Real-World Adherence Among Adults With Cystic Fibrosis Is Low A Retrospective Analysis of the CFHealthHub Digital Learning Health System

Inhaled antibiotics and mucolytics can prevent exacerbations and maintain lung function in cystic fibrosis (CF). However, treatment adherence is usually low1Daniels T. Goodacre L. Sutton C. Pollard K. Conway S. Peckham D. Accurate assessment of adherence: self-report and clinician report vs electronic monitoring of nebulizers.Chest. 2011; 140: 425-432Abstract Full Text Full Text PDF PubMed Scopus (139) Google Scholar, 2Quittner A.L. Zhang J. Marynchenko M. et al.Pulmonary medication adherence and health-care use in cystic fibrosis.Chest. 2014; 146: 142-151Abstract Full Text Full Text PDF PubMed Scopus (143) Google Scholar, 3Hoo Z.H. Curley R. Walters S.J. Campbell M.J. Wildman M.J. Exploring the implications of different approaches to estimate centre-level adherence using objective adherence data in an adult cystic fibrosis centre: a retrospective observational study.J Cyst Fibros. 2020; 19: 162-167Abstract Full Text Full Text PDF PubMed Scopus (7) Google Scholar (even for cystic fibrosis transmembrane conductance regulator modulators4Siracusa C.M. Ryan J. Burns L. et al.Electronic monitoring reveals highly variable adherence patterns in patients prescribed ivacaftor.J Cyst Fibros. 2015; 14: 621-626Abstract Full Text Full Text PDF PubMed Scopus (39) Google Scholar), which undermines treatment effectiveness.2Quittner A.L. Zhang J. Marynchenko M. et al.Pulmonary medication adherence and health-care use in cystic fibrosis.Chest. 2014; 146: 142-151Abstract Full Text Full Text PDF PubMed Scopus (143) Google Scholar Single-center studies1Daniels T. Goodacre L. Sutton C. Pollard K. Conway S. Peckham D. Accurate assessment of adherence: self-report and clinician report vs electronic monitoring of nebulizers.Chest. 2011; 140: 425-432Abstract Full Text Full Text PDF PubMed Scopus (139) Google Scholar or studies lacking objective adherence data2Quittner A.L. Zhang J. Marynchenko M. et al.Pulmonary medication adherence and health-care use in cystic fibrosis.Chest. 2014; 146: 142-151Abstract Full Text Full Text PDF PubMed Scopus (143) Google Scholar complicate the accurate representation of CF adherence levels. In addition, adherence may be over-estimated by convenience sampling and by adherence definitions that do not account for minimum required treatment.3Hoo Z.H. Curley R. Walters S.J. Campbell M.J. Wildman M.J. Exploring the implications of different approaches to estimate centre-level adherence using objective adherence data in an adult cystic fibrosis centre: a retrospective observational study.J Cyst Fibros. 2020; 19: 162-167Abstract Full Text Full Text PDF PubMed Scopus (7) Google Scholar The National Institute for Health and Care Excellence recently published the United Kingdom CF quality indicators recommending that center-level adherence data are presented,5CFHealthHub TeamNational library of quality indicators: adherence to nebulised therapy in cystic fibrosis. Last updated: 13 May 2020.https://www.nice.org.uk/standards-and-indicators/nlindicators/adherence-to-nebulised-therapy-in-cystic-fibrosisGoogle Scholar which provides an impetus to explore how to fairly represent center-level adherence. We therefore analyzed objective nebulizer adherence data that were available in the CFHealthHub digital learning health system (ISRCTN14464661) between November 2015 and May 2019 to understand adherence among adults with CF. A secondary aim was to replicate our earlier study that suggested that calculations based on agreed, rather than normative, regimens can over-estimate adherence.3Hoo Z.H. Curley R. Walters S.J. Campbell M.J. Wildman M.J. Exploring the implications of different approaches to estimate centre-level adherence using objective adherence data in an adult cystic fibrosis centre: a retrospective observational study.J Cyst Fibros. 2020; 19: 162-167Abstract Full Text Full Text PDF PubMed Scopus (7) Google Scholar This retrospective multicenter observational study included adult CF centers in Sheffield (n = 95), Southampton (n = 101), and Nottingham (n = 103), which are first-wave CFHealthHub digital learning health system centers. Participants aged ≥16 years were diagnosed by standard criteria6UK Cystic Fibrosis TrustStandards for the clinical care of children and adults with cystic fibrosis in the UK. Last updated: 01 Dec 2011.https://www.cysticfibrosis.org.uk/sites/default/files/2020-12/Cystic%20Fibrosis%20Trust%20Standards%20of%20care.pdfGoogle Scholar and used data-logging nebulizers (eTrack, PARI Pharma GmBH; and Bi-neb, Philips Healthcare) for ≥56 days. Participants were aware that their nebulizer would record every dose of medication taken and that date- and time-stamped adherence data would be transferred in real-time to the CFHealthHub digital platform but that adherence data were inaccessible during the study period. Lung transplant recipients were excluded. Researchers at each site extracted inhaled therapy prescriptions and demographic data (age, sex, pancreatic status, Pseudomonas aeruginosa status as defined by clinicians,7Hoo Z.H. Edenborough F.P. Curley R. et al.Understanding Pseudomonas status among adults with cystic fibrosis: a real-world comparison of the Leeds criteria against clinicians’ decision.Eur J Clin Microbiol Infect Dis. 2018; 37: 735-743Crossref PubMed Scopus (9) Google Scholar BMI, %FEV1, IV antibiotics use) from clinical records. Adherence was measured over a 56-day post-recruitment period while clinicians and participants were blinded to the data and was calculated as a mean of all daily adherence values. “Unadjusted adherence” was calculated as the percentage of total nebulizers completed against prescribed doses agreed between adults with CF and clinicians (ie, the denominator was personalized rather than standardized).3Hoo Z.H. Curley R. Walters S.J. Campbell M.J. Wildman M.J. Exploring the implications of different approaches to estimate centre-level adherence using objective adherence data in an adult cystic fibrosis centre: a retrospective observational study.J Cyst Fibros. 2020; 19: 162-167Abstract Full Text Full Text PDF PubMed Scopus (7) Google Scholar “Normative adherence” involved standardized numerator adjustment (daily maximum completed doses capped at 100%) and standardized denominator adjustment based on clinical characteristics (which ensured those participants without chronic P aeruginosa were prescribed at least a daily mucolytic dose and those with chronic P aeruginosa were prescribed at least once daily mucolytic plus twice daily antibiotic doses) to reflect effectiveness of treatment regimens.3Hoo Z.H. Curley R. Walters S.J. Campbell M.J. Wildman M.J. Exploring the implications of different approaches to estimate centre-level adherence using objective adherence data in an adult cystic fibrosis centre: a retrospective observational study.J Cyst Fibros. 2020; 19: 162-167Abstract Full Text Full Text PDF PubMed Scopus (7) Google Scholar To calculate normative adherence, participants with chronic P aeruginosa who were prescribed only twice daily inhaled antibiotics or once daily dornase alfa would have their data analyzed with the use of a daily denominator of “3” because consensus guidelines recommend both mucolytic and antibiotic for this subgroup.8Castellani C. Duff A.J.A. Bell S.C. et al.ECFS best practice guidelines: the 2018 revision.J Cyst Fibros. 2018; 17: 153-178Abstract Full Text Full Text PDF PubMed Scopus (314) Google Scholar There is no denominator adjustment if the minimum required doses were already fulfilled (ie, the prescribed doses define the denominator), for example a person prescribed twice daily tobramycin, daily dornase alfa, and twice daily hypertonic saline solution. In this example, the normative adherence is 60% (3/5) if tobramycin and dornase alfa were used but not hypertonic saline solution. Analyses were performed using R (version 3.6.1; www.r-project.org). Descriptive statistics (median and interquartile range [IQR]) were generated, including results for the chronic P aeruginosa subgroup. The agreement between unadjusted adherence and normative adherence were assessed with “difference-vs-average” plots. The median difference and 95% CI9Campbell M.J. Gardner M.J. Calculating confidence intervals for some non-parametric analyses.BMJ. 1988; 296: 1454-1456Crossref PubMed Scopus (201) Google Scholar were calculated to assess whether there was a systematic difference between the two; Wilcoxon signed-rank test with P < .05 was considered statistically significant. The sample size is pragmatic, with all available data used. This study included 318 adults with 146 (46%) women and 166 (52%) have chronic P aeruginosa. Adults with concurrent use of dry powder inhalers have slightly lower adherence (Table 1). Among adults who were only using nebulized treatment, unadjusted adherence was 41.5% (IQR, 15.1% to 74.1%), while normative adherence was 31.6% (IQR, 10.5% to 60.9%); median paired difference was 9.6% (95% CI, 7.4% to 11.8%); P value <.0001. The differences between unadjusted vs normative adherence were particularly pronounced in the chronic P aeruginosa subgroup, where the figures were 38.9% (IQR, 19.8% to 71.4%) and 26.0% (IQR, 10.8% to 49.2%), respectively; median paired difference was 14.5% (95% CI, 11.2% to 19.7%); P value <.0001 (Figure 1). The cohort-level median adherence was unaffected by the inclusion of dry powder inhalers or alternative definition of P aeruginosa status; further results are available by contacting the corresponding author.Table 1Demographics and Adherence Levels of Adults Only on Nebulized Treatments vs Adults With Concurrent Use of Dry Powder InhalersDemographicOnly Nebulized TreatmentaThere were no missing adherence data for all adults only on nebulized treatment. There were missing data for age (n=24; 8%), pancreatic status (n=64; 21%), BMI (n=28, 9%), %FEV1 (n=35; 12%), and days IV antibiotics (n=27; 9%). (n = 299)Concurrent Use of Dry Powder InhalerbThere were no missing adherence data for all adults who used dry powder inhalers. There were missing data only for pancreatic status (n=4; 21%). (n = 19)Age, median (IQR), y26 (20-34)28 (25-35)Women, No. (%)137 (46)9 (47)Pancreatic insufficient, No. (%)198 (84)13 (87)Chronic Pseudomonas aeruginosa infection, No. (%) Based on clinicians’ judgmentcThe number of participants defined as being chronically infected with P aeruginosa according to clinicians’ judgment.7 Among the adults included in the studies, Pseudomonas status was unavailable for 18 adults (6 %) who were deemed to be not chronically infected with P aeruginosa.147 (49)19 (100) Based on the Leeds criteriadThe number of participants defined as being chronically infected with P aeruginosa according to the Leeds criteria.124 (42)16 (84)BMI, median (IQR), kg/m222.0 (20.2-24.6)21.6 (19.6-27.0)FEV1, median (IQR), %73.0 (52.4-87.5)74.9 (57.6-86.8)IV antibiotic days, median (IQR), No.14 (0-28)14 (12-14)Daily prescribed nebulizer doses, No. (%)…… 1102 (34)11 (58) 250 (17)3 (16) 386 (29)4 (21) 435 (12)0 517 (6)0 ≥69 (3)1 (5)Prescription type, No. (%)…… Mucolytic only126 (42)13 (68) Antibiotic only22 (7)0 Both mucolytic and antibiotic148 (49)6 (32)Adult cystic fibrosis centers, No. (%)…… Sheffield95 (32)3 (16)eThe percentage reported here reflects the way that the 19 dry powder inhaler users are distributed among the three adult cystic fibrosis centers: the majority of CFHealthHub participants who used dry powder inhalers received care at Southampton Adult Cystic Fibrosis Centre or Wolfson Adult Cystic Fibrosis Centre. However, the percentage should not be used to infer that that dry powder inhaler use is lower in Sheffield Adult Cystic Fibrosis Centre compared with the Southampton Adult Cystic Fibrosis Centre or Nottingham Adult Cystic Fibrosis Centre. Very few of the CFHealthHub participants have dry powder inhalers in their inhaled treatment regimen; a substantial proportion of adults in each center had yet to be recruited as of May 2019, and the proportion of recruited adults also differed among the three centers. It is possible that many of the adults who were not recruited have dry powder inhalers in their inhaled treatment regimen. As such, the proportion of dry powder inhaler users of each center should be compared only when the majority of adults in each center have been recruited into CFHealthHub. Southampton101 (34)8 (42)eThe percentage reported here reflects the way that the 19 dry powder inhaler users are distributed among the three adult cystic fibrosis centers: the majority of CFHealthHub participants who used dry powder inhalers received care at Southampton Adult Cystic Fibrosis Centre or Wolfson Adult Cystic Fibrosis Centre. However, the percentage should not be used to infer that that dry powder inhaler use is lower in Sheffield Adult Cystic Fibrosis Centre compared with the Southampton Adult Cystic Fibrosis Centre or Nottingham Adult Cystic Fibrosis Centre. Very few of the CFHealthHub participants have dry powder inhalers in their inhaled treatment regimen; a substantial proportion of adults in each center had yet to be recruited as of May 2019, and the proportion of recruited adults also differed among the three centers. It is possible that many of the adults who were not recruited have dry powder inhalers in their inhaled treatment regimen. As such, the proportion of dry powder inhaler users of each center should be compared only when the majority of adults in each center have been recruited into CFHealthHub. Nottingham103 (34)8 (42)eThe percentage reported here reflects the way that the 19 dry powder inhaler users are distributed among the three adult cystic fibrosis centers: the majority of CFHealthHub participants who used dry powder inhalers received care at Southampton Adult Cystic Fibrosis Centre or Wolfson Adult Cystic Fibrosis Centre. However, the percentage should not be used to infer that that dry powder inhaler use is lower in Sheffield Adult Cystic Fibrosis Centre compared with the Southampton Adult Cystic Fibrosis Centre or Nottingham Adult Cystic Fibrosis Centre. Very few of the CFHealthHub participants have dry powder inhalers in their inhaled treatment regimen; a substantial proportion of adults in each center had yet to be recruited as of May 2019, and the proportion of recruited adults also differed among the three centers. It is possible that many of the adults who were not recruited have dry powder inhalers in their inhaled treatment regimen. As such, the proportion of dry powder inhaler users of each center should be compared only when the majority of adults in each center have been recruited into CFHealthHub.Unadjusted adherence,fFor adults with concurrent use of dry powder inhalers, only adherence via data-logging nebulizers can be measured objectively. Therefore, adherence levels were calculated only for nebulizer use. For example, the adherence level for someone on dornase alfa once daily and tobramycin dry powder inhaler twice daily will be calculated for dornase alfa use only. If that person had adherence of 70% to dornase alfa, then 70% was taken as global adherence to inhaled therapies. median (IQR), %41.5 (15.1-74.1)18.7 (7.2-65.8)Normative adherence,gTo calculate normative adherence, denominator adjustment would be carried out only among adults who did not fulfil the minimum required doses (ie, a minimum of once daily mucolytic for adults without chronic P aeruginosa infection; a minimum of once daily mucolytic and twice daily antibiotics for adults with chronic P aeruginosa infection). For adults with concurrent use of dry powder inhalers, the use of dry powder inhaler would be taken into account for the denominator adjustment to calculate normative adherence. For example, in a study subject with chronic P aeruginosa infection prescribed with a nebulized mucolytic and twice daily dry powder inhaled antibiotics, no extra nebulizer doses will be added to the denominator. median (IQR), %…… P aeruginosa status according to clinicians’ judgment31.6 (10.5-60.9)18.7 (6.9-53.4) P aeruginosa status according to the Leeds criteria32.2 (11.1-62.1)15.8 (3.0-31.0)IQR = interquartile range.a There were no missing adherence data for all adults only on nebulized treatment. There were missing data for age (n=24; 8%), pancreatic status (n=64; 21%), BMI (n=28, 9%), %FEV1 (n=35; 12%), and days IV antibiotics (n=27; 9%).b There were no missing adherence data for all adults who used dry powder inhalers. There were missing data only for pancreatic status (n=4; 21%).c The number of participants defined as being chronically infected with P aeruginosa according to clinicians’ judgment.7Hoo Z.H. Edenborough F.P. Curley R. et al.Understanding Pseudomonas status among adults with cystic fibrosis: a real-world comparison of the Leeds criteria against clinicians’ decision.Eur J Clin Microbiol Infect Dis. 2018; 37: 735-743Crossref PubMed Scopus (9) Google Scholar Among the adults included in the studies, Pseudomonas status was unavailable for 18 adults (6 %) who were deemed to be not chronically infected with P aeruginosa.d The number of participants defined as being chronically infected with P aeruginosa according to the Leeds criteria.e The percentage reported here reflects the way that the 19 dry powder inhaler users are distributed among the three adult cystic fibrosis centers: the majority of CFHealthHub participants who used dry powder inhalers received care at Southampton Adult Cystic Fibrosis Centre or Wolfson Adult Cystic Fibrosis Centre. However, the percentage should not be used to infer that that dry powder inhaler use is lower in Sheffield Adult Cystic Fibrosis Centre compared with the Southampton Adult Cystic Fibrosis Centre or Nottingham Adult Cystic Fibrosis Centre. Very few of the CFHealthHub participants have dry powder inhalers in their inhaled treatment regimen; a substantial proportion of adults in each center had yet to be recruited as of May 2019, and the proportion of recruited adults also differed among the three centers. It is possible that many of the adults who were not recruited have dry powder inhalers in their inhaled treatment regimen. As such, the proportion of dry powder inhaler users of each center should be compared only when the majority of adults in each center have been recruited into CFHealthHub.f For adults with concurrent use of dry powder inhalers, only adherence via data-logging nebulizers can be measured objectively. Therefore, adherence levels were calculated only for nebulizer use. For example, the adherence level for someone on dornase alfa once daily and tobramycin dry powder inhaler twice daily will be calculated for dornase alfa use only. If that person had adherence of 70% to dornase alfa, then 70% was taken as global adherence to inhaled therapies.g To calculate normative adherence, denominator adjustment would be carried out only among adults who did not fulfil the minimum required doses (ie, a minimum of once daily mucolytic for adults without chronic P aeruginosa infection; a minimum of once daily mucolytic and twice daily antibiotics for adults with chronic P aeruginosa infection). For adults with concurrent use of dry powder inhalers, the use of dry powder inhaler would be taken into account for the denominator adjustment to calculate normative adherence. For example, in a study subject with chronic P aeruginosa infection prescribed with a nebulized mucolytic and twice daily dry powder inhaled antibiotics, no extra nebulizer doses will be added to the denominator. Open table in a new tab IQR = interquartile range. In the largest and first multicenter study to use standardized measurement conventions and objective data capture among adults with CF, we confirmed low real-world nebulizer adherence. One-half of the adults had objective adherence <1 in 3, despite a universal health care system that provides nebulized medications free at the point-of-care. We replicated our earlier finding that calculation based on agreed regimens generates higher center-level adherence compared with calculations based on regimens defined by consensus around effectiveness (41.5% vs 31.6%). Not everyone is prescribed treatments defined by effectiveness because regimens may be modified with the hope of reducing burden, which creates the discrepancy between unadjusted and normative adherence. This discrepancy is most obvious among adults with chronic P aeruginosa where the minimum denominator for normative adherence (population standardization based on consensus around effectiveness) is 3 doses/day. Prescription of inhaled therapies differs between specialist centers in the United Kingdom, despite guidance by the CF Trust Standards of Care,6UK Cystic Fibrosis TrustStandards for the clinical care of children and adults with cystic fibrosis in the UK. Last updated: 01 Dec 2011.https://www.cysticfibrosis.org.uk/sites/default/files/2020-12/Cystic%20Fibrosis%20Trust%20Standards%20of%20care.pdfGoogle Scholar for example center-level dornase alfa prescription varied between 46.6% and 87.4%.10UK Cystic Fibrosis TrustUK cystic fibrosis registry annual data report 2018. Last updated: 01 Aug 2019.https://www.cysticfibrosis.org.uk/the-work-we-do/uk-cf-registry/reporting-and-resourcesGoogle Scholar The median paired difference between unadjusted vs normative adherence in this study was larger than our earlier study (9.6% vs 2.6% to 5.1%), probably because of high rates of inhaled antibiotic prescribed in Sheffield.3Hoo Z.H. Curley R. Walters S.J. Campbell M.J. Wildman M.J. Exploring the implications of different approaches to estimate centre-level adherence using objective adherence data in an adult cystic fibrosis centre: a retrospective observational study.J Cyst Fibros. 2020; 19: 162-167Abstract Full Text Full Text PDF PubMed Scopus (7) Google Scholar Limitations include selective recruitment because not all adults at the participating centers were included and adherence was measured over only the initial 56 days after recruitment. People with lowest adherence are probably the most difficult to reach,3Hoo Z.H. Curley R. Walters S.J. Campbell M.J. Wildman M.J. Exploring the implications of different approaches to estimate centre-level adherence using objective adherence data in an adult cystic fibrosis centre: a retrospective observational study.J Cyst Fibros. 2020; 19: 162-167Abstract Full Text Full Text PDF PubMed Scopus (7) Google Scholar and long-term adherence also declines over time;4Siracusa C.M. Ryan J. Burns L. et al.Electronic monitoring reveals highly variable adherence patterns in patients prescribed ivacaftor.J Cyst Fibros. 2015; 14: 621-626Abstract Full Text Full Text PDF PubMed Scopus (39) Google Scholar hence, adherence levels are still likely to be over-estimated. Data on cystic fibrosis transmembrane conductance regulator modulators use were unavailable, but only approximately 5% of adults were eligible during the study period, so impact of modulator use is expected to be small. In conclusion, our study shows low medication adherence among adults with CF. Calculating adherence levels without considering sampling strategies and the clinical appropriateness of treatment prescription may over-estimate effective adherence, highlighting the impact of data issues on center-level adherence. Role of sponsors: The sponsor had no role in the design of the study, the collection and analysis of the data, or the preparation of the manuscript.