Search

Aim: This research aims to provide an overview of the consequences of undiagnosed non-adherence in clinical trials. Methods: This research was conducted with a mixed-methods approach. It combines a literature review and qualitative semi-structured interviews with key opinion leaders. Based on this groundwork, the consequences of undiagnosed non-adherence in clinical trials were summarized and reported in a figure. This study focused on phases II, III, and IV in ambulatory settings across a variety of therapeutic areas and indications. Results: Various consequences of non-adherence in trials were investigated. In phase II, drug efficacy may be underestimated, variability in the outcomes may be high, and a distorted picture of side effects could be reported, resulting in an uncertain impression of the investigational product’s profile, and complicating decision-making. The sponsor may need to increase the sample size of the upcoming phase III study to improve its power, representing additional costs, or even terminate the study. In phase III, similar phenomena may be observed, making demonstration of efficacy to the regulatory bodies more difficult. Lastly, in phase IV, a distortion in pharmacometrics may occur; the drug may underperform, prescriptions may be refilled less often than expected, or extra expenses may be incurred by the payers. This can result in post-marketing dose reduction, new competitors coming into the market, and eventually, product withdrawal. Conclusion: This research highlighted the many potential adverse consequences of undiagnosed non-adherence in clinical trials, including additional costs. Collecting accurate data appeared to be crucial for decision-making throughout the drug development process.

Measuring adherence to medication is complex due to the diversity of contexts in which medications are prescribed, dispensed and used. The Timelines-Events-Objectives-Sources (TEOS) framework outlined a process to operationalize adherence. We aimed to develop practical recommendations for quantification of medication adherence using self-report (SR), electronic monitoring (EM) and electronic healthcare databases (EHD) consistent with the TEOS framework for adherence operationalization.An adherence methodology working group of the International Society for Medication Adherence (ESPACOMP) analysed implications of the process of medication adherence for all data sources and discussed considerations specific to SR, EM and EHD regarding the information available on the prescribing, dispensing, recommended and actual use timelines, the four events relevant for distinguishing the adherence phases, the study objectives commonly addressed with each type of data, and the potential sources of measurement error and quality criteria applicable.Four key implications for medication adherence measurement are common to all data sources: adherence is a comparison between two series of events (recommended and actual use); it refers to one or more specific medication(s); it applies to regular repeated events coinciding with known recommended dosing; and it requires separate measurement of the three adherence phases for a complete picture of patients' adherence. We propose recommendations deriving from these statements, and aspects to be considered in study design when measuring adherence with SR, EM and EHD using the TEOS framework.The quality of medication adherence estimates is the result of several design choices that may optimize the data available.

The estimated probability of progressing from phase 3 analgesic clinical trials to regulatory approval is approximately 57%, suggesting that a considerable number of treatments with phase 2 trial results deemed sufficiently successful to progress to phase 3 do not yield positive phase 3 results. Deficiencies in the quality of clinical trial conduct could account for some of this failure. An Initiative on Methods, Measurement, and Pain Assessment in Clinical Trials meeting was convened to identify potential areas for improvement in trial conduct in order to improve assay sensitivity (ie, ability of trials to detect a true treatment effect). We present recommendations based on presentations and discussions at the meeting, literature reviews, and iterative revisions of this article. The recommendations relate to the following areas: 1) study design (ie, to promote feasibility), 2) site selection and staff training, 3) participant selection and training, 4) treatment adherence, 5) data collection, and 6) data and study monitoring. Implementation of these recommendations may improve the quality of clinical trial data and thus the validity and assay sensitivity of clinical trials. Future research regarding the effects of these strategies will help identify the most efficient use of resources for conducting high quality clinical trials. PERSPECTIVE: Every effort should be made to optimize the quality of clinical trial data. This manuscript discusses considerations to improve conduct of pain clinical trials based on research in multiple medical fields and the expert consensus of pain researchers and stakeholders from academia, regulatory agencies, and industry.

The Ascertaining Barriers to Compliance (ABC) taxonomy for describing medication adherence was created in 2012, aiming to standardize terms and definitions in research and practice. The taxonomy comprises seven terms and definitions. Originally developed in English, subsequently translated into French and German, is currently being translated to Portuguese, Spanish, Czech, Romanian and Italian, aiming to promote its global use and overcome cultural barriers.To cross-culturally translate the ABC taxonomy into Portuguese for Portugal and Brazil.A systematic literature search was conducted to identify published taxonomy terms and definitions in Portuguese, and to identify panelists in medication adherence. Initial mapping of terms and definitions retrieved was scrutinized by the research team to build an e-survey. The e-survey was piloted and then sent to panelists in both countries seeking consensus using a three-round Delphi method. Consensus was defined as ≥ 85% for round 1 and ≥ 75% for round 2. Terms with agreement10% were dropped between rounds. In round 3, terms and definitions reaching agreement between 50 and 75% were classified as moderate consensus,75-95% as consensus and95% as strong consensus.A total of 778 studies were identified and 84 included, enabling the extraction of 154 terms and 32 definitions. In round 1, 164 panelists participated, 115 in round 2 and 99 in the round 3. Consensus was achieved in both countries for all seven terms and definitions, although with varying intensity of agreement. The term "Management of adherence" and the definition of "Discontinuation" obtained moderate consensus in both countries.A unified and unique ABC taxonomy in Portuguese was possible to develop for use in Portugal and in Brazil. Its use will harmonize and standardize the terms and definitions used in clinical practice and research.

Imperfect medication adherence remains the biggest predictor of treatment failure for patients with tuberculosis. Missed doses during treatment lead to relapse, tuberculosis resistance, and further spread of disease. Understanding individual patient phenotypes, population pharmacokinetics, resistance development, drug distribution to tuberculosis lesions, and pharmacodynamics at the site of infection is necessary to fully measure the impact of adherence on patient outcomes. To decrease the impact of expected variabilityin drug intake on tuberculosis outcomes, an improvement in patient adherence and new forgiving regimens that protect against missed doses are needed. In this review, we summarize emerging technologies to improve medication adherence in clinical practice and provide suggestions on how digital adherence technologies can be incorporated in clinical trials and practice and the drug development pipeline that will lead to more forgiving regimens and benefit patients suffering from tuberculosis.

Non-adherence has been well recognized for years to be a common issue that significantly impacts clinical outcomes and health care costs. Medication adherence is remarkably low even in the controlled environment of clinical trials where it has potentially complex major implications. Collection of non-adherence data diverge markedly among cardiovascular randomized trials and, even where collected, is rarely incorporated in the statistical analysis to test the consistency of the primary endpoint(s). The imprecision introduced by the inconsistent assessment of non-adherence in clinical trials might confound the estimate of the calculated efficacy of the study drug. Hence, clinical trials may not accurately answer the scientific question posed by regulators, who seek an accurate estimate of the true efficacy and safety of treatment, or the question posed by payers, who want a reliable estimate of the effectiveness of treatment in the marketplace after approval. The Non-adherence Academic Research Consortium is a collaboration among leading academic research organizations, representatives from the U.S. Food and Drug Administration and physician-scientists from the USA and Europe. One in-person meeting was held in Madrid, Spain, culminating in a document describing consensus recommendations for reporting, collecting, and analysing adherence endpoints across clinical trials. The adoption of these recommendations will afford robustness and consistency in the comparative safety and effectiveness evaluation of investigational drugs from early development to post-marketing approval studies. These principles may be useful for regulatory assessment, as well as for monitoring local and regional outcomes to guide quality improvement initiatives.

BACKGROUND Breast cancer survivors (BCS) frequently experience social, psychological challenges during the period of survivorship. These range from social, psychological and medical challenges during survivorship. Medication management like adherence and sideeffects are among the most frequent challenges reported. EHealth tools have been claimed to have the potential to support cancer survivors. OBJECTIVE The main objective of the present study was to assess BCS’ and Health Care Practitioners' (HCP) beliefs, attitudes, needs and expectations during breast cancer (BC) survivorship with a specific focus on the use and acceptability of eHealth intervention to support oral hormonal therapy (OHT) adherence. METHODS A total of 14 BC survivors, three BC nurses, four oncologists and three pharmacists were interviewed. Qualitative, semi-structured, individual interviews were conducted in French, German or Luxembourgish. The interviews were recorded, transcribed and anonymized. A thematic analysis was then performed. RESULTS BC survivors were recruited from three main cancer sites in Luxembourg, they had all been prescribed OHT and their age ranged between 42 and 68 years. The interviews revealed 6 themes (patient to survivor shift, personalized follow-up, adherence and side effect management, survivorship companion, barriers of usability, facilitators of usability) and 18 sub themes. HCP interview’s findings suggested 5 themes (shift of responsibility, personalized consultations, barriers of usability, facilitators of usability and real-time remote monitor) and 12 sub themes. All participants accepted the concept of an eHealth tool to support OHT management. Results highlighted a need for personalized real-time communication between HCP and BCS. BCS believe that an eHealth tool has the potential to provide information, motivation, reassurance and support. HCPs need a system that allows them to personalize their consultations. HCPs’ main concern with an eHealth tool is the potential additional workload such a tool could bring along. CONCLUSIONS The eHealth intervention to support BCS during their OHT is accepted by both BCS and HCPs. Such an eHealth tool could play an essential role in the shift from patient to survivors and thus support BCS during this key period of medication initiation and implementation.

Aims Managing adherence to medications is a priority for health systems worldwide. Adherence research is accumulating, yet the quality of the evidence is reduced by various methodological limitations. In particular, the heterogeneity and low accuracy of adherence measures have been highlighted in many literature reviews. Recent consensus-based guidelines advise on best practices in defining adherence (ABC) and reporting of empirical studies (EMERGE). While these guidelines highlight the importance of operational definitions in adherence measurement, such definitions are rarely included in study reports. To support researchers in their measurement decisions, we developed a structured approach to formulate operational definitions of adherence. Methods A group of adherence and research methodology experts used theoretical, methodological and practical considerations to examine the process of applying adherence definitions to various research settings, questions and data sources. Consensus was reached through iterative review of discussion summaries and framework versions. Results We introduce TEOS, a four-component framework to guide the operationalization of adherence concepts: (1) describe treatment as four simultaneous interdependent timelines (recommended and actual use, conditional on prescribing and dispensing); (2) locate four key events along these timelines to delimit the three ABC phases (first and last recommended use, first and last actual use); (3) revisit study objectives and design to fine-tune research questions and assess measurement validity and reliability needs, and (4) select data sources (e.g., electronic monitoring, self-report, electronic healthcare databases) that best address measurement needs. Conclusion Using the TEOS framework when designing research and reporting explicitly on these components can improve measurement quality.

Medication non-adherence, defined as any deviation from the regimen recommended by their healthcare provider, can increase morbidity, mortality and side effects, while reducing effectiveness. Through studying two respiratory conditions, asthma and tuberculosis (TB), we thoroughly review the current understanding of the measurement and reporting of medication adherence. In this paper, we identify major methodological issues in the standard ways that adherence has been conceptualised, defined and studied in asthma and TB. Between and within the two diseases there are substantial variations in adherence reporting, linked to differences in dosing intervals and treatment duration. Critically, the communicable nature of TB has resulted in dose-by-dose monitoring becoming a recommended treatment standard. Through the lens of these similarities and contrasts, we highlight contemporary shortcomings in the generalised conceptualisation of medication adherence. Furthermore, we outline elements in which knowledge could be directly transferred from one condition to the other, such as the application of large-scale cost-effective monitoring methods in TB to resource-poor settings in asthma. To develop a more robust evidence-based approach, we recommend the use of standard taxonomies detailed in the ABC taxonomy when measuring and discussing adherence. Regimen and intervention development and use should be based on sufficient evidence of the commonality and type of adherence behaviours displayed by patients with the relevant condition. A systematic approach to the measurement and reporting of adherence could improve the value and generalisability of research across all health conditions. ispartof: BRITISH JOURNAL OF CLINICAL PHARMACOLOGY vol:87 issue:3 pages:825-836 ispartof: location:England status: published

Objectives: Managing adherence to medications is a priority for health systems worldwide. Adherence research is accumulating, yet the quality of the evidence is reduced by various methodological limitations. In particular, the heterogeneity and low accuracy of adherence measures have been highlighted in many literature reviews. Recent consensus-based guidelines advise on best practices in defining adherence (ABC) and reporting of empirical studies (EMERGE). While these guidelines highlight the importance of operational definitions in adherence measurement; such definitions are rarely included in study reports. To support researchers in their measurement decisions, we developed a structured approach to formulate operational definitions of adherence.Methods: A group of adherence and research methodology experts used theoretical, methodological and practical considerations to examine the process of applying adherence definitions to various research settings, questions and data sources. Consensus was reached through iterative reviewing of discussion summaries and framework versions.Results: We introduce TEOS, a four-component framework to guide the operationalization of adherence concepts: 1) describe treatment as four simultaneous interdependent timelines (recommended and actual use, conditional on prescribing and dispensing); 2) locate four key events along these timelines to delimit the three ABC phases (first and last recommended use, first and last actual use); 3) revisit study objectives and design to finetune research questions and assess measurement validity and reliability needs, and 4) select data sources (e.g., electronic monitoring, self-report, electronic healthcare databases) that best address measurement needs.Conclusion: Using the TEOS framework when designing research and reporting explicitly on these components can improve measurement quality.

International audience; Poor medication adherence remains frequent in schizophrenia. The present study examined the efficacy of two month-long pilot interventions using the Medication Event Monitoring System (MEMS®). Thirty-three outpatients at high risk for relapse were randomized to receive a smartphone-based intervention, a nurse-based intervention, or treatment as usual. All patients then used the MEMS® to objectively measure medication adherence over six months. No differences were observed in adherence measures or relapse rates across the three groups. When using electronic medication monitoring as an objective measure of adherence, easily-implemented interventions may not significantly improve adherence in patients at high risk for relapse.

ObjectiveThis study aimed to assess implementation adherence (how well the patient’s actual intake matches the prescribed dosing regimen) to non-vitamin K antagonist oral anticoagulants (NOACs) and to explore experiences with and beliefs about NOACs in a real-world sample of long-term NOAC users.MethodsA cross-sectional observational study was conducted in home-dwelling adults who started taking a NOAC at least 1 year prior to inclusion. Pharmacy dispensing data were used to calculate the Medication Possession Ratio (MPR). Patients were recruited in 158 community pharmacies in Flanders, Belgium. They completed a questionnaire collecting basic characteristics and exploring self-reported adherence to NOACs (using the Medication Adherence Report Scale, MARS) and experiences with and beliefs about NOACs (using the Beliefs about Medicines Questionnaire, BMQ).ResultsA total of 766 patients (mean age 76.2±8.8 years, median CHA2DS2-VASc score 4 (IQR=3–4)) were included. The majority (93.5%) used NOAC for stroke prevention in atrial fibrillation. The median MPR was 95.2% (IQR=87.8–99.7) which corresponds with half of the study population not taking their NOAC on at least 17 cumulative days per year. Almost 21% of participants reported non-adherence on the MARS (score ConclusionsOur data indicate that long-term NOAC users have high implementation adherence and a positive attitude towards NOAC therapy. However, taking into account patients’ thromboembolic risk and NOACs’ short half-lives, further optimisation of NOAC use seems warranted in this population.

UNSTRUCTURED Despite half a century of dedicated studies, medication adherence remains far from perfect, with many patients not taking their medications as prescribed. The magnitude of this problem is rising, jeopardizing the effectiveness of evidence-based therapies. An important reason for this is the unprecedented demographic change at the beginning of the 21st century. Aging leads to multimorbidity and complex therapeutic regimens that create a fertile ground for nonadherence. As this scenario is a global problem, it needs a worldwide answer. Could this answer be provided, given the new opportunities created by the digitization of health care? Daily, health-related information is being collected in electronic health records, pharmacy dispensing databases, health insurance systems, and national health system records. These big data repositories offer a unique chance to study adherence both retrospectively and prospectively at the population level, as well as its related factors. In order to make full use of this opportunity, there is a need to develop standardized measures of adherence, which can be applied globally to big data and will inform scientific research, clinical practice, and public health. These standardized measures may also enable a better understanding of the relationship between adherence and clinical outcomes, and allow for fair benchmarking of the effectiveness and cost-effectiveness of adherence-targeting interventions. Unfortunately, despite this obvious need, such standards are still lacking. Therefore, the aim of this paper is to call for a consensus on global standards for measuring adherence with big data. More specifically, sound standards of formatting and analyzing big data are needed in order to assess, uniformly present, and compare patterns of medication adherence across studies. Wide use of these standards may improve adherence and make health care systems more effective and sustainable.

We translated the ABC adherence taxonomy (i.e., seven terms and their corresponding definitions) published by Vrijens et al. (2012) into French (F) and German (G) without changing the original meaning with the aim to promote a standardised taxonomy for medication adherence to French- and German-speaking researchers and clinicians.; A Delphi survey was performed. To generate round one, we identified French and German synonyms for the seven adherence terms through a literature search in Pubmed. Investigators translated the original English definitions into French and German. Panellists were members of ESPACOMP - the International Society for Patient Medication Adherence; experts suggested by ESPACOMP members and first authors of medication adherence publications in French and German. Google forms were used to create online questionnaires. Delphi rounds were performed until consensus was reached. The consensus was defined according to the acceptance rate as moderate consensus (50-75%), consensus (>75-95%), and strong consensus (>95%).; The literature search resulted in four to six (F) and four to seven (G) items per English term. Delphi rounds were launched between November 2016 and April 2018. Three rounds sufficed to reach consensus on all terms and definitions from 26 French-speaking and 25 German-speaking panellists. Preferred terms for medication adherence are "adhesion medicamenteuse" (82%) in French and "Medikamentenadharenz" (88%) in German.; The use of a common terminology for medication adherence with translations in French and German will contribute to standardise the vocabulary, to harmonise research projects and ultimately ease comparison of study results among researchers and clinicians.

Despite half a century of dedicated studies, medication adherence remains far from perfect, with many patients not taking their medications as prescribed. The magnitude of this problem is rising, jeopardizing the effectiveness of evidence-based therapies. An important reason for this is the unprecedented demographic change at the beginning of the 21st century. Aging leads to multimorbidity and complex therapeutic regimens that create a fertile ground for nonadherence. As this scenario is a global problem, it needs a worldwide answer. Could this answer be provided, given the new opportunities created by the digitization of health care? Daily, health-related information is being collected in electronic health records, pharmacy dispensing databases, health insurance systems, and national health system records. These big data repositories offer a unique chance to study adherence both retrospectively and prospectively at the population level, as well as its related factors. In order to make full use of this opportunity, there is a need to develop standardized measures of adherence, which can be applied globally to big data and will inform scientific research, clinical practice, and public health. These standardized measures may also enable a better understanding of the relationship between adherence and clinical outcomes, and allow for fair benchmarking of the effectiveness and cost-effectiveness of adherence-targeting interventions. Unfortunately, despite this obvious need, such standards are still lacking. Therefore, the aim of this paper is to call for a consensus on global standards for measuring adherence with big data. More specifically, sound standards of formatting and analyzing big data are needed in order to assess, uniformly present, and compare patterns of medication adherence across studies. Wide use of these standards may improve adherence and make health care systems more effective and sustainable., PK received speaker honoraria from Aflofarm, Fresenius, Polpharma, and Sandoz and received grant funding from European Union’s Horizon 2020 for GATEKEEPER project (grant agreement number 857223) and The European Commission ERASMUS+ Project Skills4Adherence (grant agreement number: 2017-1-PL01-KA202-038672), outside of this work. BV is the CEO and shareholder of AARDEX Group.

Elizabeth Whalley Buono,1 Bernard Vrijens,2 Hayden B Bosworth,3 Larry Z Liu,4 Leah L Zullig,5,6 Bradi B Granger7,8 1VP, Global Quality, External and Regulatory Affairs, MWV Healthcare, Richmond, VA, USA; 2WestRock Healthcare, Visé, Belgium; 3Division of General Internal Medicine, Department of Medicine, Duke University School of Medicine, Durham, NC, 4Center for Observational and Real World Evidence, Merck, Rahway, NJ and Weill Medical College of Cornell University, New York, NY, 5Division of General Internal Medicine, Duke University School of Medicine, 6Center for Health Services Research in Primary Care, Durham Veterans Affairs Health Care System, 7Duke University School of Nursing, 8Heart Center Nursing Research Program, Duke University Health System, Durham, NC, USA Abstract: 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. Keywords: adherence measures, medication adherence, study design, patient-reported outcomes, research methods

Gasparik, Andrea Ildiko/0000-0002-1848-2410; Gasparik, Andrea Ildiko/0000-0002-1848-2410; Cooper, Cyrus/0000-0003-3510-0709; Vrijens, Bernard/0000-0002-9090-1253; Abrahamsen, Bo/0000-0002-2730-6080; Dennison, Elaine/0000-0002-3048-4961 WOS:000501843100001 PubMed ID: 31388696 A Summary Many patients at increased risk of fractures do not take their medication appropriately, resulting in a substantial decrease in the benefits of drug therapy. Improving medication adherence is urgently needed but remains laborious, given the numerous and multidimensional reasons for non-adherence, suggesting the need for measurement-guided, multifactorial and individualized solutions. Introduction Poor adherence to medications is a major challenge in the treatment of osteoporosis. This paper aimed to provide an overview of the consequences, determinants and potential solutions to poor adherence and persistence to osteoporosis medication. Methods A working group was organized by the European Society on Clinical and Economic Aspects of Osteoporosis, Osteoarthritis and Musculoskeletal diseases (ESCEO) to review consequences, determinants and potential solutions to adherence and to make recommendations for practice and further research. A systematic literature review and a face-to-face experts meeting were undertaken. Results Medication non-adherence is associated with increased risk of fractures, leading to a substantial decrease in the clinical and economic benefits of drug therapy. Reasons for non-adherence are numerous and multidimensional for each patient, depending on the interplay of multiple factors, suggesting the need for multifactorial and individualized solutions. Few interventions have been shown to improve adherence or persistence to osteoporosis treatment. Promising actions include patient education with counselling, adherence monitoring with feedback and dose simplification including flexible dosing regimen. Recommendations for practice and further research were also provided. To adequately manage adherence, it is important to (1) understand the problem (initiation, implementation and/or persistence), (2) to measure adherence and (3) to identify the reason of non-adherence and fix it. Conclusion These recommendations are intended for clinicians to manage adherence of their patients and to researchers and policy makers to design, facilitate and appropriately use adherence interventions. European Society for Clinical and Economic Aspects of Osteoporosis, Osteoarthritis and Musculoskeletal Diseases (ESCEO) The meeting was funded by the European Society for Clinical and Economic Aspects of Osteoporosis, Osteoarthritis and Musculoskeletal Diseases (ESCEO).

Hippocrates complained that patients do not follow instructions and blame ensuing problems on the doctor. Adherence to prescribed drug regimens matters little for drugs with little medicinal power, but the more powerful the drug, the more important become both good adherence and rational prescribing. With over 700 factors associated to non-adherence, the most effective solutions to manage patient adherence rely on sound measures. With the emergence of digital health, accurate, easily understood and personally relevant feedback on medication adherence becomes available to the patient and its care team, enabling a multidisciplinary approach.

Medication adherence in drug trials is suboptimal, affecting the quality of these studies and adding significant costs. Nonadherence in this setting can lead to null findings, unduly large sample sizes and the need for dose modification after a drug has been approved. Despite these drawbacks, adherence behaviours are not consistently measured, analysed or reported appropriately in trial settings. The ESPACOMP Medication Adherence Reporting Guideline (EMERGE) offers a solution by facilitating a sound protocol design that takes this crucial factor into account. This article summarises key evidence on traditional and newer measurements of adherence, discusses implementation in clinical trial settings and makes recommendations about the analysis and interpretation of adherence data. Given the potential benefits of this approach, the authors call on regulators and the pharmaceutical industry to endorse the EMERGE guideline.

Aims The biological response to clopidogrel is highly variable and a poor responsiveness is associated with major adverse cardiac events. Adherence to therapy is a major cause of poor responsiveness but its impact on long-term platelet inhibition is unknown. The objective of the present study was to evaluate the effect of different programmes monitoring adherence to clopidogrel on platelet reactivity. Methods The study took the form of a monocentric, parallel group, randomized controlled trial. Adults treated with clopidogrel 75 mg after elective coronary stenting were randomized into one of three groups: (i) a standard of care group; (ii) a standard of care + adherence electronic monitoring group, in which drug intake was recorded but kept blinded until the study end; or (iii) an integrated care group, with regular feedback on recorded adherence. Clopidogrel response was assessed with the vasodilator-stimulated phosphoprotein–platelet reactivity index (VASP-PRI) at randomization, 3 months and 6 months. Results A total of 123 adults were enrolled and randomized. Baseline VASP-PRI was highly variable, with a mean of 48 ± 18.8%. No difference between groups in VASP-PRI was found at 6 months (P = 0.761), despite better adherence to clopidogrel in the integrated care group. However, adherence (P = 0.035) and baseline VASP-PRI (P = 0.015) were associated with VASP-PRI at 3 months and 6 months. The association between adherence and VASP-PRI was lost in patients with baseline VASP-PRI > 50%. Diabetes, CYP2C19*2 carrier status and body mass index were significant predictors of VASP-PRI. Conclusions The platelet response to clopidogrel during chronic therapy remained highly variable, despite high adherence. Different adherence monitoring programmes did not affect VASP-PRI at 6 months. Poor adherence is associated with lower VASP-PRI only in initial good responders to clopidogrel.

Different methods are available for measuring medication adherence. In this paper, we conducted a scoping review to identify and summarize evidence of all studies comparing the Medication Event Monitoring System (MEMS) with alternative methods for measuring medication adherence. A literature search was performed using the open database www.iAdherence.org that includes all original studies reporting findings from the MEMS. Papers comparing methods for measuring adherence to solid oral formulations were included. Data was extracted using a standardized extraction table. A total of 117 articles fulfilled the inclusion criteria, including 251 comparisons. Most frequent comparisons were against self-report (n = 119) and pill count (n = 59). Similar outcome measures were used in 210 comparisons (84%), among which 78 used dichotomous variables (adherent or not) and 132 used continuous measures (adherence expressed as percentage). Furthermore, 32% of all comparisons did not estimate adherence over the same coverage period and 44% of all comparisons did not use a statistical method or used a suboptimal one. Only eighty-seven (35%) comparisons had similar coverage periods, similar outcome measures and optimal statistical methods. Compared to MEMS, median adherence was grossly overestimated by 17% using self-report, by 8% using pill count and by 6% using rating. In conclusion, among all comparisons of MEMS versus alternative methods for measuring adherence, only a few used adequate comparisons in terms of outcome measures, coverage periods and statistical method. Researchers should therefore use stronger methodological frameworks when comparing measurement methods and be aware that non-electronic measures could lead to overestimation of medication adherence.

Research on assessing or managing medication adherence applies approaches from observational, interventional, and implementation science that spans many disciplines and demands coherent conceptualization, valid methods, appropriate analyses, and complete and accurate reporting. To ensure such reporting, the European Society for Patient Adherence, COMpliance, and Persistence (ESPACOMP) Medication Adherence Reporting Guideline (EMERGE) recommends standard reporting approaches based on an accepted taxonomy. This guideline is derived from a literature review, a reactive Delphi study with 26 medication adherence experts from many countries and disciplines, and feedback from ESPACOMP members. It is designed to supplement existing guidelines for health research reporting and is structured around 4 minimum reporting criteria and 17 items reflecting best reporting practice. By enhancing and harmonizing research reporting, EMERGE aims to advance research and, ultimately, patient outcomes.

Poor adherence to prescribed dosing regimens is one of the greatest sources of variation in drug response, often leading to underestimates of drug efficacy and side effects, and doses set needlessly high. The use of electronic monitors provides a continuous, compiled in real time, record of patient dosing times, dates, and patterns. Knowing the when of patient dosing activity allows one to accurately gauge drug efficacy and build reliable prognostics and claims. Objective dosing history data supports faster, smarter clinical drug development and avoids wasting time and money in medical practice. Failure to monitor individual dosing patterns means discounting the impact of poor adherence—the factor that is emerging as the single greatest cause of failed drug therapy.

Suboptimal medication adherence is a widespread problem in ambulatory care of chronic diseases, with deviations in either direction from the prescribed dosing regimen. For the non-vitamin K antagonist oral anticoagulants (NOACs), such deviations occur and can lead to bleeding or clotting, as suboptimal adherence involves temporary periods of either overdosing or underdosing. In this expert review, we discuss: (a) the proper definition of adherence in terms of its three elements: initiation, implementation, and discontinuation; (b) how adherence is reliably and accurately measured and (c) successfully enhanced, to achieve and maintain safe and effective levels of NOAC-based anticoagulation. We also discuss the comparative effects of prescribing the same total daily dose, given either once-daily or as half-strength twice-daily doses. Because NOACs have plasma half-lives of ∼12 h, the twice-daily dosing regimen is less prone than the once-daily dosing regimen to hazardously high peaks or hazardously low troughs in anticoagulant concentrations and associated actions. As in other fields of oral drug treatment, the continuity of drug action is greater with twice-daily than with once-daily dosing, despite the fact that a few more doses are skipped with twice-daily than with once-daily dosing. This paradox is explained by the disproportionately greater impact on drug action of skipping a once-daily than a twice-daily dose. Integration of these principles into real-world medication management is the next step in the improvement of oral anticoagulation.

Drugs that provide long durations of action after a last-taken dose are said to be "forgiving," as they allow the patient a degree of latitude in the timing of sequential doses. New research, by Assawasuwannakit et al.,(1) based on exemplary methods, enriches the pharmacometric analysis of forgiveness, which for several decades had been a simply descriptive reminder that the beneficial actions of some drugs can continue for hours or days after the disappearance of detectable drug.

Aims: Dual platelet inhibition using anti-P2Y12 drugs and aspirin is the standard of care in patients after percutaneous coronary interventions (PCI). Prasugrel and ticagrelor have been shown to be more potent than clopidogrel with less high on-treatment platelet reactivity. Whether differences in long-term adherence to these drugs can partly explain different antiplatelet efficacy has not been studied so far. The objective was to compare the long-term P2Y12 receptor inhibition and drug adherence to different anti-P2Y12 drugs, and to assess the impact of adherence on the pharmacodynamic effect. Methods: Monocentric, prospective, observational study. Stable outpatients treated with clopidogrel 75 mg once daily, prasugrel 10 mg once daily or ticagrelor 90 mg twice daily after PCI with stent implantation were included. Drug adherence was recorded during 6 months using electronic monitoring. Platelet responsiveness was assessed with the vasodilator-stimulated phosphoprotein platelet reactivity index (VASP-PRI) at inclusion, 3 and 6 months. Results: 120 patients had VASP-PRI and adherence data available. At 6-months, mean VASP-PRI (±SD) was 17.7 ± 11.0% with ticagrelor, 29.2 ± 15.5% with prasugrel and 47.2 ± 17.6% with clopidogrel (ANOVA, P < 0.0001). Median [IQR] taking adherence was 96 [82-100]% with ticagrelor, 100 [97-101]% with prasugrel and 100 [99-101]% with clopidogrel (p = 0.0001). Median [IQR] correct dosing was 88 [73-95]% with ticagrelor, 97 [92.5-98]% with prasugrel and 98 [96-99]% with clopidogrel (p = 0.0001). Anti-P2Y12 drug (p ≤ 0.001) and diabetes (p = 0.014) emerged as predictors of poor antiplatelet response after adjusting for age, BMI, sex, and CYP2C19∗2 carriers status. Conclusion: Drug adherence to anti-P2Y12 drugs assessed with electronic monitoring was very high. However, anti-P2Y12 drugs showed significant differences in antiplatelet activity, with newer anti-P2Y12 drugs ticagrelor and prasugrel exerting a stronger P2Y12 receptor inhibition. These data suggest that pharmacokinetic-pharmacodynamic differences between oral anti-P2Y12 drugs are more important than adherence in determining antiplatelet efficacy when adherence to prescription is high. The study was registered (Current Controlled Trials ISRCTN85949729).

Jaco Voorham,1 Bernard Vrijens,2 Job FM van Boven,3,4 Dermot Ryan,5 Marc Miravitlles,6 Lisa M Law,1 David B Price1,7 1Observational & Pragmatic Research Institute Pte Ltd, Singapore, Singapore; 2Department of Public Health Sciences, Faculty of Medicine, University of Liège, Liège, Belgium; 3Unit of PharmacoEpidemiology and PharmacoEconomics, Department of Pharmacy, 4Department of General Practice, Groningen Research Institute for Asthma and COPD, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands; 5Allergy and Respiratory Research Group, University of Edinburgh, Edinburgh, UK, 6Department of Pulmonology, Hospital Universitari Vall d’Hebron, Barcelona, Catalonia, Spain; 7Academic Primary Care, The Institute of Applied Health Sciences, University of Aberdeen, Aberdeen,UK Background: Adherence to asthma and chronic obstructive pulmonary disease (COPD) treatment has been shown to depend on patient-level factors, such as disease severity, and medication-level factors, such as complexity. However, little is known about the impact of prescription charges – a factor at the health care system level. This study used real-life data to investigate whether co-payment affects adherence (implementation and persistence) and disease outcomes in patients with asthma or COPD. Methods: A matched, historical cohort study was carried out using two UK primary care databases. The exposure was co-payment for prescriptions, which is required for most patients in England but not in Scotland. Two comparison cohorts were formed: one comprising patients registered at general practices in England and the other comprising patients registered in Scotland. Patients aged 20–59years with asthma, or 40–59years with COPD, who were initiated on fluticasone propionate/salmeterol xinafoate, were included, matched to patients in the opposite cohort, and followed up for 1year following fluticasone propionate/salmeterol xinafoate initiation. The primary outcome was good adherence, defined as medication possession ratio ≥80%, and was analyzed using conditional logistic regression. Secondary outcomes included exacerbation rate. Results: There were 1,640 patients in the payment cohort, ie, England (1,378 patients with asthma and 262 patients with COPD) and 619 patients in the no-payment cohort, ie, Scotland (512 patients with asthma and 107 patients with COPD). The proportion of patients with good adherence was 34.3% and 34.9% in the payment and no-payment cohorts, respectively, across both disease groups. In a multivariable model, no difference in odds of good adherence was found between the cohorts (odds ratio, 1.04; 95% confidence interval, 0.85–1.27). There was also no difference in exacerbation rate. Conclusion: There was no difference in adherence between matched patients registered in England and Scotland, suggesting that prescription charges do not have an impact on adherence to treatment. Keywords: implementation, adherence, asthma, chronic obstructive pulmonary disease, prescriptions, co-payment

Despite increased awareness, poor adherence to treatments for chronic diseases remains a global problem. Adherence issues are common in patients taking antihypertensive therapy and associated with increased risks of coronary and cerebrovascular events. Whilst there has been a gradual trend toward improved control of hypertension, the number of patients with blood pressure values above goal has remained constant. This has both personal and economic consequences. Medication adherence is a multifaceted issue and consists of three components: initiation, implementation, and persistence. A combination of methods is recommended to measure adherence, with electronic monitoring and drug measurement being the most accurate. Pill burden, resulting from free combinations of blood pressure lowering treatments, makes the daily routine of medication taking complex, which can be a barrier to optimal adherence. Single-pill fixed-dose combinations simplify the habit of medication taking and improve medication adherence. Re-packing of medication is also being utilized as a method of improving adherence. This paper presents the outcomes of discussions by a European group of experts on the current situation of medication adherence in hypertension.

Medication Event Monitoring System (MEMS®) is considered the gold standard for the evaluation of medication adherence, yet few studies have applied this method, especially over long periods of time.To investigate medication adherence patterns in a sample of post-discharge patients with schizophrenia monitored with MEMS caps during a six-month period.Adherence to antipsychotics was prospectively investigated using MEMS among 68 patients with schizophrenia. Treatment initiation, implementation or whether or not the patient takes his dosing regimen as prescribed, persistence or the length of time between initiation and discontinuation, and treatment discontinuation were used to describe adherence. Persistence over time was described using Kaplan-Meier curves.After discharge 16% of the patients never initiated treatment. On average 37.3% of patients adhered to treatment in the first 6months. However, a strong decrease in adherence was observed over time (p0.0001), primarily due by treatment non-persistence. Only half of the patients were persistent at 6weeks, persistence further dropped to 19.0% after 6months. Among persistent patients, implementation was consistent over time with 87.8% of patients taking their medication as prescribed on any given day.Dosing profile analysis provides further evidence for the magnitude of non-adherence with antipsychotic prescriptions among post-discharge patients with schizophrenia. Using the high precision of MEMS®, dosing profiles may provide a better understanding of non-adherence patterns and help clinicians determine optimal individualized strategies.

Contains fulltext : 169861.pdf (Publisher’s version ) (Closed access) Adequate adherence to prescribed treatment regimens can help to break the cycle of treatment failure, disease progression and subsequent treatment escalation. Unfortunately, adherence in the treatment of skin disorders such as acne, atopic dermatitis/eczema and psoriasis is often inadequate. A review of the literature identified a number of studies that tested an intervention to improve adherence in dermatology, including the following: electronic messages and/or reminders+ADs- more frequent or 'extra' clinic visits+ADs- audio-visual and internet-based interventions+ADs- and patient support programmes and/or self-management, educational training programmes. While there is no one solution or action for improving adherence, some interventions were more successful than others. We provide practical guidance on how to support adherence based on aspects of the successful interventions identified and on our collective opinion and clinical practice experience. Holding patients accountable, providing a caring and supportive environment, raising awareness of poor adherence and helping patients build a solid medication-taking habit can help to improve adherence so that patients can experience maximal treatment benefits and desired clinical outcomes.

Aim Twice daily dosing is often perceived as inferior to once daily dosing due to a higher likelihood of missing a dose. However, more important is the extent to which drug action is maintained when doses are delayed or missed. We compared the estimated inhibition of platelet aggregation (eIPA) for ticagrelor twice daily and clopidogrel once daily, based on their pharmacokinetic/pharmacodynamic relationships and patient dosing history data. Methods Drug dosing histories of 5014 patients prescribed cardiovascular medications (primarily antihypertensive medicines) were extracted from an electronically compiled dosing history database. eIPA levels were simulated for 677 twice daily and 677 once daily dosing histories over a 30 day period, based on published onset/offset models for ticagrelor and clopidogrel IPA characteristics. Results While many patients treated twice daily missed at least one dose in 30 days, only 25.7% missed two consecutive doses. By comparison, 46.8% of patients treated once daily missed at least one dose. Simulations based on patient adherence over time showed that the average mean eIPA for ticagrelor twice daily remained significantly higher than for clopidogrel once daily (81.1% vs. 55.0%, P < 0.001). Ticagrelor twice daily patients had an eIPA below 10% for 0.20% of the 30 day period compared with 2.05% for clopidogrel once daily (P = 0.0001). Conclusions The projected level of platelet inhibition remained higher for ticagrelor twice daily than clopidogrel once daily, mainly due to the higher eIPA level achieved with ticagrelor and the relatively low likelihood of missing two consecutive twice daily doses. This modelling and simulation study suggests a therapeutic benefit of ticagrelor over clopidogrel when taking into account the most common dosing omissions.

Adherence to rationally prescribed medications is essential for effective pharmacotherapy. However, widely variable adherence to protocol-specified dosing regimens is prevalent among participants in ambulatory drug trials, mostly manifested in the form of underdosing. Drug actions are inherently dose and time dependent, and as a result, variable underdosing diminishes the actions of trial medications by various degrees. The ensuing combination of increased variability and decreased magnitude of trial drug actions reduces statistical power to discern between-group differences in drug actions. Variable underdosing has many adverse consequences, some of which can be mitigated by the combination of reliable measurements of ambulatory patients' adherence to trial and nontrial medications, measurement-guided management of adherence, statistically and pharmacometrically sound analyses, and modifications in trial design. Although nonadherence is prevalent across all therapeutic areas in which the patients are responsible for treatment administration, the significance of the adverse consequences depends on the characteristics of both the disease and the medications.

Background Phosphate control is a crucial treatment goal in end-stage renal disease, but poor patient adherence to phosphate binder therapy remains a challenge. This study aimed to estimate the extent of phosphate binder adherence in hemodialysis patients and to identify potential determinants. Methods Phosphate binder adherence was measured blindly in 135 hemodialysis patients for 2 months using the medication event monitoring system. Patient data, gathered at inclusion through medical records, ad hoc questionnaires and the short form (SF)-36 health survey, included: (1) demographics, (2) perceived side-effects, belief in benefit, self-reported adherence to the therapy, (3) knowledge about phosphate binder therapy, (4) social support, and (5) quality of life (SF-36). Phosphatemia data was collected from charts. Being adherent was defined as missing

Background: Lack of adherence to medication is a trigger of graft rejection in solid-organ transplant (SOT) recipients. Objective: This exploratory study aimed to assess whether a biopsychosocial evaluation using the INTERMED instrument before transplantation could identify SOT recipients at risk of suboptimal post-transplantation adherence to immunosuppressant drugs. We hypothesized that complex patients (INTERMED>20) might have lower medication adherence than noncomplex patients (INTERMED≤20). Methods: Each patient eligible for transplantation at the University Hospital of Lausanne, Switzerland, has to undergo a pre-transplantation psychiatric evaluation. In this context the patient was asked to participate in our study. The INTERMED was completed pre-transplantation, and adherence to immunosuppressive medication was monitored post-transplantation by electronic monitors for 12 months. The main outcome measure was the implementation and persistence to two calcineurin inhibitors, cyclosporine and tacrolimus, according to the dichotomized INTERMED score (>20 or ≤20). Results: Among the 50 SOT recipients who completed the INTERMED, 32 entered the study. The complex (N=11) and noncomplex patients (N=21) were similar in terms of age, sex and transplanted organ. Implementation was 94.2% in noncomplex patients versus 87.8% in complex patients (non-significant p-value). Five patients were lost to follow-up: one was non-persistent, and four refused electronic monitoring. Of the four patients who refused monitoring, two were complex and withdrew early, and two were noncomplex and withdrew later in the study. Conclusion: Patients identified as complex pre-transplant by the INTERMED tended to deviate from their immunosuppressant regimen, but the findings were not statistically significant. Larger studies are needed to evaluate this association further, as well as the appropriateness of using a nonspecific biopsychosocial instrument such as INTERMED in highly morbid patients who have complex social and psychological characteristics.