The Effects of Feedback on Adherence to Treatment: A Systematic Review and Meta-analysis of RCTs

      Context

      The aim of this systematic review is to determine whether providing feedback, guided by subjective or objective measures of adherence, improves adherence to treatment.

      Evidence acquisition

      Data sources included MEDLINE, Embase, CINAHL, and PsycINFO, and reference lists of retrieved articles. Only RCTs comparing the effect of feedback on adherence outcome were included. Three independent reviewers extracted data for all potentially eligible studies using an adaptation of the Cochrane Library data extraction sheet. The primary outcome, change in adherence, was obtained by measuring the difference between adherence at baseline visit (prior to feedback) and at the last visit (post-feedback).

      Evidence synthesis

      Twenty-four studies were included in the systematic review, and 16 found a significant improvement in adherence in the intervention group (change in adherence range, –13% to +22%), whereas adherence worsened in the control group (change in adherence range, –32% to 10.2%). Meta-analysis included six studies, and the pooled effect showed that mean percentage adherence increased by 10.02% (95% CI=3.15%, 16.89%, p=0.004) more between baseline and follow-up in the intervention groups compared with control groups. Meta-regression confirmed that study quality, form of monitoring adherence, delivery of feedback, or study duration did not influence effect size.

      Conclusions

      Feedback guided by objective or subjective measures of adherence improves adherence and, perhaps more importantly, prevents worsening of adherence over time even when only small absolute improvements in adherence were noted. Increased use of feedback to improve treatment adherence has the potential to reduce avoidable healthcare costs caused by non-adherence.

      Context

      Adherence is defined as “the extent to which a patient’s behavior coincides with medical and health advice.”
      • Vermeire E.
      • Hearnshaw H.
      • Van Royen P.
      • Denekens J.
      Patient adherence to treatment: three decades of research. A comprehensive review.
      Subjective and objective methods have been employed to monitor adherence in both clinical trials and clinical practice.
      • Farmer K.
      Methods for measuring and monitoring medication regimen adherence in clinical trials and clinical practice.
      These include self-report, drug level monitoring, Medication Event Monitoring System (MEMS) caps; pill counts; and surrogate markers of adherence (serum carboxy-terminal collagen crosslinks [CTX] bone marker level and Disease Activity Score).
      • Farmer K.
      Methods for measuring and monitoring medication regimen adherence in clinical trials and clinical practice.
      It is estimated that up to half of medications prescribed for long-term conditions are not taken as recommended.

      National Institute for Health and Clinical Excellence (NICE). Medicines adherence: involving patients in decisions about prescribed medicines and supporting adherence. www.nice.org.uk/guidance/cg76. Published 2009. Accessed February 2015.

      Non-adherence has both medical and economic implications.

      National Institute for Health and Clinical Excellence (NICE). Medicines adherence: involving patients in decisions about prescribed medicines and supporting adherence. www.nice.org.uk/guidance/cg76. Published 2009. Accessed February 2015.

      Approximately 57% of avoidable healthcare cost incurred by suboptimal medicine use is due to non-adherence.
      • Furniss D.
      • Barber N.
      • Lyons I.
      • Eliasson L.
      • Blandford A.
      Unintentional non-adherence: can a spoon full of resilience help the medicine go down?.
      Non-adherence can be classified into two categories: intentional and unintentional non-adherence.

      National Institute for Health and Clinical Excellence (NICE). Medicines adherence: involving patients in decisions about prescribed medicines and supporting adherence. www.nice.org.uk/guidance/cg76. Published 2009. Accessed February 2015.

      The latter describes an individual willing to adhere to treatment but unable to do so owing to factors beyond their control (e.g., reduced understanding).

      National Institute for Health and Clinical Excellence (NICE). Medicines adherence: involving patients in decisions about prescribed medicines and supporting adherence. www.nice.org.uk/guidance/cg76. Published 2009. Accessed February 2015.

      Intentional non-adherence defines when an individual chooses not to follow the recommended treatment.

      National Institute for Health and Clinical Excellence (NICE). Medicines adherence: involving patients in decisions about prescribed medicines and supporting adherence. www.nice.org.uk/guidance/cg76. Published 2009. Accessed February 2015.

      It is important to understand a patient’s view of the need for treatment, concerns, and expectations in order to address non-adherence.

      National Institute for Health and Clinical Excellence (NICE). Medicines adherence: involving patients in decisions about prescribed medicines and supporting adherence. www.nice.org.uk/guidance/cg76. Published 2009. Accessed February 2015.

      • Furniss D.
      • Barber N.
      • Lyons I.
      • Eliasson L.
      • Blandford A.
      Unintentional non-adherence: can a spoon full of resilience help the medicine go down?.
      As such, there is no intervention that will address non-adherence in all patients; it is ideal to take into account individual needs when implementing an intervention.

      National Institute for Health and Clinical Excellence (NICE). Medicines adherence: involving patients in decisions about prescribed medicines and supporting adherence. www.nice.org.uk/guidance/cg76. Published 2009. Accessed February 2015.

      • Furniss D.
      • Barber N.
      • Lyons I.
      • Eliasson L.
      • Blandford A.
      Unintentional non-adherence: can a spoon full of resilience help the medicine go down?.

      National Institute for Health and Clinical Excellence (NICE). Costing statement: medicines adherence: involving patients in decisions about prescribed medicines and supporting adherence. www.nice.org.uk/guidance/cg76/resources/medicines-adherence-costing-statement2. Accessed February 2015.

      Reported interventions include enhanced support from family, peers, or allied health professionals such as pharmacists, who often delivered education, counseling, or daily treatment support.
      • Nieuwlaat R.
      • Wilczynski N.
      • Navarro T.
      • et al.
      Interventions for enhancing medication adherence.
      Several studies have employed feedback interventions to improve adherence based upon patients’ individual needs.
      • Burgess S.W.
      • Sly P.D.
      • Devadason S.G.
      Providing feedback on adherence increases use of preventive medication by asthmatic children.
      • Onyirimba F.
      • Apter A.
      • Reisine S.
      • et al.
      Direct clinician-to-patient feedback discussion of inhaled steroid use: its effect on adherence.
      • Smith S.R.
      • Rublein J.C.
      • Marcus C.
      • Brock T.P.
      • Chesney M.A.
      A medication self-management program to improve adherence to HIV therapy regimens.
      • Sabin L.L.
      • DeSilva M.B.
      • Hamer D.H.
      • et al.
      Using electronic drug monitor feedback to improve adherence to antiretroviral therapy among HIV-positive patients in China.
      • Rigsby M.O.
      • Rosen M.I.
      • Beauvais J.E.
      • et al.
      Cue-dose training with monetary reinforcement: pilot study of an antiretroviral adherence intervention.
      • Rosen M.I.
      • Dieckhaus K.
      • McMahon T.J.
      • et al.
      Improved adherence with contingency management.
      • Kalichman S.C.
      • Kalichman M.O.
      • Cherry C.
      • et al.
      Brief behavioral self-regulation counseling for HIV treatment adherence delivered by cell phone: an initial test of concept trial.
      • Mooney M.E.
      • Sayre S.L.
      • Hokanson P.S.
      • Stotts A.L.
      • Schmitz J.M.
      Adding MEMS feedback to behavioral smoking cessation therapy increases compliance with bupropion: a replication and extension study.
      • Schmitz J.M.
      • Sayre S.L.
      • Stotts A.L.
      • Rothfleisch J.
      • Mooney M.E.
      Medication compliance during a smoking cessation clinical trial: a brief intervention using MEMS feedback.
      • Elixhauser A.
      • Eisen S.A.
      • Romeis J.C.
      • Homan S.M.
      The effects of monitoring and feedback on compliance.
      • Kozuki Y.
      • Schepp G.
      Visual-feedback therapy for antipsychotic medication adherence.
      • Cramer J.A.
      • Rosenheck R.
      Enhancing medication compliance for people with serious mental illness.
      • Russell C.
      • Conn V.
      • Ashbaugh C.
      • et al.
      Taking immunosuppressive medications effectively (TIMELink): a pilot randomized controlled trial in adult kidney transplant recipients.
      • Hardstaff R.
      • Green K.
      • Talbot D.
      Measurement of compliance posttransplantation—the results of a 12-month study using electronic monitoring.
      • Ruppar T.M.
      Randomized pilot study of a behavioral feedback intervention to improve medication adherence in older adults with hypertension.
      • Wu J.R.
      • Corley D.J.
      • Lennie T.A.
      • Moser D.K.
      Effect of a medication-taking behavior feedback theory-based intervention on outcomes in patients with heart failure.
      • Duncan K.A.
      • Pozehl B.
      Staying on course: the effects of an adherence facilitation intervention on home exercise participation.
      • Kung A.W.
      • Rachman I.A.
      • Adam J.M.
      • Roeshadi D.
      • Torralba T.
      Impact of bone marker feedback on adherence to once monthly ibandronate for osteoporosis among Asian postmenopausal women.
      • Lai P.S.M.
      • Chua S.S.
      • Chew Y.Y.
      • Chan S.P.
      Effects of pharmaceutical care on adherence and persistence to bisphosphonates in postmenopausal osteoporotic women.
      • El Miedany Y.
      • El Gaafary M.
      • Palmer D.
      Assessment of the utility of visual feedback in the treatment of early rheumatoid arthritis patients: a pilot study.
      • Nadeem R.
      • Rishi M.
      • Srinivasan L.
      • Copur A.
      • Naseem J.
      Effect of visualization of raw graphic polysomnography data by sleep apnea patients on adherence to CPAP therapy.
      • Watson A.
      • Bickmore T.
      • Cange A.
      • Kulshreshtha A.
      • Kvedar J.
      An internet-based virtual coach to promote physical activity adherence in overweight adults: randomized controlled trial.
      • Shakudo M.
      • Takegami M.
      • Shibata A.
      • et al.
      Effect of feedback in promoting adherence to an exercise programme: a randomized controlled trial.
      • Reddy A.
      • Huseman T.
      • Canamucio A.
      • et al.
      Patient and partner feedback reports to improve statin medication adherence: a randomized control trial.
      Studies have monitored adherence either subjectively or objectively. Obtained adherence measures were used as guides to explore reasons for non-adherence and provided specific feedback based on the information given by participants. The aim of this systematic review is to explore whether feedback, guided by subjective or objective adherence measures, improves adherence.

      Evidence Acquisition

      Literature Search, Study Selection, and Data Extraction

      Four major databases were searched: MEDLINE (1946–2016), Embase (1974–2016), CINAHL, and PsycINFO. Key words included feedback, patient adherence, patient compliance, patient concordance, treatment adherence, and non-adherence (Appendix 1, available online). Searches were limited to RCTs.
      Studies were assessed for eligibility based on the following inclusion criteria: (1) patients of all ages; (2) use of objective or subjective measures of adherence as a guide to provide specific feedback on improving adherence; (3) RCTs; and (4) reporting of adherence as an outcome. There were no language restrictions. Studies giving general advice or reminders as an intervention were excluded. All abstracts were reviewed independently by three reviewers (MDS, RJM, and GDEM). Full-text articles were evaluated for all potentially eligible studies.
      The Delphi Tool was used for quality assessment.
      • Verhagen A.
      • de Vet H.
      • deBie R.
      • et al.
      The Delphi list: a criteria list for quality assessment of randomized clinical trials for conducting systematic reviews developed by Delphi consensus.
      Studies with a score <3/9 were excluded. Owing to the nature of these studies, masking of investigators and patients was not possible, resulting in lower quality scores (Table 1).
      Table 1Main Characteristics of All 24 Studies Included in the Systematic Review
      AuthorConditionMean age (years)Number randomizedMonitoringStudy duration, outcome measureQuality scoreBaseline % adherenceFinal visit % adherenceChange in adherence (%)p-value% effect size
      ICICICIC
      Burgess
      • Burgess S.W.
      • Sly P.D.
      • Devadason S.G.
      Providing feedback on adherence increases use of preventive medication by asthmatic children.
      ,
      Included in meta-analysis.
      Asthma9.19.326Electronic12 weeks, mean %677.5058.0084.2055.306.7–2.7<0.019.40
      Included in meta-analysis.
      Oniyirimba
      • Onyirimba F.
      • Apter A.
      • Reisine S.
      • et al.
      Direct clinician-to-patient feedback discussion of inhaled steroid use: its effect on adherence.
      ,
      Included in meta-analysis.
      Asthma45.053.030Electronic10 weeks, mean %561.0051.0076.0027.0015–24<0.000139.00
      Included in meta-analysis.
      Smith
      • Smith S.R.
      • Rublein J.C.
      • Marcus C.
      • Brock T.P.
      • Chesney M.A.
      A medication self-management program to improve adherence to HIV therapy regimens.
      ,
      Not included in meta-analysis as no SD or SE values were reported.
      HIV/AIDSNot provided
      Age range = 20–50 years.
      43Electronic12 weeks, mean %474.0070.0096.0038.0022–320.001754.00
      Not included in meta-analysis as no SD or SE values were reported.
      Sabin
      • Sabin L.L.
      • DeSilva M.B.
      • Hamer D.H.
      • et al.
      Using electronic drug monitor feedback to improve adherence to antiretroviral therapy among HIV-positive patients in China.
      ,
      Included in meta-analysis.
      HIV/AIDS36.135.168Electronic12 months, mean %586.8083.896.5084.509.70.70.00309.00
      Included in meta-analysis.
      Rigsby
      • Rigsby M.O.
      • Rosen M.I.
      • Beauvais J.E.
      • et al.
      Cue-dose training with monetary reinforcement: pilot study of an antiretroviral adherence intervention.
      ,
      Not included in meta-analysis as no SD or SE values were reported.
      HIV/AIDS44.647.255Electronic12 weeks, mean %468.0068.0055.0065.00–13–30.79–10.00
      Not included in meta-analysis as no SD or SE values were reported.
      Rosen
      • Rosen M.I.
      • Dieckhaus K.
      • McMahon T.J.
      • et al.
      Improved adherence with contingency management.
      ,
      Included in meta-analysis.
      HIV/AIDS45.842.256Electronic32 weeks, mean %462.0060.0065.0047.003–130.0116.00
      Included in meta-analysis.
      Kalichman
      • Kalichman S.C.
      • Kalichman M.O.
      • Cherry C.
      • et al.
      Brief behavioral self-regulation counseling for HIV treatment adherence delivered by cell phone: an initial test of concept trial.
      ,
      Included in meta-analysis.
      HIV/AIDS51.150.940Pill count12 weeks, mean687.4091.0094.1087.806.7–3.2<0.019.90
      Included in meta-analysis.
      Mooney
      • Mooney M.E.
      • Sayre S.L.
      • Hokanson P.S.
      • Stotts A.L.
      • Schmitz J.M.
      Adding MEMS feedback to behavioral smoking cessation therapy increases compliance with bupropion: a replication and extension study.
      Smoking42.1
      Mean age of all participants.
      55Electronic7 weeks5<0.0001
      Schmitz
      • Schmitz J.M.
      • Sayre S.L.
      • Stotts A.L.
      • Rothfleisch J.
      • Mooney M.E.
      Medication compliance during a smoking cessation clinical trial: a brief intervention using MEMS feedback.
      Smoking48.948.197Electronic7 weeks40.0001
      Elixhauser
      • Elixhauser A.
      • Eisen S.A.
      • Romeis J.C.
      • Homan S.M.
      The effects of monitoring and feedback on compliance.
      ,
      Not included in meta-analysis as no SD or SE values were reported.
      Mental Health49.1
      Mean age of all participants.
      93Electronic4–8 months, percentage complied450.0052.0048.4062.20–1.610.2>0.05–11.80
      Not included in meta-analysis as no SD or SE values were reported.
      Kozuki
      • Kozuki Y.
      • Schepp G.
      Visual-feedback therapy for antipsychotic medication adherence.
      ,
      Not included in meta-analysis as no SD or SE values were reported.
      Mental Health46.5
      Mean age of all participants.
      30Electronic12 weeks, mean rate578.4088.5087.9068.409.5–20.10.02629.60
      Not included in meta-analysis as no SD or SE values were reported.
      Cramer
      • Cramer J.A.
      • Rosenheck R.
      Enhancing medication compliance for people with serious mental illness.
      Mental Health464881Electronic6 months30.08
      Russell
      • Russell C.
      • Conn V.
      • Ashbaugh C.
      • et al.
      Taking immunosuppressive medications effectively (TIMELink): a pilot randomized controlled trial in adult kidney transplant recipients.
      Post-transplant surgery51.544.015Electronic9 months40.03
      Hardstaff
      • Hardstaff R.
      • Green K.
      • Talbot D.
      Measurement of compliance posttransplantation—the results of a 12-month study using electronic monitoring.
      Post-transplant surgeryNot provided48Electronic12 months3
      Statistical analysis not performed. I, intervention group; C, control group.
      Ruppar
      • Ruppar T.M.
      Randomized pilot study of a behavioral feedback intervention to improve medication adherence in older adults with hypertension.
      ,
      Not included in meta-analysis as no SD or SE values were reported.
      Hypertension72.573.015Electronic20 weeks, median adherence475.5034.1094.3040.0018.85.90.0112.90
      Not included in meta-analysis as no SD or SE values were reported.
      Wu
      • Wu J.R.
      • Corley D.J.
      • Lennie T.A.
      • Moser D.K.
      Effect of a medication-taking behavior feedback theory-based intervention on outcomes in patients with heart failure.
      ,
      Not included in meta-analysis as no SD or SE values were reported.
      Heart failure63.658.682Electronic10 months, mean rate496.0094.0094.0084.00–2–100.0218.00
      Not included in meta-analysis as no SD or SE values were reported.
      Duncan
      • Duncan K.A.
      • Pozehl B.
      Staying on course: the effects of an adherence facilitation intervention on home exercise participation.
      Heart failure66.0
      Mean age of all participants.
      13Subjective12 weeks3<0.05
      Kung
      • Kung A.W.
      • Rachman I.A.
      • Adam J.M.
      • Roeshadi D.
      • Torralba T.
      Impact of bone marker feedback on adherence to once monthly ibandronate for osteoporosis among Asian postmenopausal women.
      Osteoporosis65.666.3596Subjective12 months50.16
      Lai
      • Lai P.S.M.
      • Chua S.S.
      • Chew Y.Y.
      • Chan S.P.
      Effects of pharmaceutical care on adherence and persistence to bisphosphonates in postmenopausal osteoporotic women.
      ,
      Included in meta-analysis.
      Osteoporosis65.367.1198Subjective12 months, mean596.8597.3897.9796.171.12–1.21<0.052.33
      Included in meta-analysis.
      El Miedany
      • El Miedany Y.
      • El Gaafary M.
      • Palmer D.
      Assessment of the utility of visual feedback in the treatment of early rheumatoid arthritis patients: a pilot study.
      Rheumatoid arthritis50.551.0111Subjective12 months5<0.01
      Nadeem
      • Nadeem R.
      • Rishi M.
      • Srinivasan L.
      • Copur A.
      • Naseem J.
      Effect of visualization of raw graphic polysomnography data by sleep apnea patients on adherence to CPAP therapy.
      Sleep apnea57.355.540Electronic1 month40.61
      Watson
      • Watson A.
      • Bickmore T.
      • Cange A.
      • Kulshreshtha A.
      • Kvedar J.
      An internet-based virtual coach to promote physical activity adherence in overweight adults: randomized controlled trial.
      Exercise44.140.670Electronic12 weeks30.07
      Shakudo
      • Shakudo M.
      • Takegami M.
      • Shibata A.
      • et al.
      Effect of feedback in promoting adherence to an exercise programme: a randomized controlled trial.
      Exercise39.340.4105Electronic12 weeks50.36
      Reddy
      • Reddy A.
      • Huseman T.
      • Canamucio A.
      • et al.
      Patient and partner feedback reports to improve statin medication adherence: a randomized control trial.
      Statin65.664.1126Electronic13 weeks70.001
      Note: Boldface indicates statistical significance (p<0.05). The % effect size is the difference between the intervention and control arms, in the change in % adherence of baseline and follow-up. Columns with no values are where baseline and final visit adherence were not reported in the paper but statistical analysis was performed.
      a Included in meta-analysis.
      b Not included in meta-analysis as no SD or SE values were reported.
      c Age range = 20–50 years.
      d Mean age of all participants.
      e Statistical analysis not performed.I, intervention group; C, control group.
      The data extraction sheet was adapted from Cochrane Library (Appendix 2, available online)

      Cochrane Library. Data collection form intervention review—RCTs only. http://hiv.cochrane.org/sites/hiv.cochrane.org/files/uploads/Data%20extraction%20form_RCTs.docx. Accessed March 2014.

      and was performed independently by the three reviewers above. The chosen primary outcome measure was change in adherence (CA) from baseline, calculated by subtracting adherence at baseline from adherence at the last visit. Analyses were carried out in Stata, version 13.1.

      Meta-analysis

      Studies presenting raw data with SD or SE values, on adherence in both intervention and control groups, allowed data to be extracted for a meta-analysis. CA was calculated for both intervention and control groups, and the effect size included in the meta-analysis was the difference in this change (intervention – control). As the SE of the difference in change was not reported, this was calculated conservatively as square root of [(SD1^2 / n1) + (SD2^2 / n2)], therefore, assuming a covariance of 0.
      • Altman D.
      A random effects meta-analysis was used to pool study results. Meta-regression analyses were performed assessing if effectiveness of the intervention varied by study characteristics (i.e., study quality); form of monitoring adherence (self-reported or electronic); who administered the feedback (treating clinician or someone else); and study duration. The analysis was also stratified by form of monitoring adherence, by running separate meta-analyses for those who self-reported and those who were monitored electronically. A funnel plot was used to assess the potential publication bias of included studies.

      Evidence Synthesis

      Literature Search

      The authors identified 3,041 citations and removal of duplicates left 3,008 studies, of which 96 were related to the area of interest. Reference lists revealed no new articles. Altogether, 24 studies met the inclusion criteria (Figure 1).
      Figure 1.
      Figure 1PRISMA study inclusion flowchart.
      CINAHL, Cumulative Index to Nursing and Allied Health Literature.
      Feedback has been evaluated as an intervention in 12 healthcare areas. Forms of monitoring included electronic monitoring such as MEMS or electronic dose monitors (devices recording the date/time of bottle opening); the pill count method; and subjective approaches (i.e., self-report diaries). Study characteristics and main outcomes are summarized in Table 1. CA could only be calculated for 12 studies. The remaining studies did not specify adherence either at the beginning or end of the study. A total of six studies were included in the meta-analysis as these provided both the baseline and final visit adherence along with the SD/SE data needed for pooled analysis.

      Asthma

      Two studies explored feedback on adherence for use of preventative inhalers in asthma.
      • Burgess S.W.
      • Sly P.D.
      • Devadason S.G.
      Providing feedback on adherence increases use of preventive medication by asthmatic children.
      • Onyirimba F.
      • Apter A.
      • Reisine S.
      • et al.
      Direct clinician-to-patient feedback discussion of inhaled steroid use: its effect on adherence.
      Burgess and colleagues
      • Burgess S.W.
      • Sly P.D.
      • Devadason S.G.
      Providing feedback on adherence increases use of preventive medication by asthmatic children.
      objectively monitored adherence in children using the Smart inhaler, which calculated the date/time of inhaler actuation and number of dispensed doses. Parents and children in the intervention group viewed their monitor results monthly for 4 months, whereas controls were masked to their monitor recordings. A significant difference in adherence between the two groups (p<0.01) was reported. CA was +6.7% in the intervention group and –2.7% for controls.
      Oniyirimba et al.
      • Onyirimba F.
      • Apter A.
      • Reisine S.
      • et al.
      Direct clinician-to-patient feedback discussion of inhaled steroid use: its effect on adherence.
      evaluated a similar intervention in an adult population using metered dose inhaler chronologs. Adherence improved from 61% to 70% for the intervention group but declined in the controls (p<0.0001; CA of +15% and –24%, respectively).

      HIV/AIDS

      Five studies explored the effects of feedback in HIV/AIDS medication adherence.
      • Smith S.R.
      • Rublein J.C.
      • Marcus C.
      • Brock T.P.
      • Chesney M.A.
      A medication self-management program to improve adherence to HIV therapy regimens.
      • Sabin L.L.
      • DeSilva M.B.
      • Hamer D.H.
      • et al.
      Using electronic drug monitor feedback to improve adherence to antiretroviral therapy among HIV-positive patients in China.
      • Rigsby M.O.
      • Rosen M.I.
      • Beauvais J.E.
      • et al.
      Cue-dose training with monetary reinforcement: pilot study of an antiretroviral adherence intervention.
      • Rosen M.I.
      • Dieckhaus K.
      • McMahon T.J.
      • et al.
      Improved adherence with contingency management.
      • Kalichman S.C.
      • Kalichman M.O.
      • Cherry C.
      • et al.
      Brief behavioral self-regulation counseling for HIV treatment adherence delivered by cell phone: an initial test of concept trial.
      Smith and colleagues
      • Smith S.R.
      • Rublein J.C.
      • Marcus C.
      • Brock T.P.
      • Chesney M.A.
      A medication self-management program to improve adherence to HIV therapy regimens.
      measured adherence to anti-retroviral medication using MEMS, with the intervention group viewing results monthly. Adherence in the intervention group was higher throughout the study (p=0.0017). CA was +22% in the intervention group and –32% for controls.
      Sabin et al.
      • Sabin L.L.
      • DeSilva M.B.
      • Hamer D.H.
      • et al.
      Using electronic drug monitor feedback to improve adherence to antiretroviral therapy among HIV-positive patients in China.
      used a similar approach, although consisting of a pre-intervention period (allowing participants for stratification into high/low adherence before randomization) and a 6-month intervention period. A significant increase in adherence in the intervention group, who viewed and discussed their data, was reported, with controls remaining unchanged at 12 weeks (p=0.003). CA was +9.7% and +0.7%, respectively. Participants were considered non-adherent if medications were not taken within 1 hour of scheduled dose time; this is a stricter adherence measure than other studies and may result in an underestimate of actual adherence.
      Rigsby and colleagues
      • Rigsby M.O.
      • Rosen M.I.
      • Beauvais J.E.
      • et al.
      Cue-dose training with monetary reinforcement: pilot study of an antiretroviral adherence intervention.
      explored feedback effects with and without rewards. Three groups were assessed: control; MEMs feedback (intervention); and MEMs feedback plus cash reinforcement. The latter group viewed their MEMS results, discussed any problems with adherence, and received cash for each dose taken within 2 hours of the scheduled time. Adherence in all groups worsened over time. CA showed better results with reward (control, –1%; intervention, –13%; intervention plus cash, –3%). Feedback alone had no effect on adherence.
      Rosen et al.
      • Rosen M.I.
      • Dieckhaus K.
      • McMahon T.J.
      • et al.
      Improved adherence with contingency management.
      similarly evaluated the effects of rewards together with feedback. One medication became the reinforced medication (RM) for which rewards were given whereas the remainder were non-RM. MEMS feedback for medication adherence to both RM and non-RM were provided to the intervention group. By Week 16, adherence had improved 15% for RM in the intervention group, with similar results for non-RM. Medication adherence significantly decreased in controls for both RM and non-RM (p=0.01).
      • Rosen M.I.
      • Dieckhaus K.
      • McMahon T.J.
      • et al.
      Improved adherence with contingency management.
      CA values were 0% for intervention RM, +3% for intervention non-RM, –13% for control RM, and –13% for control non-RM. MEMS feedback improved adherence during the first 16 weeks (p=0.01), but RM did not increase adherence (p=0.09).
      • Rosen M.I.
      • Dieckhaus K.
      • McMahon T.J.
      • et al.
      Improved adherence with contingency management.
      Kalichman and colleagues
      • Kalichman S.C.
      • Kalichman M.O.
      • Cherry C.
      • et al.
      Brief behavioral self-regulation counseling for HIV treatment adherence delivered by cell phone: an initial test of concept trial.
      monitored adherence by undertaking unannounced pill counts in all participants. Phone calls informed the intervention group of their adherence. Increase in adherence from 87.4% to 94.1% at 4-month follow-up was noted (p<0.01), with the controls decreasing from 91% to 87.8% (CA of +6.7% and –3.2%, respectively).

      Smoking

      Mooney et al.
      • Mooney M.E.
      • Sayre S.L.
      • Hokanson P.S.
      • Stotts A.L.
      • Schmitz J.M.
      Adding MEMS feedback to behavioral smoking cessation therapy increases compliance with bupropion: a replication and extension study.
      explored the role of MEMS feedback on adherence to bupropion for smoking cessation. The intervention group received their MEMS adherence weekly in graphical form. Adherence was reported as greater in the intervention group (77%) compared with controls (54%) at all time points. Schmitz and colleagues
      • Schmitz J.M.
      • Sayre S.L.
      • Stotts A.L.
      • Rothfleisch J.
      • Mooney M.E.
      Medication compliance during a smoking cessation clinical trial: a brief intervention using MEMS feedback.
      used a similar approach, and adherence in the intervention group remained relatively stable (73%) with a decrease in adherence in controls (48%) (p=0.0001).

      Mental Health

      Elixhauser et al.
      • Elixhauser A.
      • Eisen S.A.
      • Romeis J.C.
      • Homan S.M.
      The effects of monitoring and feedback on compliance.
      assessed adherence to lithium medication for bipolar disorder with MEMS. The intervention group received feedback based on MEMS recorded adherence and serum lithium levels. Controls received information of their serum lithium levels alone. Adherence was calculated from self-reported diaries provided to all participants. CA was –1.6% in the intervention group and +10.2% in controls (p>0.05). Kozuki and colleagues
      • Kozuki Y.
      • Schepp G.
      Visual-feedback therapy for antipsychotic medication adherence.
      used electronic pill bottles with an electronic chip in the cap (similar to MEMS) to monitor adherence to antipsychotic medications. The intervention group viewed a graphical display of their adherence at each visit and were encouraged to discuss any concerns with adherence. Controls received supportive counseling only. Adherence improved in the interventional group but declined for controls (CA of +9.5% and –20.5%, respectively; p=0.026).
      • Kozuki Y.
      • Schepp G.
      Visual-feedback therapy for antipsychotic medication adherence.
      Cramer et al.
      • Cramer J.A.
      • Rosenheck R.
      Enhancing medication compliance for people with serious mental illness.
      also investigated effects of visual feedback from MEMS on adherence to antipsychotic medications. Overall adherence was 76% in the intervention group and 57% in controls (p=0.08).

      Post-transplant Surgery

      Two studies assessed feedback using MEMs recordings on adherence to immunosuppressive medication post-kidney transplant surgery.
      • Russell C.
      • Conn V.
      • Ashbaugh C.
      • et al.
      Taking immunosuppressive medications effectively (TIMELink): a pilot randomized controlled trial in adult kidney transplant recipients.
      • Hardstaff R.
      • Green K.
      • Talbot D.
      Measurement of compliance posttransplantation—the results of a 12-month study using electronic monitoring.
      Russell and colleagues
      • Russell C.
      • Conn V.
      • Ashbaugh C.
      • et al.
      Taking immunosuppressive medications effectively (TIMELink): a pilot randomized controlled trial in adult kidney transplant recipients.
      provided MEMs feedback to intervention participants at each follow-up visit and reported a significant improvement in adherence (intervention group CA, +0.128; control CA, +0.065; adherence was reported as an adherence score; p=0.03). Hardstaff et al.
      • Hardstaff R.
      • Green K.
      • Talbot D.
      Measurement of compliance posttransplantation—the results of a 12-month study using electronic monitoring.
      delivered feedback at the first follow-up visit only (four total) and found no significant difference (adherence worsened by 48% for intervention and 52% for control).

      Hypertension

      Ruppar and colleagues
      • Ruppar T.M.
      Randomized pilot study of a behavioral feedback intervention to improve medication adherence in older adults with hypertension.
      recorded adherence to antihypertensive medication using MEMs over 20 weeks. A higher increase in adherence was noted in the intervention group compared with controls (CA of +18.8% and +5.9%, respectively; p=0.008).
      • Ruppar T.M.
      Randomized pilot study of a behavioral feedback intervention to improve medication adherence in older adults with hypertension.

      Heart Failure

      Wu et al.
      • Wu J.R.
      • Corley D.J.
      • Lennie T.A.
      • Moser D.K.
      Effect of a medication-taking behavior feedback theory-based intervention on outcomes in patients with heart failure.
      recruited participants with poor adherence (<88% considered non-adherent) after an initial trial of MEMS recording without feedback. Selected study participants were randomized into one of three groups: control; counseling (LITE) group; and counseling plus feedback (PLUS) group. The PLUS group was shown a visual display of adherence from the MEMS report, missed doses were identified, and barriers to medication adherence discussed. The LITE group received information about the importance of medication but no MEMS recording data. Controls received standard care. The authors concluded that adherence was better in the PLUS group compared with the controls at all time points (CA of –2% and –10%, respectively; p=0.021) but no significant difference was noted between the PLUS and LITE groups (CA of –2% and +1%, respectively; p=0.804).
      Duncan and colleagues
      • Duncan K.A.
      • Pozehl B.
      Staying on course: the effects of an adherence facilitation intervention on home exercise participation.
      explored the effect of feedback on exercise adherence in patients undergoing cardiac rehabilitation. All participants completed weekly diaries regarding their exercise frequency/duration. Individuals were independently assessed and given exercise targets. The intervention group received regular e-mails with graphs depicting their exercise progress (from diary information) followed by feedback in the form of problem-solving guidance to achieve preset exercise targets.
      • Duncan K.A.
      • Pozehl B.
      Staying on course: the effects of an adherence facilitation intervention on home exercise participation.
      A significant increase in exercise duration was noted (intervention group CA, +6.9; control CA, +2.8; p<0.05). Similar results were reported for exercise frequency (intervention CA, –0.7; control CA, –1.2; p<0.01). Although minimal changes, the results were significant as adherence was reported as the mean of preset exercise duration and frequency targets achieved. The intervention group achieved a mean of 108.7% and 104.6% for exercise duration and frequency, respectively. Controls achieved a mean of 84.9% and 64% for exercise duration and frequency, respectively.
      • Duncan K.A.
      • Pozehl B.
      Staying on course: the effects of an adherence facilitation intervention on home exercise participation.

      Osteoporosis and Rheumatoid Arthritis

      Kung et al.
      • Kung A.W.
      • Rachman I.A.
      • Adam J.M.
      • Roeshadi D.
      • Torralba T.
      Impact of bone marker feedback on adherence to once monthly ibandronate for osteoporosis among Asian postmenopausal women.
      assessed the impact of bone marker CTX (measure of disease activity, an indirect measure of adherence), feedback on adherence to monthly bisphosphonate medication in the treatment of osteoporosis. The intervention group reviewed CTX levels rather than medication adherence. Medication adherence was self-reported using the Osteoporosis Patient Treatment Satisfaction Questionnaire (OPSAT-Q). No significant difference in adherence between the intervention and controls was reported (proportion of adherent participants were 92.6% for intervention 96.0% for control, p=0.16).
      Lai and colleagues
      • Lai P.S.M.
      • Chua S.S.
      • Chew Y.Y.
      • Chan S.P.
      Effects of pharmaceutical care on adherence and persistence to bisphosphonates in postmenopausal osteoporotic women.
      used a similar approach and concluded that adherence was higher in the intervention group compared with controls but this change did not lead to a significant decrease in bone marker levels (intervention CA, +1.12%; control CA, –1.21%; p<0.05).
      El Miedany et al.
      • El Miedany Y.
      • El Gaafary M.
      • Palmer D.
      Assessment of the utility of visual feedback in the treatment of early rheumatoid arthritis patients: a pilot study.
      studied the effect of visual feedback of disease marker parameters on adherence to disease-modifying antirheumatic drugs in rheumatoid arthritis. The intervention group viewed a graphical display of their disease marker parameters, with controls being given this result verbally as routine care. A significantly higher overall medication adherence in the intervention group (percentage adherence, 92.7%) compared with controls (percentage adherence, 69.6%) (p<0.01) was reported.
      • El Miedany Y.
      • El Gaafary M.
      • Palmer D.
      Assessment of the utility of visual feedback in the treatment of early rheumatoid arthritis patients: a pilot study.

      Sleep Apnea

      Nadeem and colleagues
      • Nadeem R.
      • Rishi M.
      • Srinivasan L.
      • Copur A.
      • Naseem J.
      Effect of visualization of raw graphic polysomnography data by sleep apnea patients on adherence to CPAP therapy.
      evaluated the effects of showing patient polysomnographic data on adherence to continuous positive airway pressure therapy in sleep apnea. The intervention group viewed a graphic display of their polysomnograph on a computer screen, whereas the control group received a three-page report used in standard practice. Adherence was monitored using an adherence data card attached to the continuous positive airway pressure device. No significant improvement in adherence to therapy was reported, with overall adherence of 38% for the intervention group and 47% in controls (p=0.61).

      Exercise

      Watson et al.
      • Watson A.
      • Bickmore T.
      • Cange A.
      • Kulshreshtha A.
      • Kvedar J.
      An internet-based virtual coach to promote physical activity adherence in overweight adults: randomized controlled trial.
      investigated the role of feedback guided by pedometer results to improve adherence to physical activity in overweight/obese adults. Step-counting pedometers were worn continuously on shoes for a total of 12 weeks. The intervention group received personalized feedback, including problem solving based on their current pedometer result, which was compared to preset targets. The controls were able to view activity levels but did not receive personalized feedback. No significant difference was noted in percentage change in step counts between the two groups (p=0.07).
      • Watson A.
      • Bickmore T.
      • Cange A.
      • Kulshreshtha A.
      • Kvedar J.
      An internet-based virtual coach to promote physical activity adherence in overweight adults: randomized controlled trial.
      Shakudo and colleagues
      • Shakudo M.
      • Takegami M.
      • Shibata A.
      • et al.
      Effect of feedback in promoting adherence to an exercise programme: a randomized controlled trial.
      applied a similar approach and reported that percentage achievement of target exercise level was 26.5% in the intervention group and 17.4% in controls (p=0.36).

      Statins

      Reddy et al.
      • Reddy A.
      • Huseman T.
      • Canamucio A.
      • et al.
      Patient and partner feedback reports to improve statin medication adherence: a randomized control trial.
      investigated the effect of guided feedback (GlowCap Bottle) on adherence to statin medication. There were three groups: intervention group, control group, and a partner intervention group, whereby the report from the GlowCap Bottle was also sent to a designated family member/friend of the participant. A significant difference in overall adherence was noted between the two intervention groups (individual and partner feedback) and controls (89% and 86% vs 67%, respectively; p=0.001).
      • Reddy A.
      • Huseman T.
      • Canamucio A.
      • et al.
      Patient and partner feedback reports to improve statin medication adherence: a randomized control trial.
      The authors continued to monitor adherence once the 13-week intervention period was over. The higher adherence rates achieved in the intervention groups were not sustained once intervention was stopped.
      • Reddy A.
      • Huseman T.
      • Canamucio A.
      • et al.
      Patient and partner feedback reports to improve statin medication adherence: a randomized control trial.

      Meta-analysis Results

      Of the 24 identified studies, six presented raw data with SD or SE values on adherence in both an intervention and a control group, allowing data to be extracted for a meta-analysis.
      • Burgess S.W.
      • Sly P.D.
      • Devadason S.G.
      Providing feedback on adherence increases use of preventive medication by asthmatic children.
      • Onyirimba F.
      • Apter A.
      • Reisine S.
      • et al.
      Direct clinician-to-patient feedback discussion of inhaled steroid use: its effect on adherence.
      • Sabin L.L.
      • DeSilva M.B.
      • Hamer D.H.
      • et al.
      Using electronic drug monitor feedback to improve adherence to antiretroviral therapy among HIV-positive patients in China.
      • Rosen M.I.
      • Dieckhaus K.
      • McMahon T.J.
      • et al.
      Improved adherence with contingency management.
      • Kalichman S.C.
      • Kalichman M.O.
      • Cherry C.
      • et al.
      Brief behavioral self-regulation counseling for HIV treatment adherence delivered by cell phone: an initial test of concept trial.
      • Lai P.S.M.
      • Chua S.S.
      • Chew Y.Y.
      • Chan S.P.
      Effects of pharmaceutical care on adherence and persistence to bisphosphonates in postmenopausal osteoporotic women.
      Six other studies reported mean adherences but without SD or SE values, and therefore could not be included in the meta-analysis.
      • Smith S.R.
      • Rublein J.C.
      • Marcus C.
      • Brock T.P.
      • Chesney M.A.
      A medication self-management program to improve adherence to HIV therapy regimens.
      • Rigsby M.O.
      • Rosen M.I.
      • Beauvais J.E.
      • et al.
      Cue-dose training with monetary reinforcement: pilot study of an antiretroviral adherence intervention.
      • Cramer J.A.
      • Rosenheck R.
      Enhancing medication compliance for people with serious mental illness.
      • Russell C.
      • Conn V.
      • Ashbaugh C.
      • et al.
      Taking immunosuppressive medications effectively (TIMELink): a pilot randomized controlled trial in adult kidney transplant recipients.
      • Wu J.R.
      • Corley D.J.
      • Lennie T.A.
      • Moser D.K.
      Effect of a medication-taking behavior feedback theory-based intervention on outcomes in patients with heart failure.
      Meta-analysis of the six studies showed a significant difference in change in mean percentage adherence between the intervention and control groups, with the intervention groups showing a greater improvement (p=0.004). The pooled effect of the six studies estimates that mean percentage adherence increased by 10.02 (95% CI=3.15, 16.89) more between baseline and follow-up in the intervention groups compared with controls (Figure 2). Of the 12 studies that reported an effect size, one reported median values (Wu and colleagues
      • Wu J.R.
      • Corley D.J.
      • Lennie T.A.
      • Moser D.K.
      Effect of a medication-taking behavior feedback theory-based intervention on outcomes in patients with heart failure.
      ) and one reported the percentage of patients who complied (Elixhauer et al.
      • Elixhauser A.
      • Eisen S.A.
      • Romeis J.C.
      • Homan S.M.
      The effects of monitoring and feedback on compliance.
      ). For the ten studies reporting a mean percentage adherence, a weighted mean was calculated to investigate if studies that could be included in the meta-analysis differed from those that could not. The weighted mean was 11.29, similar to the main meta-analysis result.
      Figure 2.
      Figure 2Results of random-effects meta-analysis of the effects of feedback on change in mean percentage adherence between intervention and control groups.
      The I2 value from the random effects meta-analysis of the six studies, showing the amount of variation in the effect size attributable to study heterogeneity, was small (26.3%, p= –0.237, Figure 2). This was also reflected in the between-study SD (τ=5.335), demonstrating a small, non-significant effect of study heterogeneity. Meta-regression analysis indicated that the study effect size was not significantly associated with study quality, form of monitoring adherence, delivery of feedback, or study duration (p=0.818, 0.335, 0.348, and 0.0.226, respectively). However, when the analysis was stratified by electronic monitoring (four studies) and self-report (two studies), the pooled effect size was higher in studies with electronic monitoring: 14.175 (95% CI=4.64, 23.70) and 5.53 (95% CI= –4.37, 15.43), respectively, although this was not a statistically significant difference.
      A funnel plot was produced to assess potential publication bias, but difficult to interpret given the small number of studies. No clear evidence of publication bias was found with the funnel plot, showing relatively good balance (Appendix 3, available online).

      Discussion

      In total, 16 studies found significant improvements in adherence in the intervention group, compared with controls, across a range of medical conditions.
      • Burgess S.W.
      • Sly P.D.
      • Devadason S.G.
      Providing feedback on adherence increases use of preventive medication by asthmatic children.
      • Onyirimba F.
      • Apter A.
      • Reisine S.
      • et al.
      Direct clinician-to-patient feedback discussion of inhaled steroid use: its effect on adherence.
      • Smith S.R.
      • Rublein J.C.
      • Marcus C.
      • Brock T.P.
      • Chesney M.A.
      A medication self-management program to improve adherence to HIV therapy regimens.
      • Sabin L.L.
      • DeSilva M.B.
      • Hamer D.H.
      • et al.
      Using electronic drug monitor feedback to improve adherence to antiretroviral therapy among HIV-positive patients in China.
      • Rosen M.I.
      • Dieckhaus K.
      • McMahon T.J.
      • et al.
      Improved adherence with contingency management.
      • Mooney M.E.
      • Sayre S.L.
      • Hokanson P.S.
      • Stotts A.L.
      • Schmitz J.M.
      Adding MEMS feedback to behavioral smoking cessation therapy increases compliance with bupropion: a replication and extension study.
      • Russell C.
      • Conn V.
      • Ashbaugh C.
      • et al.
      Taking immunosuppressive medications effectively (TIMELink): a pilot randomized controlled trial in adult kidney transplant recipients.
      • Ruppar T.M.
      Randomized pilot study of a behavioral feedback intervention to improve medication adherence in older adults with hypertension.
      • Wu J.R.
      • Corley D.J.
      • Lennie T.A.
      • Moser D.K.
      Effect of a medication-taking behavior feedback theory-based intervention on outcomes in patients with heart failure.
      • Duncan K.A.
      • Pozehl B.
      Staying on course: the effects of an adherence facilitation intervention on home exercise participation.
      • Lai P.S.M.
      • Chua S.S.
      • Chew Y.Y.
      • Chan S.P.
      Effects of pharmaceutical care on adherence and persistence to bisphosphonates in postmenopausal osteoporotic women.
      • El Miedany Y.
      • El Gaafary M.
      • Palmer D.
      Assessment of the utility of visual feedback in the treatment of early rheumatoid arthritis patients: a pilot study.
      Although feedback did not result in a considerable increase in adherence in three of these studies, no decline in adherence in the intervention group occurred as with controls.
      • Burgess S.W.
      • Sly P.D.
      • Devadason S.G.
      Providing feedback on adherence increases use of preventive medication by asthmatic children.
      • Rosen M.I.
      • Dieckhaus K.
      • McMahon T.J.
      • et al.
      Improved adherence with contingency management.
      • Lai P.S.M.
      • Chua S.S.
      • Chew Y.Y.
      • Chan S.P.
      Effects of pharmaceutical care on adherence and persistence to bisphosphonates in postmenopausal osteoporotic women.

      Meta-analysis

      Six studies were included in the meta-analysis, which all showed a significantly greater increase in adherence in the intervention group (overall effect size, 10.02; 95% CI=3.15, 16.89). Oniyirimba and colleagues
      • Onyirimba F.
      • Apter A.
      • Reisine S.
      • et al.
      Direct clinician-to-patient feedback discussion of inhaled steroid use: its effect on adherence.
      showed the greatest increase, with an effect size of 39. In this study, feedback was given on two occasions in face-to-face consultations by the treating clinician as opposed to other members of the research team. Meta-regression analysis showed study effect size was not associated with the professional background of the person giving feedback; therefore, reasons for a greater improvement in adherence in this study is unclear. The I2 value of 26.3% also shows low heterogeneity between the studies, indicating the effect sizes are comparable.
      • Higgins J.
      • Thompson S.
      • Deeks J.
      • Altman D.
      Measuring inconsistency in meta-analyses.
      Given the heterogeneity in the reporting of results, a limitation of this study was that only six studies could be included in the meta-analysis. Owing to this small number, the results of the meta-analysis should be interpreted with caution. More emphasis should be placed on the narrative synthesis of the review.

      Factors Influencing Effects of Feedback

      Two studies reported an improvement in adherence in controls, while adherence worsened in the intervention group.
      • Cramer J.A.
      • Rosenheck R.
      Enhancing medication compliance for people with serious mental illness.
      • Nadeem R.
      • Rishi M.
      • Srinivasan L.
      • Copur A.
      • Naseem J.
      Effect of visualization of raw graphic polysomnography data by sleep apnea patients on adherence to CPAP therapy.
      Although not statistically significant, it is important to explore factors that may have influenced the results. In the study by Elixahauser et al.
      • Elixhauser A.
      • Eisen S.A.
      • Romeis J.C.
      • Homan S.M.
      The effects of monitoring and feedback on compliance.
      exploring feedback in bipolar disorder, it may be that the feedback group recorded their adherence more accurately in diaries being aware adherence measures from MEMS containers were available to the research team. Controls, who did not receive MEMS containers, may have over-reported adherence (often the case with self-reported measures).
      • Zeller A.
      • Ramseier E.
      • Teagtmeyer A.
      • Battegay E.
      Patients’ self-reported adherence to cardiovascular medication using electronic monitors as comparators.
      Three studies exploring feedback in HIV, post-transplant, and heart failure medication adherence reported decreases in adherence in both the intervention and control groups.
      • Rigsby M.O.
      • Rosen M.I.
      • Beauvais J.E.
      • et al.
      Cue-dose training with monetary reinforcement: pilot study of an antiretroviral adherence intervention.
      • Hardstaff R.
      • Green K.
      • Talbot D.
      Measurement of compliance posttransplantation—the results of a 12-month study using electronic monitoring.
      • Wu J.R.
      • Corley D.J.
      • Lennie T.A.
      • Moser D.K.
      Effect of a medication-taking behavior feedback theory-based intervention on outcomes in patients with heart failure.
      However, other studies exploring the effect of feedback in the same diseases found a significant increase in adherence.
      • Smith S.R.
      • Rublein J.C.
      • Marcus C.
      • Brock T.P.
      • Chesney M.A.
      A medication self-management program to improve adherence to HIV therapy regimens.
      • Sabin L.L.
      • DeSilva M.B.
      • Hamer D.H.
      • et al.
      Using electronic drug monitor feedback to improve adherence to antiretroviral therapy among HIV-positive patients in China.
      • Rosen M.I.
      • Dieckhaus K.
      • McMahon T.J.
      • et al.
      Improved adherence with contingency management.
      • Kalichman S.C.
      • Kalichman M.O.
      • Cherry C.
      • et al.
      Brief behavioral self-regulation counseling for HIV treatment adherence delivered by cell phone: an initial test of concept trial.
      • Russell C.
      • Conn V.
      • Ashbaugh C.
      • et al.
      Taking immunosuppressive medications effectively (TIMELink): a pilot randomized controlled trial in adult kidney transplant recipients.
      • Ruppar T.M.
      Randomized pilot study of a behavioral feedback intervention to improve medication adherence in older adults with hypertension.
      This indicates subtle differences between similar studies may influence the effects of feedback on adherence.

      Surrogate Adherence Markers

      Feedback using surrogate markers as an indirect measure of adherence resulted in mixed results.
      • Kung A.W.
      • Rachman I.A.
      • Adam J.M.
      • Roeshadi D.
      • Torralba T.
      Impact of bone marker feedback on adherence to once monthly ibandronate for osteoporosis among Asian postmenopausal women.
      • Lai P.S.M.
      • Chua S.S.
      • Chew Y.Y.
      • Chan S.P.
      Effects of pharmaceutical care on adherence and persistence to bisphosphonates in postmenopausal osteoporotic women.
      • El Miedany Y.
      • El Gaafary M.
      • Palmer D.
      Assessment of the utility of visual feedback in the treatment of early rheumatoid arthritis patients: a pilot study.
      • Nadeem R.
      • Rishi M.
      • Srinivasan L.
      • Copur A.
      • Naseem J.
      Effect of visualization of raw graphic polysomnography data by sleep apnea patients on adherence to CPAP therapy.
      Kung and colleagues
      • Kung A.W.
      • Rachman I.A.
      • Adam J.M.
      • Roeshadi D.
      • Torralba T.
      Impact of bone marker feedback on adherence to once monthly ibandronate for osteoporosis among Asian postmenopausal women.
      reported no significant difference in adherence to bisphosphonates when CTX bone marker levels were given as a form of feedback. By contrast, two other studies concluded that adherence was significantly higher in the intervention group compared with controls.
      • Lai P.S.M.
      • Chua S.S.
      • Chew Y.Y.
      • Chan S.P.
      Effects of pharmaceutical care on adherence and persistence to bisphosphonates in postmenopausal osteoporotic women.
      • El Miedany Y.
      • El Gaafary M.
      • Palmer D.
      Assessment of the utility of visual feedback in the treatment of early rheumatoid arthritis patients: a pilot study.
      Although Lai et al.
      • Lai P.S.M.
      • Chua S.S.
      • Chew Y.Y.
      • Chan S.P.
      Effects of pharmaceutical care on adherence and persistence to bisphosphonates in postmenopausal osteoporotic women.
      reported an increase in adherence (self-reported) to taking bisphosphonate in the intervention group, this improvement did not correlate with a decrease in bone marker levels. Therefore, surrogate markers do not appear to be an appropriate method of quantifying adherence, particularly if they do not change immediately with adherence to medication. In addition, as adherence was self-reported in these studies, adherence may have been overestimated.

      Use of Counseling/Incentives to Improve Adherence

      Wu and colleagues
      • Wu J.R.
      • Corley D.J.
      • Lennie T.A.
      • Moser D.K.
      Effect of a medication-taking behavior feedback theory-based intervention on outcomes in patients with heart failure.
      used a different approach whereby participants were allocated to one of three groups: control, counseling, and counseling plus intervention. Although adherence was significantly higher in the counseling plus intervention group compared with the controls, difference in adherence was not noted between the counseling and counseling plus feedback group. It is not necessarily feedback alone that improves adherence but also education of patients regarding their medical condition and encouraging positive behavioral beliefs. Increased attention by health professionals may contribute to improvements in adherence also.
      Two studies explored the effect of feedback with and without rewards (monetary incentives).
      • Rigsby M.O.
      • Rosen M.I.
      • Beauvais J.E.
      • et al.
      Cue-dose training with monetary reinforcement: pilot study of an antiretroviral adherence intervention.
      • Rosen M.I.
      • Dieckhaus K.
      • McMahon T.J.
      • et al.
      Improved adherence with contingency management.
      Both concluded that simultaneous use of rewards did not modify the effects obtained with feedback alone. Informing patients about their adherence and educating them on ways to improve adherence is more effective than rewards.

      Influence of Individual Providing Feedback

      In two studies, feedback was provided by the treating clinician as opposed to other research staff.
      • Onyirimba F.
      • Apter A.
      • Reisine S.
      • et al.
      Direct clinician-to-patient feedback discussion of inhaled steroid use: its effect on adherence.
      • Sabin L.L.
      • DeSilva M.B.
      • Hamer D.H.
      • et al.
      Using electronic drug monitor feedback to improve adherence to antiretroviral therapy among HIV-positive patients in China.
      In the study by Sabin et al.,
      • Sabin L.L.
      • DeSilva M.B.
      • Hamer D.H.
      • et al.
      Using electronic drug monitor feedback to improve adherence to antiretroviral therapy among HIV-positive patients in China.
      adherence improved by 9.7% in the feedback group. However, other HIV studies in which feedback was given by research staff also found similar improvements, with one study reporting a 30% increase in adherence.
      • Smith S.R.
      • Rublein J.C.
      • Marcus C.
      • Brock T.P.
      • Chesney M.A.
      A medication self-management program to improve adherence to HIV therapy regimens.
      • Rosen M.I.
      • Dieckhaus K.
      • McMahon T.J.
      • et al.
      Improved adherence with contingency management.
      • Kalichman S.C.
      • Kalichman M.O.
      • Cherry C.
      • et al.
      Brief behavioral self-regulation counseling for HIV treatment adherence delivered by cell phone: an initial test of concept trial.
      There is no evidence, including from the meta-regression analysis, that the effect of feedback is influenced by the provider’s professional background.

      Effect of Feedback on Different Ages

      Only one study explored the effect of feedback on adherence in children.
      • Burgess S.W.
      • Sly P.D.
      • Devadason S.G.
      Providing feedback on adherence increases use of preventive medication by asthmatic children.
      Burgess and colleagues
      • Burgess S.W.
      • Sly P.D.
      • Devadason S.G.
      Providing feedback on adherence increases use of preventive medication by asthmatic children.
      reported a CA of 6.7% when parents of asthmatic children received feedback regarding their child’s adherence. Oniyirimba et al.
      • Onyirimba F.
      • Apter A.
      • Reisine S.
      • et al.
      Direct clinician-to-patient feedback discussion of inhaled steroid use: its effect on adherence.
      noted a CA of 15% in adult asthmatics who received feedback. The authors postulate that children may feel less involved in the feedback discussions and are unable to understand the advice given, resulting in poor cooperation with parents and, therefore, less improvement in adherence compared with adults. Further studies are needed to explore the impact of feedback adherence in children and identify strategies to engage children of various ages in feedback. In children, feedback with rewards may be more beneficial.

      Visualization of Results

      Two main methods of feedback were used in the studies. A total of seven studies provided MEMS/electronic dose monitors and indirect markers of adherence data verbally.
      • Burgess S.W.
      • Sly P.D.
      • Devadason S.G.
      Providing feedback on adherence increases use of preventive medication by asthmatic children.
      • Onyirimba F.
      • Apter A.
      • Reisine S.
      • et al.
      Direct clinician-to-patient feedback discussion of inhaled steroid use: its effect on adherence.
      • Kalichman S.C.
      • Kalichman M.O.
      • Cherry C.
      • et al.
      Brief behavioral self-regulation counseling for HIV treatment adherence delivered by cell phone: an initial test of concept trial.
      • Cramer J.A.
      • Rosenheck R.
      Enhancing medication compliance for people with serious mental illness.
      • Hardstaff R.
      • Green K.
      • Talbot D.
      Measurement of compliance posttransplantation—the results of a 12-month study using electronic monitoring.
      • Kung A.W.
      • Rachman I.A.
      • Adam J.M.
      • Roeshadi D.
      • Torralba T.
      Impact of bone marker feedback on adherence to once monthly ibandronate for osteoporosis among Asian postmenopausal women.
      • Lai P.S.M.
      • Chua S.S.
      • Chew Y.Y.
      • Chan S.P.
      Effects of pharmaceutical care on adherence and persistence to bisphosphonates in postmenopausal osteoporotic women.
      The remaining studies provided adherence data graphically where participants were able to visualize the MEMS/electronic dose monitor recordings as a graph and discuss missed doses at specific times.
      • Smith S.R.
      • Rublein J.C.
      • Marcus C.
      • Brock T.P.
      • Chesney M.A.
      A medication self-management program to improve adherence to HIV therapy regimens.
      • Sabin L.L.
      • DeSilva M.B.
      • Hamer D.H.
      • et al.
      Using electronic drug monitor feedback to improve adherence to antiretroviral therapy among HIV-positive patients in China.
      • Rigsby M.O.
      • Rosen M.I.
      • Beauvais J.E.
      • et al.
      Cue-dose training with monetary reinforcement: pilot study of an antiretroviral adherence intervention.
      • Rosen M.I.
      • Dieckhaus K.
      • McMahon T.J.
      • et al.
      Improved adherence with contingency management.
      • Mooney M.E.
      • Sayre S.L.
      • Hokanson P.S.
      • Stotts A.L.
      • Schmitz J.M.
      Adding MEMS feedback to behavioral smoking cessation therapy increases compliance with bupropion: a replication and extension study.
      • Russell C.
      • Conn V.
      • Ashbaugh C.
      • et al.
      Taking immunosuppressive medications effectively (TIMELink): a pilot randomized controlled trial in adult kidney transplant recipients.
      • Ruppar T.M.
      Randomized pilot study of a behavioral feedback intervention to improve medication adherence in older adults with hypertension.
      • Wu J.R.
      • Corley D.J.
      • Lennie T.A.
      • Moser D.K.
      Effect of a medication-taking behavior feedback theory-based intervention on outcomes in patients with heart failure.
      • Duncan K.A.
      • Pozehl B.
      Staying on course: the effects of an adherence facilitation intervention on home exercise participation.
      • Kung A.W.
      • Rachman I.A.
      • Adam J.M.
      • Roeshadi D.
      • Torralba T.
      Impact of bone marker feedback on adherence to once monthly ibandronate for osteoporosis among Asian postmenopausal women.
      • Watson A.
      • Bickmore T.
      • Cange A.
      • Kulshreshtha A.
      • Kvedar J.
      An internet-based virtual coach to promote physical activity adherence in overweight adults: randomized controlled trial.
      In general, studies allowing visualization of adherence data reported a higher improvement in adherence, with five studies showing a CA >10% in the intervention group.
      • Smith S.R.
      • Rublein J.C.
      • Marcus C.
      • Brock T.P.
      • Chesney M.A.
      A medication self-management program to improve adherence to HIV therapy regimens.
      • Sabin L.L.
      • DeSilva M.B.
      • Hamer D.H.
      • et al.
      Using electronic drug monitor feedback to improve adherence to antiretroviral therapy among HIV-positive patients in China.
      • Rosen M.I.
      • Dieckhaus K.
      • McMahon T.J.
      • et al.
      Improved adherence with contingency management.
      • Russell C.
      • Conn V.
      • Ashbaugh C.
      • et al.
      Taking immunosuppressive medications effectively (TIMELink): a pilot randomized controlled trial in adult kidney transplant recipients.
      • Duncan K.A.
      • Pozehl B.
      Staying on course: the effects of an adherence facilitation intervention on home exercise participation.
      Only one study using verbal reporting found similar improvements.
      • Onyirimba F.
      • Apter A.
      • Reisine S.
      • et al.
      Direct clinician-to-patient feedback discussion of inhaled steroid use: its effect on adherence.
      Graphical display of MEMS data gives more in-depth information regarding timing/frequency of missed medication doses, allowing for more detailed discussion with the examiner. Participants can also view their progression over the study period.

      Limitations

      The main strength of this study is that only RCTs were included—the most reliable method of determining whether a causal relationship exists between treatment and outcome.
      • Akobeng A.
      Understanding randomised controlled trials.
      A robust selection process was applied; all studies were reviewed and quality assessed by three independent reviewers. This review was not limited to any particular field of health care and covered a broad range of conditions. Other strengths included no limitation of language or age and bibliography hand searches.
      Limited data were available from some studies, which resulted in only six studies being suitable for the meta-analysis. Moreover, some studies reported data qualitatively and it was not possible to calculate CA from available data, making comparisons more difficult. Also, some RCTs included in the review used self-reporting methods, which may not be a reliable measure of adherence.

      Conclusions

      Overall, this systematic review shows that feedback of adherence can influence adherence outcomes. In most studies, a significant improvement in adherence was reported, whereas in some feedback was shown to prevent worsening of adherence over time. Greater improvements were reported when feedback was given in a graphical form versus verbal feedback. The current review shows adherence was not influenced by the provider’s professional background; therefore, it is not necessary for feedback to be given by a clinician. This systematic review shows that feedback on adherence has significant potential to improve treatment. Non-adherence costs are both personal and economic, not only resulting in a lack of improvement or deterioration in health for the patient, but also financial costs of wasted medication and increased demands for health care when health deteriorates. Administering feedback to patients has the potential to reduce both personal and economic healthcare costs. Feedback is an important element to be incorporated in treatment and future studies.

      Acknowledgments

      Irene Gottlob, MD, UnivDoz, and Rebecca J. McLean, PhD, are co-last authors.
      This study was supported by the Ulverscroft Foundation (Leicester, UK).
      No financial disclosures were reported by the authors of this paper.

      Appendix A. Supplementary material

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