A framework for understanding sources of bias in medication adherence research.

The sources of bias in medication adherence research have not been comprehensively explored. We aimed to identify biases expected to affect adherence research and to develop a framework for mapping these onto the phases of adherence (initiation, implementation and discontinuation). A literature search was conducted, key papers were reviewed and a Catalogue of Bias was consulted. The specific biases related to adherence measurement and metrics were mapped onto the phases of adherence using a tabular matrix. Twenty-three biases were identified, of which 11 were specifically relevant to adherence measures and metrics. The mapping framework showed differences in the numbers and types of biases associated with each measure and metric while highlighting those common to many adherence study designs (e.g., unacceptability bias and apprehension bias). The framework will inform the design of adherence studies and the development of risk of bias tools for adherence research.

HIV Treatment Adherence Self-efficacy Scale for Pakistani HIV/AIDS patients: Translation and psychometric evaluation.

AIM: This study translated HIV-Adherence Self-efficacy scale (HIV-ASES) and evaluated its psychometric properties in Pakistani HIV/AIDS patients. BACKGROUND: High level of adherence to highly active antiretroviral therapy (HAART) is required in management of HIV/AIDS; and it is significantly associated with self-efficacy for adherence to treatment. Understanding and enhancing adherence self-efficacy is a huge challenge for care management staff including nurses, counselors and doctors due to paucity of research and availability of valid and reliable instruments in Urdu language to assess HIV treatment adherence self-efficacy. METHODS: Brislin's translation method was used to translate HIV-ASES in Urdu. A cross-sectional survey consisting of a demographic questionnaire and Urdu HIV-ASES was administered on 300 HIV/AIDS patients seeking treatment in a government hospital. SPSS-20 and Mplus 8.1 were used for statistical analysis. RESULTS: Semantic, content, conceptual and technical equivalence between source and target versions were established. The final Confirmatory Factor Analysis model had 0.95 CFI and 0.06 RMSEA (CI = 0.04-0.08). Cronbach's alpha was 0.89 for full scale, 0.81 for integration, and 0.88 for perseverance subscales. CONCLUSION: Urdu HIV-ASES is a valid and a reliable instrument for assessing HIV treatment adherence self-efficacy for further research, intervention and management of HIV/AIDS.

Comparison of the predictive performance of adherence measures for virologic failure detection in people living with HIV: a systematic review and pairwise meta-analysis.

A critical feature of an adherence assessment tool is its ability to predict virologic failure in people living with HIV (PLHIV). We, therefore, aimed to compare the predictive performance of commonly used adherence measures. We systematically searched MEDLINE, Embase and LILACS up to February 2018, to identify relevant observational studies comparing the effects of any two of the following adherence measurements on virologic outcomes: electronic monitoring, pill count, pharmacy refill, self-report and physician assessment. We analyzed data by pairwise meta-analyzes with a random-effects model. The proportion of virologic failures among non-adherent participants in each adherence measure was used to calculate the odds ratio (OR), with 95% Confidence Intervals (95%CI). Heterogeneity was assessed, with potential causes identified by sensitivity and subgroup analysis. We included 38 studies with individual patient data for 18,010 patients. All possible comparisons between pairs of the five adherence measures were considered and a total of nine comparison groups could be established. Meta-analysis suggested that self-report was a better predictor of virologic failure than pill count when the recall period was within one week (OR: 2.35, 95%CI: 1.07-5.18, p = 0.03). Physician assessment had higher odds of predicting virologic failure than did either self-report (OR: 2.63, 95%CI: 1.37-5.26, p < 0.01) or pharmacy refill (OR: 3.57, 95%CI: 1.69-7.14, p < 0.001). There was no difference in the predictive performance between any of the other measures that we were able to compare (p > 0.05). The combination of multiple measures did not increase the predictive value when compared to any of the measures alone. Low-cost and simple adherence measures such as self-report predict virologic failure better than or equally well as objective measures. Our results suggest that there is no need to use expensive or time-consuming adherence measures when the objective is to identify PLHIV at risk of treatment failure.

Advancing the Science and Practice of Medication Adherence.

Medication adherence remains a significant unmet challenge for optimizing patient outcomes. Recent advances in the conceptualization, measurement, and support of medication adherence offer fresh opportunities to make a meaningful impact on adherence-related behavior and outcomes. These advances emphasize the multifaceted and dynamic nature of medication adherence, provide novel methods for monitoring medication adherence in clinical care, and articulate a set of multilevel strategies to more effectively improve and sustain medication adherence. Here, we offer recommendations for how clinicians can better engage with, and benefit from, these innovations to improve patient medication adherence and associated treatment outcomes.

How Presentation of Drug Detection Results Changed Reports of Product Adherence in South Africa, Uganda and Zimbabwe.

Accurate estimates of study product use are critical to understanding and addressing adherence challenges in HIV prevention trials. The VOICE trial exposed a significant gap between self-reported adherence and drug detection. The VOICE-D qualitative study was designed to better understand non-adherence during VOICE, and was conducted in 2 stages: before (stage 1) and after (stage 2) drug detection results were provided to participants. Transcripts from 44 women who participated in both stages were analysed to understand the effect of presenting drug detection data on narratives of product use. Thirty-six women reported high adherence in stage 1, yet admitted non-use in stage 2, three reported high adherence in both stages (contrary to their drug detection results) and five had consistent responses across both stages and drug results. Presenting objective measures of use may facilitate more accurate product use reporting and should be evaluated in future prevention trials.

Impact of hospitalization on medication adherence estimation in claims data.

WHAT IS KNOWN AND OBJECTIVE: Pharmacy claims are commonly used to assess medication adherence. It is unclear how different approaches to handling hospitalizations compare to the gold standard of using outpatient and inpatient drug data. This study aimed to compare the impact of different approaches to handling hospitalizations on medication adherence estimation in administrative claims data. METHODS: We identified ß-blocker initiators after myocardial infarction (MI) and statin initiators regardless of hospitalization histories in the population-based, Taiwan database, which includes outpatient and inpatient drug claims data. Adherence to ß-blockers or to statins during a 365-day follow-up period was estimated in outpatient pharmacy claims using the proportion of days covered (PDC) in three ways: ignoring hospitalizations (PDC1); subtracting hospitalized days from the denominator (PDC2); and assuming drug use on all hospitalized days (PDC3). We compared these to an approach that incorporated inpatient drug use (PDC4). We also used a hypothetical example to examine variations across approaches in several scenarios, such as increasing hospitalized days. RESULTS AND DISCUSSION: Mean 365-day PDC was 74% among 1729 post-MI ß-blocker initiators (range: 73.1%-74.9%) and 44% among 69 435 statins initiators (range: 43.5%-44.0%), which varied little across approaches. Differences across approaches increased with increasing number of hospitalized days. For patients hospitalized for >28 days, mean difference across approaches was >15%. PDC3 consistently yielded the highest value and PDC1 the lowest. WHAT IS NEW AND CONCLUSIONS: On average, different approaches to handling hospitalizations lead to similar adherence estimates to the gold standard of incorporating inpatient drug use. When patients have many hospitalization days during follow-up, the choice of approach should be tailored to the specific setting.

Medication adherence and persistence in heart failure: A protocol for a systematic review and meta-analysis.

OBJECTIVE: To study medication adherence and persistence among heart failure patients, assess the methods utilised for estimating medication adherence, and identify optimal adherence thresholds and their impact on clinical outcomes. METHODS: A systematic search will be conducted in PubMed, Embase, CINAHL, Web of Science, and Scopus databases. Observational studies assessing medication adherence or persistence among heart failure patients via electronic healthcare databases will be included. A narrative synthesis will describe medication adherence and persistence reported and methods used to measure it. A meta-analysis will be attempted to evaluate the impact of secondary medication adherence (multiple and by drug class) on clinical outcomes, including hospitalisation, emergency visits, and mortality. The I2 statistic will be employed to study heterogeneity and the GRADE framework to evaluate evidence certainty. This protocol follows the Preferred Reporting Items for Systematic Review and Meta-Analysis Protocols guidelines and is registered with the Prospective Register of Ongoing Systematic Reviews CRD42024509542. DISCUSSION: This study aims to evaluate medication adherence and persistence in heart failure management through electronic health databases, intending to explore widely used measurement methods and their limitations, and to identify adherence thresholds associated with improved clinical outcomes. By examining these aspects, we anticipate proposing enhancements for future research and establishing desired adherence goals. This approach highlights the expected significance of our findings in advancing patient care and research methodologies.

Agreement Between Measures of Adherence to Isoniazid Preventive Therapy Among People With HIV in Uganda.

Background: Isoniazid (INH) preventative therapy is recommended for people with HIV (PWH) in resource-constrained settings. Valid measures are needed to assess adherence. We aimed to examine agreement between measures overall and by level of social desirability. Methods: PWH with latent tuberculosis (TB) were recruited in Mbarara, Uganda. Past 30-day adherence was measured by the number of days with pill bottle openings using a medication event monitoring system (MEMS) and self-reported number of days pills taken. INH concentration (INH plus acetyl INH and their ratio) in hair samples was measured. We used Bland-Altman plots to examine agreement between adherence measures and calculated the area under the receiver operating characteristics curve (AUROC) to determine if INH hair concentration predicted optimal MEMS-measured adherence (≥90%). Results: A total of 301 participants enrolled; 92% were virologically suppressed, and adherence was high. The median (interquartile range [IQR]) number of pill bottle openings in 30 days was 28 (24-30) compared with 30 (28-30) via self-report. The median INH concentration (IQR) was 36.2 (17.2-62.4), and the INH:acetyl ratio was 2.43 (0.99-3.92). Agreement between self-reported and MEMS adherence was greater at more optimal adherence levels. INH:acetyl INH ratio was not predictive of optimal adherence according to MEMS (AUROC, 0.62; 95% CI, 0.52-0.72) in a subset (n = 161). Conclusions: Lower MEMS adherence levels compared with self-report suggest the need for objective adherence measures. Biologic measures have potential, although in this study INH concentration was not predictive of MEMS measured adherence. More data are needed to assess the accuracy of biologic measures.

Validation of an Instrument for Measuring Adherence to Treatment With Immunomodulators in Patients With Multiple Myeloma.

Background: Validate the Treatment Adherence Measure (TAM) instrument in outpatients with MM concerning construct validity, reliability and the ceiling and floor effects. Methods: This cross-sectional study included patients diagnosed with MM previously treated with an immunomodulator for at least one month, aged 18 or over, and followed-up in the investigated outpatient clinics. Adherence to immunomodulators was measured by TAM. The TAM's reliability was assessed using Cronbach's alpha; The association between adherence and health-related quality of life was investigated to analyze the divergent and convergent construct, measured by the Quality of Life Questionnaire core (QLQ-C30) and the Quality of Life Questionnaire Multiple Myeloma module (QLQ-MY20). The presence of a ceiling or floor effect in the TAM was also analyzed. Results: Eighty-four patients were included in the study, achieving 97.6% adherence. Cronbach's alpha was 0.41, and the hypothesis of convergent construct validity was confirmed, with statistical significance, in contrast to the hypothesis of divergent construct validity. The presence of the ceiling effect in TAM suggested that this instrument does not allow changes to be detected in individuals concerning adherence to IMiDs. Conclusion: TAM instrument did not show satisfactory validity and reliability to measure MM's adherence. MM patients treated at oncohematological outpatient clinics in a metropolitan region of southeastern Brazil showed high adherence to IMiDs.

Measuring Medication Adherence in a Population-Based Asthma Administrative Pharmacy Database: A Systematic Review and Meta-Analysis.

BACKGROUND: Limited studies have systematically reviewed the literature to identify and compare the various database methods and optimal thresholds for measuring medication adherence specific to adolescents and adults with asthma. In the present study, we aim to identify the methods and optimal thresholds for measuring medication adherence in population-based pharmacy databases. METHODS: We searched PubMed, Embase, International Pharmaceutical Abstracts (IPA), Web of Science, Google Scholar, and grey literature from January 1, 1998, to March 16, 2021. Two independent reviewers screened the studies, extracted the data, and assessed the quality of the studies. A quantitative knowledge synthesis was employed. RESULTS: Thirty-eight (38) retrospective cohort studies were eligible. This review identified 20 methods for measuring medication adherence in adolescent and adult asthma administrative health records. Two measures namely the medication possession ratio (MPR) and proportion of days covered (PDC) were commonly reported in 87% of the literature included in this study. From the meta-analysis, asthma patients who achieved adherence threshold of "0.75-1.00" [OR: 0.56, 95% CI: 0.41 to 0.77] and ">0.5" [OR: 0.71, 95% CI: 0.54 to 0.94] were less likely to experience asthma exacerbation. CONCLUSION: Despite their limitations, the PDC and the MPR still remain the most common measures for assessing adherence in asthma pharmacy claim databases. The evidence synthesis showed that an adherence threshold of at least 0.75 is optimal for classifying adherent and non-adherent asthma patients.

Refill Adherence Measures and Its Association with Economic, Clinical, and Humanistic Outcomes Among Pediatric Patients: A Systematic Review.

Although refill adherence measures (RAMs) are widely reviewed on their use among adult patients, existing reviews on adherence among children have only focused on self-report measures and electronic monitoring. Hence, this systematic review aims to examine the use of RAMs and their association with economic, clinical, and humanistic outcomes (ECHO) among pediatric patients. A literature search was conducted in Pubmed, Embase, CINAHL, and PsycINFO. Studies published in English involving subjects aged ≤18 years were included if RAMs were analyzed with ECHO. Of the 35 included studies, the majority (n = 33) were conducted in high-income countries. Asthma was the most common condition (n = 9) studied. Overall, 60.6% of 33 clinical outcomes reported among 22 studies was positive (improved clinical outcomes with improved adherence), while 21.9% of 32 economic outcomes reported among 16 studies was positive (reduced healthcare utilization or cost outcomes with improved adherence). Only four studies evaluated the relationship of adherence with 11 humanistic outcomes, where the majority (72.7%) were considered unclear. RAMs are associated with ECHO and can be considered for use in the pediatric population. Future studies could explore the use of RAMs in low-income countries, and the association of RAMs with quality of life.

Pitfalls of medication adherence approximation through EHR and pharmacy records: Definitions, data and computation.

BACKGROUND AND PURPOSE: Patients' adherence to medication is a complex, multidimensional phenomenon. Dispensation data and electronic health records are used to approximate medication-taking through refill adherence. In-depth discussions on the adverse effects of data quality and computational differences are rare. The purpose of this article is to evaluate the impact of common pitfalls when computing medication adherence using electronic health records. PROCEDURES: We point out common pitfalls associated with the data and operationalization of adherence measures. We provide operational definitions of refill adherence and conduct experiments to determine the effect of the pitfalls on adherence estimations. We performed statistical significance testing on the impact of common pitfalls using a baseline scenario as reference. FINDINGS: Slight changes in definition can significantly skew refill adherence estimates. Pickup patterns cause significant disagreement between measures and the commonly used proportion of days covered. Common data related issues had a small but statistically significant (p < 0.05) impact on population-level and significant effect on individual cases. CONCLUSION: Data-related issues encountered in real-world administrative databases, which affect various operational definitions of refill adherence differently, can significantly skew refill adherence values, leading to false conclusions about adherence, particularly when estimating adherence for individuals.

Measuring adherence to antipsychotic medications for schizophrenia: Concordance and validity among a community sample in rural China.

BACKGROUND: Despite the abundance of measures to assess medication adherence by persons suffering schizophrenia, few studies have evaluated their concordance and validity against a reference standard in resource-poor community settings. We explored the concordance and validity of several measures to assess antipsychotic medication adherence in a resource-poor community. METHOD: Based on a random sample of 278 villagers diagnosed with schizophrenia from Liuyang, Hunan Province, China, we used a concordance correlation coefficient (rc) and Kappa statistic to assess agreement among pill counts, refill records, clinician rating, Drug Attitude Inventory (DAI), and the Brief Adherence Rating Scale (BARS). The validity of various measures was evaluated by their concordance and sensitivity/specificity to home-based unannounced pill count (UPC) as the reference standard. RESULTS: The estimated proportion of adherent patients according to all measures (41% ~ 88%) was substantially higher than identified by UPC (35%). Concordance between any two measures was poor (rc/Kappa mostly <0.30). Validity of various measures also was poor against the UPC (rc < 0.20; Kappa <0.16), although refill records and the structured instruments (BARS) performed better than office-based pill counts and clinician impression. BARS, DAI and clinician rating were not sensitive to changes in adherence and would likely underestimate any program effect. CONCLUSION: In resource-poor community settings, most measures assessed in this study should not be used alone as they overestimated adherence, underestimated program effect, and had poor validity. A combination of UPC and several other measures may provide more insight into clinical trials and programmatic management.

Coming full circle in the measurement of medication adherence: opportunities and implications for health care.

There is little debate that medication nonadherence is a major public health issue and that measuring nonadherence is a crucial step toward improving it. Moreover, while measuring adherence is becoming both more feasible and more common in the era of electronic information, the reliability and usefulness of various measurements of adherence have not been well established. This paper outlines the most commonly used measures of adherence and discusses the advantages and disadvantages of each that depend on the purpose for which the measure will be used. International consensus statements on definitions and guidelines for selection and use of medication adherence measures were reviewed. The quality of recommended measures was evaluated in selected publications from 2009 to 2014. The most robust medication adherence measures are often ill suited for large-scale use. Less robust measures were found to be commonly misapplied and subsequently misinterpreted in population-level analyses. Adherence assessment and measurement were rarely integrated into standard patient care practice patterns. Successful scalable and impactful strategies to improve medication adherence will depend on understanding how to efficiently and effectively measure adherence.

Novel Adherence Measures for Infusible Therapeutic Agents Indicated for Rheumatoid Arthritis.

BACKGROUND: Published studies on adherence to biologic medications show that many types of calculation methods are used. However, infused biologics are not well-suited to typical measures of adherence, such as proportion of days covered. OBJECTIVE: To construct and assess 7 novel adherence measures potentially applicable to infusible biologic agents and compare outcomes for 2 infusible biologics used for the treatment of patients with rheumatoid arthritis (RA). METHODS: Adults (aged ≥18 years) diagnosed with RA (ie, 2 or more 714.x claims) who received ≥24 months of continuous medical and pharmacy eligibility and who started taking abatacept or infliximab therapy were selected from a large commercial insurer database of medical and pharmacy claims. The 7 new adherence measures included cumulative amount of time with a refill gap ≥20% (CG20) beyond the expected infusion interval, cumulative time off treatment, days of uninterrupted use (DoUU), observed versus expected refill ratio (OvERR), repeated observations of underuse (RoUU), variance in time between infusions, and time to discontinuation (TTD). Mean observed infusion intervals were calculated and served as a reference measure of adherence. RESULTS: The mean maintenance intervals approximated recommended guidelines. The mean observed infusion interval for abatacept recipients was 33 days (recommended, 28 days); it was 53 days (recommended, 56 days) for patients receiving infliximab. Three measures demonstrated a significant positive relationship to the mean observed infusion interval-CG20 (r = .258), DoUU (r = .212), and TTD (r = .081; P <.05). OvERR (r = -.072) and RoUU (r = -.189; P <.05) showed significant negative correlations. Real-world comparisons showed that adherence was significantly (P <.001) greater for the infliximab group according to most measures. CONCLUSION: New measures of adherence correlate significantly with mean maintenance intervals. Future studies should examine relationships between these adherence measures and clinically relevant end points and/or cost outcomes to determine their predictive utility. Alternative methods of reporting adherence may have greater clinical significance than traditional measures.

Impact of a pharmaceutical care program on clinical evolution and antiretroviral treatment adherence: a 5-year study.

BACKGROUND: Antiretroviral treatments (ART) form the basis of adequate clinical control in human immunodeficiency virus-infected patients, and adherence plays a primary role in the grade and duration of the antiviral response. The objectives of this study are: (1) to determine the impact of the implementation of a pharmaceutical care program on improvement of ART adherence and on the immunovirological response of the patients; and (2) to detect possible correlations between different adherence evaluation measurements. METHODS: A 60-month long retrospective study was conducted. Adherence measures used were: therapeutic drug monitoring, a simplified medication adherence questionnaire, and antiretroviral dispensation records (DR). The number of interviews and interventions related to adherence made for each patient in yearly periods was related to the changes in the adherence variable (measured with DR) in these same yearly periods. The dates when the laboratory tests were drawn were grouped according to proximity with the study assessment periods (February-May, 2005-2010). RESULTS: A total of 528 patients were included in the study. A significant relationship was observed between the simplified medication adherence questionnaire and DR over the 60-month study period (P < 0.01). Improvement was observed in the mean adherence level (P < 0.001), and there was a considerable decrease in the percentage of patients with CD4+ lymphocytes less than 200 cells/mm(3) (P < 0.001). A relationship was found between the number of patients with optimum adherence levels and the time that plasma viral load remained undetected. The number of interviews and interventions performed in each patient in the first 12 months from the onset of the pharmaceutical care program (month 6), was related to a significant increase in adherence during this same time period. CONCLUSION: The results suggest that the establishment and permanence of a pharmaceutical care program may increase ART adherence, increase permanence time of the patient with undetectable plasma viral loads, and improve patients' lymphocyte count.