A machine-learning assisted review of the use of habit formation in medication adherence interventions for long-term conditions

Figures & data

Figure 1. Screening flow-diagram.

Table 1. Study characteristics.

First author (Year)	Disease group and characteristics	Description of medication and dosage	Participant characteristics	n per group randomized	Intervention and comparator	Maximum follow-up period
Barankay (2020)	Statin prescription; self-reported non-adherence; LDL-C level > 100 mg/dL and diagnosed ASCVD /10-year CVD risk score > 7.5% OR LDL-C > 190 mg/dL and no other risk factors OR both	Pills; One pill bottle opening per day expected	Mean age (SD) = 58.5 (10.3); female = 519 (64.5%)	Simple daily sweepstakes: n = 199; Deadline sweepstakes: n = 204; Sweepstakes plus deposit contract: n = 201; Control: n = 201	Simple daily sweepstakes; Deadline sweepstakes; Sweepstakes plus deposit contract; vs Control	6 months
De Bruin (2010)	Diagnosis of HIV; ≥6 months on HAART; ≥18 years old	Pills; Majority of participants (90% + ) on polytherapy	Mean age (SD): intervention = 47.3 (9.8); control = 48.7(9.8); Male %: intervention = 92%, control = 90%	Intervention n = 66; control n = 67	Electronic Monitoring-Based Counselling vs usual care	8–9 months
Farmer (2016)	Diagnosis of type-2 diabetes for ≥3 months; ≥18 years old; no known CVD events	Pills; One medication session daily	Mean age (SD): Action planning = 61.5(11.1), usual care = 63.9(12); Male%: Action planning = 54, usual care = 59	Intervention n clusters = 30, n participants = 265; Control: n clusters = 29, n participants = 378	Brief action planning intervention vs usual care	12 months
Gregoriano (2019)	Diagnosis of asthma and/or COPD; prescribed daily inhaled medication and at least one exacerbation in the previous 12 months	Puff inhaled/dry powders; Intervention mean medications prescribed daily (SD) = 1.9 (0.8); Control mean(SD) = 2.0 (0.8)	Mean age (SD): Intervention = 64.7(12.4); Control = 69.0 (8.8); Male(%): Intervention = 61%; Control(%) = 69%	Total n randomised (n) = 169; Total entering baseline visit (n) = 165: Intervention = 84; Control n = 81	Daily alarm clock and support phone calls vs control	6 months
Haynes (1976)	Cardiovascular medication pill-count < 80% and high blood pressure (≥90 mm Hg); Dominion Foundries employees	Pills; dosage not stated	Mean age (SD) not reported. Male %: intervention = 100%, control = 100%	Intervention n = 20; control n = 19	Behavioural intervention vs usual care	6 months
Lin (2017)	People with CAD that had undergone CABG; responsible for self-administration of medications; not meeting criteria for other pre-specified comorbid diseases or health problems	Pills; Prescriptions across the sample: > 90% aspirin, 80% + beta blockers, 60% + ACE inhibitors, 70% + lipid lowering drugs	Mean age (SD): Intervention = 74.32 (5.26), control = 75.23 (5.82); Male%: intervention = 67.4%, control = 65.3%	Intervention: n centres = 6, n participants = 144; Control: n = 6 centres, n participants = 144	Multifaceted intervention including motivational interviewing vs usual care	18 months
Milam (2005)	Diagnosis of HIV for ≥3 months; attending participating HIV clinic; sexually active in past 3 months; ≥18 years old	Pills; Mean number of pills per day (SD) = 4.39 (1.8)	Mean age (SD): adherence intervention = 39(8.1); safer sex group = 39(7.8); Male %: adherence intervention = 87.9%; safer sex arm = 89.2%	Adherence arm: n clusters = 2, n participants = 149; safe sex intervention: n clusters = 4, n participants = 288	Brief adherence intervention vs safe sex intervention (no adherence component)	17–18 months
O’Dwyer (2020)	People prescribed salmeterol/fluticasone Diskus inhaler for asthma, COPD, or other (3-6% unknown diagnosis); filled ≥3 prescriptions in past 6 months	Inhaled medications; dosage not stated for this sample	Mean age (SD): Biofeedback group = 54(15), demonstration group = 53(15); control = 55(13); Male %: Biofeedback group = 42%; demonstration group = 57%; control = 50%	Biofeedback group: n clusters = 27, n participants = 74; Demonstration group: n clusters = 37, n participants = 56; Control group: n clusters = 10, n participants = 22	Biofeedback or demonstration vs usual care	6 months
Pakpour (2015)	Diagnosis of epilepsy; ≥18 years old; independently responsible for medication taking; prescribed AEDs	Pills; Majority of participants (∼70%) on monotherapy^a	Mean age (SD): intervention = 41.37 (16.25), comparator = 39.86(15.01); Female %: intervention = 32.8%; control = 35.5%	Intervention n = 137; control n = 138	Multimodal behavioural intervention vs usual care	6 months
Reddy (2017)	Veterans with diagnosis of CAD; 30–75 years old; <80% adherence at entry to study	Pills; 1 session daily	Mean age (SD): Individual feedback = 65.6(4.1), partner feedback = 64.9(6.2), usual care = 64.1(6.6); Male %: Individual feedback = 100%, partner feedback = 96.3%, control = 91.7%	Individual feedback n = 36; partner feedback n = 54; control n = 36	Individual feedback or partner feedback vs usual care	26 weeks
Russell (2020)	People prescribed ≥1 twice-daily immunosuppressive medication following kidney transplant; ≥18 years old; functioning kidney transplant; no other life-shortening diagnosis	Pills; At least 1 medication, administered twice daily	Mean age (SD): SystemCHANGE = 53(11.2), Attention control = 50.7(9.7); Male%: SystemCHANGE = 66.7%; attention control = 50%	Intervention n = 45; control n = 44	SystemCHANGE intervention vs attention control	12 months
Stacy (2009)	Dyslipidaemia; ≥21 years; enrolled in pharmacy plan and placed claim for a statin prescription	Pills; 57.8% prescribed 3 + medications	Mean age: intervention = 54.6, control = 54.2; Females: intervention = 62.1%; control = 62.7%	Intervention: n = 298; Enhanced care control n = 280	Interactive voice response technology intervention vs enhanced care control	6 months
Tang (2014)	Diagnosis of epilepsy; ≥16 years old; AEDs prescribed ≥6 months; non-adherence occurred in the last 6 months	Pills; Not stated	Mean age (SD): Education and behavioural intervention = 30.8(11.6), Education only = 31.6(13); male%: Education and behavioural intervention = 58.9%; education only = 49.1%	Education and behavioural intervention n = 65, Education only n = 59,	Education plus behavioural intervention vs education only	6 months
Tuldrà (2000)	Attending HIV-outpatient clinic; initiating first or second line HAART	Pills; Mean (SD) doses per day = 3(2)	Mean age (SD): intervention = 39(10), control = 38(7); male%: intervention = 73%; control = 79%	Intervention: n = 55; Control n = 61	Psychoeducative intervention vs usual care	48 weeks
Wildman (2021)	Diagnosis of CF; ≥16 years old	Nebulised; dosage not stated for this sample	Mean age (SD): Intervention = 31.1(10.6), control = 30.3(10.8); Female%: intervention = 51.3%, control = 50.8%	Intervention n = 305; control n = 303	CFHealthHub intervention vs usual care	12 months

CAD = Coronary artery disease; AED = anti-epileptic drug; ASCVD = Atherosclerotic cardiovascular disease; LDL-C = Low density lipoprotein cholesterol; HIV = Human immunodeficiency virus; HAART = Highly active anti-retroviral therapy; COPD = Chronic obstructive pulmonary disease; CVD = cardiovascular disease; CABG = coronary artery bypass graft; CF = cystic fibrosis; SD = standard deviation.

^a Based on n in Table 1 of (Pakpour et al., 2015).

Table 2. ‘Habit formation’ intervention content and findings.

First author (Year)	Intervention name	BCTs coded^a	Intervention duration to assessment timepoint details	Data collection	Adherence summary and timepoint measured	Adjustments to estimates	n (I,C) analysed	Effect on adherence (nearest 6 months)	Direction of effect and effect size (nearest 6 months)^b	Effect on adherence > 6 months	Effect on habit
Gregoriano (2019)	Daily alarm clock and support phone calls vs control	1.2 Problem solving; 2.2 Feedback on behaviour; 7.1 Prompts/cues; 8.1 Behavioural practice/rehearsal; 8.3 Habit formation	Intervention delivered over 6 months	Electronic device or POEMs where appropriate for dry powder medications	Mean number of days (max 200) that taking-adherence was in target adherence range (80-100%)	n/a	I (Puff inhaler) = 57, I (Dry powders) = 41 C(Puff inhaler) = 60, C (Dry powders) = 49	Significant difference for puff inhalers and dry powder capsules: Puff inhalers, Intervention mean(SD) = 81.6(14.2), control mean(SD) = 60.1(30.3), p < .001; Dry powders Intervention mean(SD) = 89.6(9.8), Control mean(SD) = 80.2(21.3), p = .01	Favours intervention Puff inhalers: Unadjusted d (95%CI) = 0.90 (0.52, 1.28) Dry powders: Unadjusted d (95%CI) = 0.55 (0.13, 0.97)	n/a	Not measured
Haynes (1976)	Behavioural intervention vs usual care	1.2 Problem solving; 1.3 Goal setting (outcome); 1.4 Action planning; 1.6 Discrepancy between current behaviour and goal; 2.2 Feedback on behaviour; 2.3 Self-monitoring of behaviour; 2.4 Self-monitoring of outcome of behaviour; 2.6 Biofeedback; 3.1 Social support (unspecified); 7.1 Prompts/cues; 8.1 Behavioural practice/ rehearsal; 8.3 Habit formation; 10.4 Social reward; 10.10 Reward (outcome); 12.1 Restructuring the physical environment	Intervention delivered over full 6 months	Unused pill count	Change in adherence at 6-months, adherence calculated as proportion of pills prescribed that are taken in the month of follow-up	n/a	I = 20 C = 18	Significant difference: Intervention mean (SE) = 65.8(8.2) vs control mean(SE) = 43.2 (10.1), Baseline adjusted difference = 22.8, p = .025	Favours intervention Unadjusted Hedges g (95%CI) = 0.56 (−0.09, 1.21)	n/a	Not measured
Milam (2005)	Brief adherence intervention vs safe sex intervention (no adherence component)	1.2 Problem solving 1.4 Action planning 7.1 Prompts/cues 8.1 Behavioural practice/ rehearsal 8.3 Habit formation	Intervention delivered until month 10–11	Self-report of number of pills taken over past 7 days	Percent of patients whose 7-day adherence > 95% measured at 17–18 months	Income, ethnicity, employment status, AIDS diagnosis, HAART regimen (vs. non-HAART), and number of pills per day, adherence at baseline and clustering	I = 149 C = 288	No significant effect: Intervention n(%) = 128 (85.9%) vs control n(%) = 201(69.8%). Adjusted OR = 2.05, [95% CI: 0.92 to 4.56], p = .077	Favours intervention (Unadjusted) RR (95% CI) = 1.23 (1.11, 1.36)	(Outcome measured at 17–18 months)	Not measured
Russell (2020)	SystemChange™ vs attention control	1.1 Goal setting (behaviour) 1.4 Action planning 1.5 Review behaviour goals 1.6 Discrepancy between current behaviour and goal 2.2 Feedback on behaviour 4.4 Behavioural experiments 15.3 Focus on past success	Intervention delivered over 6 months	MEMS-cap	Adherence rate defined as doses taken on time/total doses at 6 months	Ethnicity, marital status, perceived health score, and perceived social support	I = 45 C = 44	Significant difference: Intervention mean(SD) = 0.81(0.25) vs control mean(SD) = 0.64(0.24), p < .001. Adjusted difference B = 0.2 (95% CI = 0.12 to 0.27; SE = 0.039, p < .001)	Favours intervention Unadjusted d (95%CI) = 0.69(0.27, 1.12)	Significant difference at 12 months: Intervention mean(SD) = 0.65(0.37) vs control mean(SD) = 0.53(0.29), p = .004. Adjusted B = 0.16 (95% CI = 0.06 to 0.26; SE = 0.05) p < .001. Favours intervention. Unadjusted d (95%CI) = 0.36 (−0.06, 0.78)	Not measured
Tang (2014)	Education plus behavioural intervention vs education only	1.4 Action planning 7.1 Prompts/cues 8.1 Behavioural practice/rehearsal 8.3 Habit formation 9.1 Credible source	Intervention delivered over full 6 months	Morisky Medication Adherence Scale (MMAS-4)	Number of individuals whose self-report adherence improved at 6-months.	n/a	I = 56 C = 53	Favours intervention. No significant effect: Intervention n improved (%) = 36(64.3%) vs Control n improved (%) = 33 (62.3%), p = 0.827	Favours intervention RR(95% CI) = 1.03 (0.78, 1.37)	n/a	Not measured
Wildman (2021)	CFHealthHub intervention vs usual care	1.1 Goal setting (behaviour) 1.2 Problem solving 1.4 Action planning 1.5 Review behavioural goals 1.6 Discrepancy between current behaviour and goal 2.2 Feedback on behaviour 2.3 Self-monitoring of behaviour 3.2 Social support (practical) 4.1 Instruction on how to perform the behaviour 5.1 Information about health consequences 5.2 Salience of consequences 6.1 Demonstration of the behaviour 7.1 Prompts/cues 8.1 Behavioural practice/rehearsal 8.3 Habit formation 8.7 Graded tasks 9.1 Credible source 10.4 Social reward 12.1 Restructure the physical environment 12.5 Adding objects to the environment 15.3 Focus on past success 15.4 Self-talk 16.3 Vicarious consequences	Intervention delivered over 12-month period	PARI eTrack™ electronic device	Normative adherence (adjustments made for ideal treatment for effectiveness) at 12 months	Treatment arm, time in weeks, baseline adherence (first two weeks), and past-year IV days	I = 295 C = 293	Favours intervention. Significant effect: intervention mean(SD) = 52.9%(31.4) vs control mean(SD) = 34.9%(31.7), adjusted mean difference = 9.5% (95%CI, 8.6-10.4)	Favours intervention Adjusted d (95%CI) = 1.71 (1.52, 1.90)	(Outcome measured at 12 months)	Favours intervention

I = Intervention; C = Control; MEMS = Medication event monitoring system; POEMs = Polymedication Electronic Monitoring System; HAART = Highly active anti-retroviral therapy; SE = standard error; SD = standard deviation; CI = confidence interval.

^a BCTs in bold represent BCTs coded by the study authors directly, using Michie et al.’s (2013) taxonomy.

^b The effect size was estimated for each RCT based on the raw observed data; if this was not available on the adjusted difference.

Table 3. Quality assessment.

Study	Domain 1	Domain 2	Domain 3	Domain 4	Domain 5	Overall summary
Barankay (2020)	Low	High	High	Low	Some concerns	High
De Bruin (2010)	Low	Low	High	Low	Some concerns	High
Farmer (2016)	Low	Some concerns	High	Low	Some concerns	High
Gregoriano (2019)^a	Low	High	High	Low	Some concerns	High
Haynes (1976)^a	Some concerns	Low	Low	Low	Some concerns	Some concerns
Lin (2017)^b	Low	Low	High	High	Some concerns	High
Milam (2005)^a	High	Some concerns	High	High	Some concerns	High
O’Dwyer (2020)	High	Low	High	Low	Some concerns	High
Pakpour (2015)^b	Low	Low	Low	High	Some concerns	High
Reddy (2017)	Low	Low	Low	Low	Some concerns	Some concerns
Russell (2020)^a	High	Low	Some concerns	Low	Some concerns	High
Stacy (2009)	Low	High	Low	Low	Some concerns	High
Tang (2014)^a	High	High	High	High	Some concerns	High
Tuldrà (2000)	Some concerns	Low	High	High	Some concerns	High
Wildman (2021)^a^,^b	Low	Low	Low	Low	Some concerns	Some concerns

Domain 1: risk of bias arising from the randomisation process; Domain 2: risk of bias due to deviations from the intended intervention (effect of assignment to intervention); Domain 3: risk of bias due to missing outcome data; Domain 4: risk of bias in measurement of an outcome; Domain 5: risk of bias in selection of reported result. ‘High’ refers to high risk of bias and ‘low’ refers to low risk of bias in the respective domain.

^a Studies coded to have used context-dependent repetition in the intervention content.

^b Studies which measured change in habit strength.

Pakpour, A. H., Gholami, M., Esmaeili, R., Naghibi, S. A., Updegraff, J. A., Molloy, G. J., & Dombrowski, S. U. (2015). A randomized controlled multimodal behavioral intervention trial for improving antiepileptic drug adherence. Epilepsy & Behavior, 52, 133–142. http://doi.org/10.1016/j.yebeh.2015.08.036

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Michie, S., Richardson, M., Johnston, M., Abraham, C., Francis, J., Hardeman, W., Eccles, M. P., Cane, J., & Wood, C. E. (2013). The behavior change technique taxonomy (v1) of 93 hierarchically clustered techniques: Building an international consensus for the reporting of behavior change interventions. Annals of Behavioral Medicine, 46(1), 81–95. https://doi.org/10.1007/s12160-013-9486-6

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Data availability

Python source code available from Github: https://github.com/lkrobinson/active_learning_systematic_review/blob/main/README.md.