOTT provide a unique opportunity to assess expectations and characteristics at the time of oxygen initiation that are associated with treatment adherence. These findings may inform strategies to promote adherence in other COPD populations prescribed LTOT.
      In this secondary analysis of LOTT data, we explore characteristics associated with high oxygen adherence. We hypothesize that self-efficacy constructs, such as readiness and confidence, are strongly associated with high adherence. We also hypothesize that characteristics associated with high adherence differ over short-, medium-, and long-term intervals of follow-up and between those initiated on continuous versus intermittent oxygen.

      2. METHODS (see the Appendix for additional details)

      2.1 Study design

      In brief, the LOTT was a multicenter randomized controlled trial of supplemental oxygen therapy versus no supplemental oxygen therapy (no placebo, unblinded) for patients with stable COPD and moderate resting hypoxemia or normal resting saturation and moderate hypoxemia during exercise [
      • Albert R.K.
      • Au D.H.
      • Blackford A.L.
      • Casaburi R.
      • Cooper Jr., J.A.
      • Criner G.J.
      • Diaz P.
      • Fuhlbrigge A.L.
      • Gay S.E.
      • Kanner R.E.
      • MacIntyre N.
      • Martinez F.J.
      • Panos R.J.
      • Piantadosi S.
      • Sciurba F.
      • Shade D.
      • Stibolt T.
      • Stoller J.K.
      • Wise R.
      • Yusen R.D.
      • Tonascia J.
      • Sternberg A.L.
      • Bailey W.
      Long-term Oxygen Treatment Trial Research Group
      A randomized trial of long-term oxygen for COPD with moderate desaturation.
      ,
      • Yusen R.D.
      • Criner G.J.
      • Sternberg A.L.
      • Au D.H.
      • Fuhlbrigge A.L.
      • Albert R.K.
      • Casaburi R.
      • Stoller J.K.
      • Harrington K.F.
      • Cooper Jr., J.A.D.
      • Diaz P.
      • Gay S.
      • Kanner R.
      • MacIntyre N.
      • Martinez F.J.
      • Piantadosi S.
      • Sciurba F.
      • Shade D.
      • Stibolt T.
      • Tonascia J.
      • Wise R.
      • Bailey W.C.
      LOTT Research Group
      The Long-term Oxygen Treatment Trial (LOTT) for chronic obstructive pulmonary disease: rationale, design, and lessons learned.
      ]. Participants had post-randomization follow-up for at least one and up to six years [
      • Albert R.K.
      • Au D.H.
      • Blackford A.L.
      • Casaburi R.
      • Cooper Jr., J.A.
      • Criner G.J.
      • Diaz P.
      • Fuhlbrigge A.L.
      • Gay S.E.
      • Kanner R.E.
      • MacIntyre N.
      • Martinez F.J.
      • Panos R.J.
      • Piantadosi S.
      • Sciurba F.
      • Shade D.
      • Stibolt T.
      • Stoller J.K.
      • Wise R.
      • Yusen R.D.
      • Tonascia J.
      • Sternberg A.L.
      • Bailey W.
      Long-term Oxygen Treatment Trial Research Group
      A randomized trial of long-term oxygen for COPD with moderate desaturation.
      ,
      • Yusen R.D.
      • Criner G.J.
      • Sternberg A.L.
      • Au D.H.
      • Fuhlbrigge A.L.
      • Albert R.K.
      • Casaburi R.
      • Stoller J.K.
      • Harrington K.F.
      • Cooper Jr., J.A.D.
      • Diaz P.
      • Gay S.
      • Kanner R.
      • MacIntyre N.
      • Martinez F.J.
      • Piantadosi S.
      • Sciurba F.
      • Shade D.
      • Stibolt T.
      • Tonascia J.
      • Wise R.
      • Bailey W.C.
      LOTT Research Group
      The Long-term Oxygen Treatment Trial (LOTT) for chronic obstructive pulmonary disease: rationale, design, and lessons learned.
      ]. LOTT was approved by the institutional review board at each participating center, and all participants provided written informed consent.

      2.2 Study population

      Our study population consisted of the participants randomized to supplemental oxygen therapy in the LOTT. Previous publications have described LOTT eligibility criteria and the characteristics of study participants at trial entry [
      • Albert R.K.
      • Au D.H.
      • Blackford A.L.
      • Casaburi R.
      • Cooper Jr., J.A.
      • Criner G.J.
      • Diaz P.
      • Fuhlbrigge A.L.
      • Gay S.E.
      • Kanner R.E.
      • MacIntyre N.
      • Martinez F.J.
      • Panos R.J.
      • Piantadosi S.
      • Sciurba F.
      • Shade D.
      • Stibolt T.
      • Stoller J.K.
      • Wise R.
      • Yusen R.D.
      • Tonascia J.
      • Sternberg A.L.
      • Bailey W.
      Long-term Oxygen Treatment Trial Research Group
      A randomized trial of long-term oxygen for COPD with moderate desaturation.
      ,
      • Yusen R.D.
      • Criner G.J.
      • Sternberg A.L.
      • Au D.H.
      • Fuhlbrigge A.L.
      • Albert R.K.
      • Casaburi R.
      • Stoller J.K.
      • Harrington K.F.
      • Cooper Jr., J.A.D.
      • Diaz P.
      • Gay S.
      • Kanner R.
      • MacIntyre N.
      • Martinez F.J.
      • Piantadosi S.
      • Sciurba F.
      • Shade D.
      • Stibolt T.
      • Tonascia J.
      • Wise R.
      • Bailey W.C.
      LOTT Research Group
      The Long-term Oxygen Treatment Trial (LOTT) for chronic obstructive pulmonary disease: rationale, design, and lessons learned.
      ].

      2.3 Supplemental oxygen prescription

      Participants with moderate resting hypoxemia at trial entry received a prescription for continuous oxygen, while those with normal saturation at rest and desaturation during exercise at trial entry were prescribed intermittent oxygen [
      • Albert R.K.
      • Au D.H.
      • Blackford A.L.
      • Casaburi R.
      • Cooper Jr., J.A.
      • Criner G.J.
      • Diaz P.
      • Fuhlbrigge A.L.
      • Gay S.E.
      • Kanner R.E.
      • MacIntyre N.
      • Martinez F.J.
      • Panos R.J.
      • Piantadosi S.
      • Sciurba F.
      • Shade D.
      • Stibolt T.
      • Stoller J.K.
      • Wise R.
      • Yusen R.D.
      • Tonascia J.
      • Sternberg A.L.
      • Bailey W.
      Long-term Oxygen Treatment Trial Research Group
      A randomized trial of long-term oxygen for COPD with moderate desaturation.
      ,
      • Yusen R.D.
      • Criner G.J.
      • Sternberg A.L.
      • Au D.H.
      • Fuhlbrigge A.L.
      • Albert R.K.
      • Casaburi R.
      • Stoller J.K.
      • Harrington K.F.
      • Cooper Jr., J.A.D.
      • Diaz P.
      • Gay S.
      • Kanner R.
      • MacIntyre N.
      • Martinez F.J.
      • Piantadosi S.
      • Sciurba F.
      • Shade D.
      • Stibolt T.
      • Tonascia J.
      • Wise R.
      • Bailey W.C.
      LOTT Research Group
      The Long-term Oxygen Treatment Trial (LOTT) for chronic obstructive pulmonary disease: rationale, design, and lessons learned.
      ]. Patients in the intermittent oxygen group were prescribed oxygen for exercise and during sleep. LOTT did not evaluate patients for hypoxemia during sleep. All patients randomized to supplemental oxygen received a stationary system and a portable oxygen delivery system.

      2.4 Oxygen adherence intervention

      LOTT participants randomized to receive supplemental oxygen therapy also received an adherence intervention that investigators designed to promote use of LTOT. The oxygen adherence intervention was comprised of regular telephone contacts by research staff. Study-trained and certified adherence educators delivered the oxygen adherence intervention. At each contact, staff used motivational interviewing techniques to explore the participant's perceptions of readiness, confidence and importance to use oxygen and to address ambivalence towards use by discussing their self-identified barriers and solutions to it [
      • Yusen R.D.
      • Criner G.J.
      • Sternberg A.L.
      • Au D.H.
      • Fuhlbrigge A.L.
      • Albert R.K.
      • Casaburi R.
      • Stoller J.K.
      • Harrington K.F.
      • Cooper Jr., J.A.D.
      • Diaz P.
      • Gay S.
      • Kanner R.
      • MacIntyre N.
      • Martinez F.J.
      • Piantadosi S.
      • Sciurba F.
      • Shade D.
      • Stibolt T.
      • Tonascia J.
      • Wise R.
      • Bailey W.C.
      LOTT Research Group
      The Long-term Oxygen Treatment Trial (LOTT) for chronic obstructive pulmonary disease: rationale, design, and lessons learned.
      ]. Participants received the ongoing oxygen adherence intervention while follow-up outcomes were assessed. Participants self-reported their perceived readiness, confidence, and importance to use LTOT (each on a scale of 0–10, where 0 = not at all and 10 = very much) at the time of treatment initiation, when they knew whether they would receive continuous or intermittent oxygen. Contacts began at the visit when participants were assigned to oxygen, followed by telephone calls weekly during the first month, monthly for 6 months, and bi-monthly in months 6–10, and visits yearly through the end of follow-up [
      • Yusen R.D.
      • Criner G.J.
      • Sternberg A.L.
      • Au D.H.
      • Fuhlbrigge A.L.
      • Albert R.K.
      • Casaburi R.
      • Stoller J.K.
      • Harrington K.F.
      • Cooper Jr., J.A.D.
      • Diaz P.
      • Gay S.
      • Kanner R.
      • MacIntyre N.
      • Martinez F.J.
      • Piantadosi S.
      • Sciurba F.
      • Shade D.
      • Stibolt T.
      • Tonascia J.
      • Wise R.
      • Bailey W.C.
      LOTT Research Group
      The Long-term Oxygen Treatment Trial (LOTT) for chronic obstructive pulmonary disease: rationale, design, and lessons learned.
      ].

      2.5 Oxygen adherence assessments

      At each follow-up adherence contact, participants estimated average hours (0–24) of oxygen use per day in the prior week. Every 4 months, at contacts comprising the LOTT's follow-up visit schedule for all randomized participants, participants randomized to oxygen also self-reported oxygen use separately for stationary and portable oxygen, by selecting the average daily hours of oxygen use in the prior week from categories of ≤4, 5–8, 9–16, or 17–24 h/day. The two streams of self-reports were merged for analyses.
      We defined short-, medium-, and long-term time intervals as specified in Table 1 and calculated each participant's average daily oxygen use in each of the three intervals. We defined high adherence to supplemental oxygen as average supplemental oxygen use ≥16 h/day (2/3 of the expected time) for those assigned to continuous supplemental oxygen therapy, and ≥8 h/day for those assigned to intermittent supplemental oxygen therapy [
      • Albert R.K.
      • Au D.H.
      • Blackford A.L.
      • Casaburi R.
      • Cooper Jr., J.A.
      • Criner G.J.
      • Diaz P.
      • Fuhlbrigge A.L.
      • Gay S.E.
      • Kanner R.E.
      • MacIntyre N.
      • Martinez F.J.
      • Panos R.J.
      • Piantadosi S.
      • Sciurba F.
      • Shade D.
      • Stibolt T.
      • Stoller J.K.
      • Wise R.
      • Yusen R.D.
      • Tonascia J.
      • Sternberg A.L.
      • Bailey W.
      Long-term Oxygen Treatment Trial Research Group
      A randomized trial of long-term oxygen for COPD with moderate desaturation.
      ]. It is reasonable to expect patients to be in bed for 7–8 h and to be active 3–4 h a day. We estimated that the majority would wear oxygen approximately 12 h a day. Thus, the definition of high adherence in the intermittent group (at least 8 h/day) is based on use during 2/3 of the expected time.
      Table 1Definitions for duration of follow-up and level of oxygen adherence.
      Definition
      Duration of Follow-up
      Over all follow-upOxygen equipment delivery day through end of follow-up
      Short-termOxygen equipment delivery day through day 30
      Medium-termDays 270 through day 365 (months 9 through 12)
      Long-termDays 366 through end of follow-up (months 13 to end)
      Oxygen Adherence
       Participants prescribed continuous oxygen (24-h)
      Low<16 h/day on average
      High≥16 h/day on average
       Participants prescribed intermittent oxygen (during exercise and sleep)
      Low<8 h/day on average
      High≥8 h/day on average

      2.6 Statistical analysis

      We compared baseline characteristics between the oxygen prescription groups using Fisher's exact test, chi-squared test, or analysis of variance. Multivariate logistic regression was used to explore characteristics associated with high adherence (yes vs. no) in each of the 6 groups determined by oxygen prescription (continuous, intermittent) and time interval (short-, medium-, long-term) [
      • Lindsey C.
      • Sheather S.
      Best subsets variable selection in nonnormal regression models.
      ]. The candidate set of characteristics for high adherence in the short-term included baseline factors chosen a priori for their potential impact on adherence: 1) constructs from the Social Cognitive Theory: self-reported ratings of readiness, confidence, and importance and 2) general or COPD-related health experiences and symptoms. The candidate sets of characteristics for high adherence in the medium-term and long-term included the candidate characteristics for high adherence in the short-term plus post-randomization measures of COPD exacerbation and high adherence or not during the prior interval. All models adjusted for age, race, and sex. For each analysis, best subsets variable selection identified the model with the lowest Akaike information criterion out of all possible models for the candidate set of characteristics [
      • Lindsey C.
      • Sheather S.
      Best subsets variable selection in nonnormal regression models.
      ,
      • Akaike H.
      A new look at the statistical model identification.
      ,
      • Wang Z.
      Model selection using the Akaike information criterion.
      ]. Model fit was assessed using the Hosmer-Lemeshow test [
      • Hosmer D.W.J.
      • Lemeshow S.
      Applied Logistic Regression.
      ]. Analyses were completed in SAS (Cary, NC) or STATA (College Station, TX).

      3. RESULTS (see the Appendix for additional details)

      3.1 Participant characteristics

      Three hundred sixty-eight participants were randomized to supplemental oxygen in the LOTT; 359 (97.6%) completed at least one oxygen adherence contact and were included in this analysis. Two hundred and fourteen participants (59.6%) were prescribed continuous oxygen, 68 (31.8%) of whom had resting hypoxemia only. One hundred forty-five participants (40.4%) were prescribed intermittent oxygen during exercise and sleep.
      Compared to those starting intermittent oxygen, participants who started continuous oxygen had significantly higher pack-years of cigarette smoking, body mass index, post-bronchodilator forced expiratory volume in 1 s (FEV1), prevalence of coronary vascular disease and diabetes mellitus, and lower prevalence of prior participation in pulmonary rehabilitation (Table 2). At baseline, participants started on continuous oxygen had significantly lower readiness and confidence scores to use oxygen (7.6 ± 2.7 vs. 8.9 ± 1.9, P < 0.0001 and 8.4 ± 2.1 vs. 8.8 ± 1.6, P = 0.02, respectively), and a trend of lower perceived importance of oxygen use (7.8 ± 2.5 vs. 8.3 ± 2.3, P = 0.05), compared to those initiated on intermittent oxygen (Table 2).
      Table 2Baseline participant characteristics by oxygen prescription group.
      Continuous (24-h; N = 214)Intermittent (during exercise and sleep; N = 145)P
      Fisher's exact test, chi-square test, or t-test for difference between groups.
      Demographics
       Age (years; mean ± SD)68.0 ± 6.968.5 ± 8.30.58
       White race86.4%82.1%0.30
       Hispanic ethnicity3.3%2.1%0.75
       Female gender25.7%29.7%0.47
      Exposures, symptoms, and physiologic measures
       Lives with a smoker13.6%17.2%0.37
       Current smoker33.2%24.8%0.10
       Pack-years tobacco cigarette smoking (mean ± SD)65.7 ± 39.257.7 ± 26.70.03
       Wheeze or whistling in chest55.1%51.7%0.52
       Nasal dryness or bloody nose or discharge ≥ 1x/mo40.7%43.5%0.66
       MMRC dyspnea score
      128.0%22.8%0.37
      230.4%32.4%
      334.6%40.7%
      47.0%4.1%
      Body mass index (kg/m2; mean ± SD)29.9 ± 6.827.2 ± 5.7<0.0001
      Hemoglobin (g/dL; mean ± SD)14.6 ± 1.514.4 ± 1.40.12
      6-min walk distance (ft; mean ± SD)1035 ± 3191100 ± 3070.06
      Post BD FEV1 (L; mean ± SD)1.38 ± 0.471.22 ± 0.510.002
      Post BD FEV1 percent predicted (%; mean ± SD)48 ± 1545 ± 180.08
      Post BD FEV1/FVC (mean ± SD)0.48 ± 0.130.44 ± 0.130.003
      Healthcare utilization and comorbidities
       Pulmonary rehabilitation ever21.5%36.6%0.003
       Ever used home oxygen prior to entry29.4%30.3%>0.99
       COPD exacerbation in 3 months prior to entry17.3%17.2%0.99
       Hospitalization in year prior to entry
      Status re: hospitalization in year prior to entry was missing for 24 continuous patients and 1 intermittent patient; collection of this data item began after protocol revisions instituted in September 2009.
      23.2%20.8%0.69
       Coronary vascular disease38.3%24.8%0.009
       Diabetes23.8%13.8%0.02
       Osteoarthritis, sciatica, chronic back problem47.2%53.1%0.28
      Psychosocial measures
       Ratings of Social Cognitive Theory constructs (scored 0–10)
      Readiness to use oxygen (mean ± SD)7.6 ± 2.78.9 ± 1.9<0.0001
      Confidence in using oxygen (mean ± SD)8.4 ± 2.18.8 ± 1.60.02
      Importance of using oxygen (mean ± SD)7.8 ± 2.58.3 ± 2.30.05
       SGRQ total score (mean ± SD)49.7 ± 19.350.7 ± 16.90.60
       Epworth sleepiness score (mean ± SD)7.3 ± 4.06.3 ± 3.80.03
      SD = standard deviation; MMRC = modified Medical Research Council; FEV1 = forced expiratory volume in 1 s; FVC = forced vital capacity; COPD = chronic obstructive pulmonary disease; SGRQ = St. George's Respiratory Questionnaire.
      a Fisher's exact test, chi-square test, or t-test for difference between groups.
      b Status re: hospitalization in year prior to entry was missing for 24 continuous patients and 1 intermittent patient; collection of this data item began after protocol revisions instituted in September 2009.

      3.2 Characteristics of self-efficacy are associated with high oxygen adherence

      In multivariable analysis, higher ratings of readiness and confidence to use oxygen were strongly associated with high adherence in the first 30 days of oxygen use (Table 3). For each unit increase in readiness, there was a 21% (odds ratio (OR) 1.21, 95% confidence interval [CI] 1.04–1.40, P = 0.008) increase in the odds of high adherence in the continuous group and a 94% (OR 1.94, 95% CI 1.45–2.59, P < 0.001) increase in the odds of high adherence in the intermittent group (Table 3).
      Table 3Characteristics associated with high adherence to LTOT in the short-, medium-, and long-term by oxygen prescription group.
      Continuous GroupIntermittent Group
      Odds ratio95% CIPOdds ratio95% CIP
      Short term (1st 30 days; N = 212)Short term (1st 30 days; N = 145)
      Age at trial entry (per year)1.00(0.96, 1.05)0.99Age at trial entry (per year)1.06(0.99, 1.12)0.09
      White race (vs. other)0.57(0.22, 1.45)0.24White race (vs. other)0.73(0.23, 2.36)0.60
      Female (vs. male)0.85(0.42, 1.72)0.66Female (vs. male)2.08(0.72, 5.99)0.18
      Self-reported rating of readiness to use oxygen at randomization (per unit)1.21(1.05, 1.40)0.008Self-reported rating of readiness to use oxygen at randomization (per unit)1.94(1.45, 2.59)<0.001
      Exacerbation in 3 mos prior to trial entry (yes vs. no)2.37(0.97, 5.78)0.06Exacerbation in 3 mos prior to trial entry (yes vs. no)0.37(0.12, 1.11)0.08
      Ever participated in pulmonary rehabilitation as of trial entry (yes vs. no)3.02(1.29, 7.05)0.01Ever diagnosed with cardiovascular disease as of trial entry (yes vs. no)0.22(0.08, 0.60)0.003
      Self-reported rating of confidence in using oxygen at randomization (per unit)1.24(1.03, 1.50)0.03MMRC dyspnea score at trial entry (per unit)0.58(0.32, 1.04)0.07
      Current tobacco smoker at trial entry (yes vs. no)0.49(0.25, 0.96)0.04SGRQ total score at trial entry (per unit)1.02(0.99, 1.05)0.16
      Model goodness of fit: Hosmer-Lemeshow χ2 (df = 3) = 4.30 with P = 0.23, indicating good fit.Model goodness of fit: Hosmer-Lemeshow χ2 (df = 3) = 3.84, P = 0.28, indicating good fit.
      Medium term (months 912; N = 208)Medium term (months 912; N = 139)
      Age at trial entry (per year)0.96(0.91, 1.01)0.10Age at trial entry (per year)1.11(1.03, 1.20)0.007
      White race (yes vs. no)0.94(0.33, 2.70)0.90White race (vs. other)0.68(0.15, 2.97)0.60
      Female (vs. male)0.35(0.15, 0.86)0.02Female (vs. male)0.24(0.07, 0.79)0.02
      High adherence in the 1st 30 days since starting oxygen (yes vs. no)15.85(7.24, 34.73)<0.001High adherence in the 1st 30 days since starting oxygen (yes vs. no)5.11(1.63, 15.97)0.005
      Self-reported rating of importance of using oxygen at randomization (per unit)1.23(1.05, 1.44)0.01Self-reported rating of importance of using oxygen at randomization (per unit)1.38(1.10, 1.73)0.005
      Exacerbation in 1st 8 months since starting oxygen (yes vs. no)2.32(0.99, 5.43)0.05Wheeze or whistling in chest at trial entry (yes vs. no)6.15(2.03, 18.68)0.001
      Post BD FEV1 at trial entry (per L)0.45(0.18, 1.10)0.086-min walk distance at trial entry (per 10 ft)0.97(0.95, 0.99)0.002
      Ever used home oxygen before trial entry (yes vs. no)1.97(0.89, 4.37)0.10Hemoglobin level at trial entry (per g/dL)0.53(0.33, 0.87)0.01
      Living with a smoker at trial entry (yes vs. no)6.25(1.41, 27.80)0.02
      Model goodness of fit: Hosmer-Lemeshow χ2 (df = 3) = 3.33, P = 0.53, indicating good fit.Ever diasagnosed with cardiovascular disease as of trial entry (yes vs. no)0.26(0.07, 0.94)0.04
      Current tobacco smoker as of trial entry (yes vs. no)0.36(0.11, 1.15)0.08
      Ever diagnosed with osteoarthritis, sciatica, chronic back problems as of trial entry (yes vs. no)0.41(0.15, 1.14)0.09
      Exacerbation in 3 mos prior to trial entry (yes vs. no)3.61(0.82, 15.76)0.09
      Model goodness of fit: Hosmer-Lemeshow χ2 (df = 3) = 1.24, P = 0.74, indicating good fit.
      Long term (month 13 to end of follow-up; N = 187)Long term (month 13 to end of follow-up; N = 133)
      Age at trial entry (per year)1.08(1.01, 1.16)0.02Age at trial entry (per year)0.96(0.89, 1.04)0.34
      White race (yes vs. no)1.46(0.46, 4.58)0.52White race (vs. other)5.35(0.95, 30.06)0.06
      Female (vs. male)2.04(0.71, 5.84)0.19Female (vs. male)2.11(0.44, 10.23)0.35
      High adherence in months 9–12 (yes vs. no)12.49(4.90, 31.79)<0.001High adherence in months 9–12 (yes vs. no)38.08(6.96, 208.20)<0.001
      High adherence in the first 30 days (yes vs. no)2.95(1.17, 7.43)0.02High adherence in the 1st 30 days (yes vs. no)3.33(0.91, 12.22)0.07
      6-min walk distance at trial entry (per 10 feet)0.99(0.98, 1.01)0.206-min walk distance at trial entry (per 10 feet)0.98(0.96, 1.00)0.05
      SGRQ total score at trial entry (per unit)1.03(1.01, 1.06)0.01Hospitalized in year prior to trial entry (yes vs. no)20.22(1.54, 266.25)0.02
      Hemoglobin level at trial entry (per g/dL)1.37(1.00, 1.88)0.05Ever diagnosed with osteoarthritis, sciatica, chronic back problems as of trial entry (yes vs. no)0.23(0.06, 0.89)0.03
      Self-reported rating of readiness to use oxygen at randomization (per unit)1.18(0.98, 1.41)0.08Epworth Sleepiness Scale score at trial entry (per unit)1.18(0.98, 1.42)0.08
      Post BD FEV1 at trial entry (per L)2.32(0.87, 6.20)0.09
      Model goodness of fit: Hosmer-Lemeshow χ2 (df = 3) = 5.25, P = 0.15, indicating good fit.Model goodness of fit: Hosmer-Lemeshow χ2 (df = 3) = 3.40, P = 0.33, indicating good fit.
      For each outcome, the model shown is that with the lowest Akaike information criterion (16, 17). Odds ratios, 95% confidence intervals, and P values (Wald chi-squared tests) were determined from multiple logistic regression of high adherence in the indicated time frame (yes vs. no) on the candidate set of characteristics. For each model, inclusion of age, race and sex was forced; the other characteristics were identified by best variable subsets selection (15) using the Akaike information criterion and were selected from the candidate set of characteristics for the outcome (20 for short-term adherence; 22 for medium-term adherence; and 23 for long-term adherence). See Appendix for additional details.
      LTOT = long-term oxygen treatment; MMRC = modified Medical Research Council; BD = bronchodilator; FEV1 = forced expiratory volume in 1 s; SGRQ = St. George's Respiratory Questionnaire.

      3.3 Characteristics associated with high oxygen adherence differ over time

      Female sex, higher self-reported importance to use oxygen at oxygen initiation, and high adherence in the first 30 days were significantly associated with high adherence in the medium term of 9–12 months in multivariable analysis in both the continuous and intermittent use groups. For each unit increase in baseline rating of importance, there was a 23% (OR 1.23; 95% CI 1.04–1.44, P = 0.01) increase in the odds of high adherence in months 9–12 in the continuous group and a 38% (OR 1.38, 95% CI 1.10–1.73; P = 0.005) increase in the intermittent group (Table 3). For the continuous group, the odds of high adherence in months 9–12 was 15.85 (P < 0.001; 95% CI 7.24–34.73) times greater for those with high adherence compared to low adherence in the first 30 days. For the intermittent group, the odds ratio was 5.11 (P = 0.005; 95% CI 1.63–15.97).
      High long-term adherence in months 13 to the end of follow-up was associated with high oxygen adherence in the medium-term of months 9–12. Compared to those with low adherence in the medium-term, those with high adherence in the medium-term had greater odds of high adherence in the long-term: OR 12.49 (P < 0.001; 95% CI 4.90–31.79) and OR 38.08 (P < 0.001; 95% CI 6.96–208.20) in the continuous and intermittent groups, respectively (Table 3).

      3.4 Characteristics associated with high oxygen adherence differ by prescription group

      In the continuous group, a history of participation in pulmonary rehabilitation was significantly associated with high adherence in the short-term, while current smokers were less likely to have high adherence in the short-term in multivariable analysis (Table 3). In the intermittent group, those with a higher 6-min walk distance were less likely to have high adherence in the medium term. Participants in the intermittent group with comorbidities of cardiovascular disease, osteoarthritis, or back problems had a lower odds of high oxygen adherence in the medium- and long-term.

      4. Discussion

      This secondary study of LOTT participants randomly assigned to receive supplemental oxygen coupled with an oxygen adherence intervention demonstrates that high self-reported ratings of readiness and confidence to use oxygen at the time of treatment initiation are associated with high adherence in COPD participants with moderate hypoxemia at rest or with exertion prescribed LTOT. This is a novel and clinically meaningful finding as it highlights efficacy expectations that can be enhanced through counseling prior to oxygen initiation to improve treatment adherence. In addition, early oxygen adherence predicts later adherence. We also show that characteristics associated with high adherence differ initally and over time, and between those prescribed continuous versus intermittent oxygen. Importance was significantly associated with medium-term adherence, suggesting that efficacy expectations are important in the short-term while outcome expectations are important in the medium-term.
      These findings suggest that the initiation of LTOT and the immediate 30 days thereafter are critical times to focus educational and motivational efforts that may have long-lasting effects on adherence. Sources of patient instruction and support are currently limited, which mostly include the delivery person (64%) and less commonly the clinician (8%) [
      • Jacobs S.S.
      • Lindell K.O.
      • Collins E.G.
      • Garvey C.M.
      • Hernandez C.
      • McLaughlin S.
      • Schneidman A.M.
      • Meek P.M.
      Patient perceptions of the adequacy of supplemental oxygen therapy: results of the American Thoracic Society nursing assembly oxygen working group survey.
      ]. Our study provides guidance for the content of provider communications, namely to assess and optimize patients’ self-efficacy, perceived readiness and confidence, to use oxygen when it is initially prescribed. Our findings can potentially guide the development of future interventions to enhance long-term adherence [
      • Holm K.E.
      • Casaburi R.
      • Cerreta S.
      • Gussin H.A.
      • Husbands J.
      • Porszasz J.
      • Prieto-Centurion V.
      • Sandhaus R.A.
      • Sullivan J.L.
      • Walsh L.J.
      • Krishnan J.A.
      Patient involvement in the design of a patient-centered clinical trial to promote adherence to supplemental oxygen therapy in COPD.
      ].
      Oxygen use prior to trial entry did not predict high adherence during the trial. Providers should not take previous oxygen use as reassurance that the patient will use and adhere to a new prescription. Participation in pulmonary rehabilitation predicted short-term high oxygen adherence. We speculate that this setting allowed opportunities for providers to educate patients about the use of LTOT, which facilitated adherence. One-third of the participants assigned to continuous oxygen were active cigarette smokers, which was significantly associated with lower odds of high adherence at 30 days. Individuals who are active smokers prescribed continuous oxygen require ongoing education to maintain high oxygen adherence, compared to those starting intermittent oxygen.
      The strengths of this analysis include the large, well characterized study population, assessments at the initiation of LTOT, a theoretical framework for behavior change, and longitudinal follow-up over a long duration. We acknowledge that the group of COPD participants who volunteered for LOTT may not represent the general population of patients who meet current guidelines to initiate LTOT. These results must also be interpreted in the context of participants receiving an embedded intervention to promote oxygen adherence during the trial. Despite this best case scenario of an adherence intervention, 42.5% of the continuous group and 25.5% of the intermittent group had low adherence during the first 30 days. It is unlikely that the adherence intervention confounded the results, as we focus on baseline measurements of self-efficacy constructs, and ratings of readiness and confidence tended to be unchanged over time (see Appendix). In fact, high oxygen adherence decreased over time in the continuous group (see Appendix).
      The LOTT showed no significant benefit with oxygen in the population studied. Our findings might not apply to patients with COPD and severe hypoxemia who may have greater motivation to adhere with oxygen treatment believing that it is necessary for their health. Nevertheless, our participants may have enrolled in the LOTT with the belief that supplemental oxygen would improve their health, and participants like the ones we studied may progress to meet the current guidelines, so understanding their barriers to adherence is relevant. Our findings may also be relevant to understanding adherence to other behavior changes often promoted in persons with COPD such as engagement in physical activity, bronchodilator medication use, and use of action plans for acute exacerbations.
      Oxygen use was assessed by self-report which generally over-reports use compared to objective measures [
      • Casaburi R.
      • Porszasz J.
      • Hecht A.
      • Tiep B.
      • Albert R.K.
      • Anthonisen N.R.
      • Bailey W.C.
      • Connett J.E.
      • Cooper Jr., J.A.
      • Criner G.J.
      • Curtis J.
      • Dransfield M.
      • Lazarus S.C.
      • Make B.
      • Martinez F.J.
      • McEvoy C.
      • Niewoehner D.E.
      • Reilly K.K.
      • Scanlon P.
      • Scharf S.M.
      • Sciurba F.C.
      Woodruff P for the COPD Clinical Research Network. Influence of lightweight ambulatory oxygen on oxygen use and activity patterns of COPD patients receiving long-term oxygen therapy.
      ,
      • Ringbæk T.
      • Lange P.
      • Viskum K.
      Compliance with LTOT and consumption of mobile oxygen.
      ,
      • Walshaw M.J.
      • Lim R.
      • Evans C.C.
      • Hind C.R.K.
      Prescription of oxygen concentrators for long term oxygen treatment: reassessment in one district.
      ,
      • Lin S.V.
      • Kuna S.T.
      • Bogen D.K.
      A novel device for measuring long-term oxygen therapy adherence: a preliminary validation.
      ]. Thus, there may be a response bias overclassifying high adherence in LOTT. However, we previously found good agreement between self-reports of oxygen use with objective measurement of serial concentrator meter readings in 100 LOTT participants for whom meter readings were available [
      • Albert R.K.
      • Au D.H.
      • Blackford A.L.
      • Casaburi R.
      • Cooper Jr., J.A.
      • Criner G.J.
      • Diaz P.
      • Fuhlbrigge A.L.
      • Gay S.E.
      • Kanner R.E.
      • MacIntyre N.
      • Martinez F.J.
      • Panos R.J.
      • Piantadosi S.
      • Sciurba F.
      • Shade D.
      • Stibolt T.
      • Stoller J.K.
      • Wise R.
      • Yusen R.D.
      • Tonascia J.
      • Sternberg A.L.
      • Bailey W.
      Long-term Oxygen Treatment Trial Research Group
      A randomized trial of long-term oxygen for COPD with moderate desaturation.
      ]. Our definitions of oxygen adherence have precedence as cut-offs of >15 h per day or >17–18 h per day have been previously used to define adherence and oxygen use that is efficacious [
      Nocturnal Oxygen Therapy Trial Group
      Continuous or nocturnal oxygen therapy in hypoxemic chronic obstructive lung disease: a clinical trial.
      ,
      • Katsenos S.
      • Constantopoulos S.H.
      Long-term oxygen therapy in COPD: factors affecting and ways of improving patient compliance.
      ,
      • Ringbæk T.
      • Lange P.
      • Viskum K.
      Compliance with LTOT and consumption of mobile oxygen.
      ,
      • Lacasse Y.
      • Lecours R.
      • Pelletier C.
      • Begin R.
      • Maltais F.
      Randomised trial of ambulatory oxygen in oxygen-dependent COPD.
      ,
      • Vergeret J.
      • Brambilla C.
      • Mounier L.
      Portable Oxygen Therapy: use and benefit in hypoxaemic COPD patients on long-term oxygen therapy.
      ]. We do not know the level of physical activity or the sleep patterns of the participants in the intermittent group to determine how many hours of daily oxygen they should have used. Nevertheless, our definition of high oxygen adherence, ≥8 h/day, appears to be a reasonable estimate in this population.
      We acknowledge that our assessment of readiness, confidence, and importance is not based on a validated questionnaire with known psychometric properties and minimum clinically important differences. Nevertheless, the wording of the questions used to assess readiness, confidence, and importance are based on face validity and the responses are modeled on the commonly used visual analog scale.

      5. Conclusions

      Efficacy and outcome expectations assessed by self-reported readiness, confidence, and importance to use oxygen are associated with high adherence among LOTT participants assigned to supplemental oxygen. While characteristics that are associated with high adherence depend on the time from the initiation of treatment and type of oxygen prescription, it appears that once high adherence is established it is likely to continue. This finding highlights the importance of early intervention to promote adherence to supplemental oxygen use.

      Author contributions and guarantor statement

      Conception and design: Marilyn L. Moy, Kathleen F. Harrington, Anne L. Fuhlbrigge.
      Analysis and interpretation: Alice L. Sternberg, Marilyn L. Moy, Kathleen F. Harrington, Anne L Fuhlbrigge, Jerry Krishnan, James Tonascia, Richard Casaburi, Roger Yusen, Ai-Yui Tan.
      Drafting the manuscript for important intellectual content: all authors.
      All authors read and approved the final manuscript. Alice L. Sternberg and James Tonascia had full access to all the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.

      Summary conflict of interest statement

      Drs Moy, Albert, Diaz, Kanner, Krishnan, Panos, Stibolt, and Yusen have nothing to disclose.
      Dr. Stoller has no conflicts relevant to this work.
      Ms. Sternberg and Dr Tonascia report grants from NIH/NHLBI during the conduct of the study. Dr. Tan reports grants from National Institutes of Health (NIH)/National Heart, Lung, and Blood Institute (NHLBI) institutional training grant during the conduct of the study. Dr. Harrington reports grants from NHLBI, grants from NIDA, grants from HRSA during the conduct of the study.
      Dr. Au reports grants from NIH/NHLBI during the conduct of the study and personal fees from Gilead Sciences and Novartis Inc, both outside the submitted work.
      Dr. Casaburi reports stock ownership in Inogen, Inc., outside the submitted work.
      Dr. Criner reports grants from Boehringer- Ingelheim, grants from Novartis, grants from Astra Zeneca, grants from Respironics, grants from MedImmune, grants from Actelion, grants from Forest, grants from Pearl, grants from Ikaria, grants from Aeris, grants from PneumRx, grants from Pulmonx, and other from HGE Health Care Solutions, Inc, Amirall, Boehringer- Ingelheim, and Holaira, all outside the submitted work.
      Dr. Fuhlbrigge has received grant support from the NHBLI, AHRQ and PCORI related to asthma and COPD studies. She also has received personal fees from GSK, AstraZeneca and Icon Medical Imaging for consulting on investigations in asthma and COPD.

      Funding support

      The Long-term Oxygen Treatment Trial (LOTT) was supported through federal funding from the National Heart, Lung, and Blood Institute, National Institutes of Health, Department of Health and Human Services [contracts HHSN268200736183C, HHSN268200736184C, HHSN268200736185C, HHSN268200736186C, HHSN268200736187C, HHSN268200736188C, HHSN268200736189C, HHSN268200736190C, HHSN268200736191C, HHSN268200736192C, HHSN268200736193C, HHSN268200736194C, HHSN268200736195C, HHSN268200736196C, HHSN268200736197C, Y1-HR-7019-01, and Y1-HR-8076-01] in cooperation with the Centers for Medicare and Medicaid Services, Department of Health and Human Services.

      Appendix A. Supplementary data

      The following is the Supplementary data to this article:

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