e19546 Background: The objective of this work was to evaluate the predictors of adherence to lenalidomide, taken in successive 21-day/7-day on/off cycles. Electronic monitoring was used to track day-by-day adherence to cycles. Methods: This study involved participants diagnosed with multiple myeloma and initiating lenalidomide at 2 hematology centers in Israel. Medication adherence was measured using the Medication Event Monitoring System (MEMS, www.aardexgroup.com). Lenalidomide was stored in bottles closed with an electronic cap, which timestamped each opening. This work focuses on how well a patient implements the dosing regimen, while they are on treatment. Implementation during on cycles was operationalized as a daily variable, equal to 1 if there was exactly 1 intake, to 0 otherwise. 13 predictors were considered and are detailed below. The influence of the predictors was studied longitudinally through one multivariate analysis. The significance level was taken at 0.05/13 = 0.0038, using the Bonferroni correction. Results: 93 subjects were included in the study, and 8 were excluded from the analysis, because they did not use the MEMS Cap as intended. Characteristics of the 85 participants are presented in Table 1. In some categories, percentages do not add up to 100 % because of missing data. Table 1 shows that a low number of pills prescribed per day, low ISS stage and high ECOG status positively influenced implementation. In addition, the quality of implementation did not decrease over time. Conclusions: Electronic monitoring of adherence allows fine-grained quantification of adherence to on/off drug regimens. This study investigated the demographic predictors of implementation adherence to an on/off regimen. A low number of pills per day positively influenced adherence, probably because of healthier patients and less complex regimens. A low ISS stage positively influenced adherence, probably also because of healthier patients. A high ECOG status positively influenced adherence, which was unexpected and could be related to the degree of help received by less functional patients. Clinical trial information: NCT02733224 . Predictor Median (Q1 – Q3) or % per category Coefficient p Time 64 (30 – 102) -0.0047 0.420 Gender Male (68 %)Female (32 %) -0.23 0.537 Age at lenalidomide initiation (years) 68 (60 – 74) -0.044 0.033 Educational level Less than high school (9 %)12 years (41 %)Academic (39 %) 0.30 0.187 Living with partner No (16 %)Yes (79 %) -0.30 0.531 Participation in a myeloma patient support group No (76 %)Yes (20 %) 0.21 0.644 Number of pills per day (for any indication) 5 (4 – 7) -0.53 0.000 ISS stage at diagnosis 1 (16 %)2 (19 %)3 (19 %) -0.99 0.000 Disease duration at initiation (months) 19 (5.75 – 45.7) -0.024 0.051 ECOG performance status scale 0 (45 %)1 (14 %)2 (6 %) 3.1 0.000 Line of myeloma therapy 1 (15 %)2 (66 %)3 (15 %) -0.22 0.749 Route for additional medications Oral (47 %)Subcutaneous (48 %) 0.64 0.233 Hospital Rabin (42 %)Sheba (58 %) 0.88 0.050

Background and Purpose: Adherence to oral anticancer therapy correlates with outcome. Lenalidomide (LEN) is an oral mainstay treatment for multiple myeloma (MM), administered in 21-day/7-day (on/off) cycles. Data on LEN adherence is limited. Electronic monitoring (EM) represents the most reliable adherence assessment method. Experimental Approach: We conducted a prospective observational study using electronic medication event monitoring (MEMS®) in lenalidomide-naïve multiple myeloma patients to quantify adherence during on/off cycles and identify patterns of non-adherence in real-world practice. On and off cycles were determined semi-automatically. Implementation adherence was calculated as the proportion of prescribed drug taken, during each on cycle and across all on cycles. Daily adherence predictors were analyzed using logistic regression with generalized estimating equations. Key Results: Eighty-five patients were included. Median age was 68 years, 66% received LEN as a second-line treatment, 75% of patients perfectly adhered to the recommended 21/7-day on/off cycle. Median implementation adherence was 100%. Only 4% of patients had a proportion of doses taken below 90%. All doses were taken by 51% of patients, while 9% missed ≥4 doses. Among the 13 predictors investigated, only age under 80 and participation in a support group were statistically significant. Conclusions: this novel assessment of LEN adherence in MM patients demonstrated high implementation adherence and cycle duration compliance.

The objective of this current opinion paper is to draw global attention to medication adherence, emphasizing its crucial role in drug trials. Frequently, trialists lean on traditional approaches to assess medication adherence, which, while comfortable, may only reveal what trialists desire rather than offering the essential insights needed for informed decision making in drug development. Understanding drug exposure and medication adherence is paramount when evaluating the effectiveness and safety of investigational medications. Without a comprehensive understanding of how patients adhere to their prescribed treatment regimens, the integrity and dependability of clinical trial results can be compromised. This paper emphasizes the need for measures that accurately and reliably assess medication intake behaviors, enabling the differentiation between minor dosing errors and significant deviations that may impact the drug's efficacy and safety. Accurate knowledge of drug exposure empowers researchers to make informed decisions, identify potential confounding factors, and appropriately interpret study outcomes, ultimately ensuring the validity and reliability of the research findings. By prioritizing drug exposure assessment and medication adherence measurement, clinical trials can enhance their scientific rigor, contribute to more accurate evaluations of investigational medications, and ultimately speed up the development process.

ObjectiveTo assess tofacitinib and self‐injectable tumor necrosis factor inhibitor (TNFi) adherence using the Medication Event Monitoring System (MEMS) and characterize association with adherence in patients with rheumatoid arthritis (RA).MethodsEligible patients were enrolled from the Forward Databank within 6 months of initiating tofacitinib or injectable TNFi or from participating clinics where these were first prescribed. MEMS caps and patient diaries were used to compile dosing over 9 months. Demographics and disease characteristics were collected every 6 months, and the Beliefs about Medicines Questionnaire only at baseline. Adherence along with its components, initiation, implementation, and persistence, were calculated.ResultsOf the 112 consented to participate, 82 (73%) remained in the final analysis with recruitment from clinics 47 (57%) and Forward 35 (43%). Sixty‐two (76%) initiated tofacitinib with 87% taking it quaque die and twenty (24%) TNFi. At 9 months, 77% of tofacitinib were persistent versus 70% for TNFi (P = 0.65), and implementation was similar (0.84 vs. 0.82; P = 0.57). In multivariable models, increased baseline patient global assessment was consistently associated with discontinuation (hazard ratio 1.31 [1.07‐1.61]). There was increased adherence to methotrexate (MTX) when taking tofacitinib that led to higher combined adherence for tofacitinib than TNFi (0.81 vs. 0.69; P = 0.03), but no significant differences remained in multivariable models. In sensitivity analysis, consistent morning intake for tofacitinib and evening intake for MTX was associated with improved adherence.ConclusionWe found no statistical differences in adherence between patients with RA initiating tofacitinib and self‐injectable TNFi, although 15% to 30% were nonadherent. Concomitant MTX, patient global assessment, and a consistent time of day intake were associated with adherence.

Background: Lenalidomide (LEN) is an oral mainstay of modern multiple myeloma (MM) treatment (given in 21day/7day (ON/OFF) cycles usually for 3-6 cycles). Non-adherence to oral anticancer therapy occurs in ~30% of cancer patients and is generally associated with adverse outcomes. Adherence to LEN in MM entails both adherence to duration of ON/OFF cycles as well as implementation adherence (defined as deviations from the dosing schedule while taking the drug (e.g., dosing/timing issues)). Data on adherence in MM is limited to retrospective pharmacy refill records showing 14.5% LEN implementation non-adherence (i.e., medication possession ratio <80%). There is no data on adherence to duration of LEN ON/OFF cycles. Electronic monitoring (EM) is the most reliable adherence measure to date, allowing assessment of both daily implementation adherence and duration of ON/OFF cycles Aims: (1) To assess adherence to duration of LEN ON/OFF cycles; (2) To assess EM implementation adherence to LEN during ON cycles. Methods: Using a prospective observational design including a convenience sample of LEN-naïve adult patients receiving LEN-based regimens for once-daily treatment of MM at 2 hematology centers in Israel (5/2016-11/2019). Adherence to ON/OFF cycle duration and implementation adherence was monitored using EM (MEMS®, AARDEX) for a maximum of 4 consecutive ON/OFF cycles. The MEMS® registers the date and time of each bottle opening as a proxy for LEN intake. Patients gave informed consent and were told about the EM adherence assessment. An ON cycle started with the first LEN dose after ≥ 5 days without intake and ended with the last dose prior ≥5 days without intake. OFF cycles were defined as periods between two ON cycles. The duration of ON/OFF cycles was expressed in days (median / IQR) and the proportion of patients adhering to ON/OFF cycles was calculated. Implementation adherence during ON cycles was calculated twofold: (1) the proportion of days with any LEN intakes during ON cycles; (2) the proportion of prescribed drug taken was calculated (N-intakes/N-monitored-days). The number of patients with a proportion of days with intakes below 90% was calculated, since this cutoff was clinically relevant in a prior study of chronic myeloid leukemia patients. Descriptive statistics were calculated as appropriate. Results: 85 of 93 patients enrolled were included in this analysis. Eight were excluded due to the inability to initiate use of the EM device and no patients were lost to follow-up. Sample characteristics are: 27 (32%) females; median age 68 years [IQR 60-74]; no. of pills/day, 5 [IQR 4-7]; prior disease duration, 19 months [IQR 5.75 - 45.7]; regimen: LEN-dexamethasone with (n=43, 51%) or without (n=38, 44%) additional drugs (5% missing); treatment line: 1st = 15%, 2nd = 66%, 3rd = 15% (4% missing). The median duration of follow-up was 133 days [IQR 77-152] and no. of cycles was 3 [IQR 1-4]. The median duration of ON/OFF cycles was 21 [21-21] and 7 [7-7] days, respectively (Figure 1). Adherence to ON/OFF cycle (21/7) duration was 75% (64/83). ON cycles shorter than 21 days were associated with a number of doses taken approximately equal to the duration of the cycle (e.g., duration = 20 days, median doses = 19). On the other hand, cycles longer than 21 days approximately corresponded to 21 doses taken, meaning that patients prolonged the ON cycle to make up for missed doses. Median LEN implementation adherence was 99% [IQR: 97%-100%; range: 50%-100%]. Figure 2 shows the proportion of doses taken for each ON segment. All doses were taken by 43 patients (51%). One missed dose occurred in 18 (21%) subjects, two in 9 (11%), three in 7 (8%), and 8 (9%) had ≥4 missed doses, at any stage. Two or more consecutive doses were missed once in 8 patients (9%) and twice in 2 (2%). The proportion of days with intakes was below 90% in 4 patients (5%). Conclusions: This study is the first to assess both adherence to LEN cycle duration and implementation adherence in patients with MM, using EM. 75% of patients fully adhered to the recommended 21-days-ON / 7-days-OFF cycles. LEN implementation adherence was high. Given that non-adherent patients are typically less willing to participate in EM a selection bias can not be excluded. While this data is somewhat reassuring, further research should determine which degree of deviation from the dosing schedule leads to adverse clinical outcomes. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

The Senegal pre-exposure prophylaxis (PrEP) Demonstration Project was an open-label cohort study assessing the delivery of daily oral PrEP to HIV-negative female sex workers (FSWs) in four Ministry of Health (MoH)-run clinics in Dakar, Senegal. We assessed uptake, retention in care, and adherence over up to 12 months of follow-up as well as HIV infection rates. Between July and November 2015, 350 individuals were approached and 324 (92.6%) were preliminarily eligible. Uptake was high, with 82.4% of eligible participants choosing to enroll and take PrEP. The mean age of those enrolled was 37.7 years (SD = 8.7), and approximately half had not attended school (41.2%). Among the 267 participants who were prescribed PrEP, 79.9 and 73.4% were retained in PrEP care at 6 and 12 months, respectively. Older age among FSWs was found to be the only significant predictor of lower discontinuation. We did not find significant differences in retention by site, education, condom use, or HIV risk perception. There were no new HIV infections at follow-up. Our results showed evidence of high interest in PrEP and very good PrEP retention rates among FSWs at 12-month follow-up when offered in MoH-run clinics, with older age as the only significant predictor of higher PrEP retention. This highlights the role that these clinics can play in expanding PrEP access nationwide.

ObjectiveTo assess methotrexate (MTX) adherence using the Medication Event Monitoring System (MEMS) and characterize associations with adherence in patients with rheumatoid arthritis (RA).MethodsEligible patients participated in Forward, the National Databank for Rheumatic Diseases, and recently (12 months or sooner) initiated oral MTX. MEMS was used to compile MTX weekly dosing over 24 weeks. The Beliefs about Medicines Questionnaire (BMQ) was completed, and baseline demographics and disease characteristics obtained. MTX adherence (percentage of weeks dose taken correctly), implementation (percentage of weeks dose taken correctly from initiation until last dose), and persistence (duration from initiation to last dose) were calculated. Analyses measured associations between patient characteristics and adherence, modeled using logistic generalized estimating equations and censored Poisson regression, and persistence modeled using Cox regression.ResultsOverall, 60 of 119 eligible patients were included in the analysis. MTX adherence, implementation, and persistence were 75%, 80%, and 83%, respectively, at 24 weeks. Demographics and disease characteristics were generally similar between patients with 1 week or less and 2 weeks or more of missed MTX. Unemployment, less disability, higher Patient Global scores, and no prior disease‐modifying antirheumatic drug (DMARD) use were associated with correct dosing. No significant differences in adherence were observed between patients receiving concomitant MTX versus MTX monotherapy, and biologic DMARD‐experienced versus biologic DMARD‐naïve patients. Higher scores in BMQ Specific Necessity (indicating a greater belief in the necessity of the medication) was associated with a decreased likelihood of dosing at an interval shorter than prescribed (odds ratio 0.89).ConclusionEven in a participatory group over a short period, MTX adherence was suboptimal and associated with certain demographics, medication experience, and beliefs about medicines. This suggests a need for screening and alternative treatment opportunities in nonadherent MTX patients with RA.

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.

Identifying nonadherence (NA) in chronic myeloid leukemia (CML) remains a challenge. Tyrosine kinase inhibitor adherence was measured by electronic monitoring and Basel Assessment of Adherence to Immunosuppressive Medications Scale (BAASIS) self-report in 55 CML patients over 4 months. The BAASIS had 67% sensitivity and 71% specificity for diagnosing NA. The BAASIS and the risk factors for NA found in this study provide a basis for identifying nonadherent CML patients. Background: There are inconsistencies in reports on correlates for nonadherence (NA) to tyrosine kinase inhibitors (TKIs) in chronic myeloid leukemia (CML). The diagnostic accuracy of subjective adherence measures using electronic monitoring (EM) as the reference standard is yet to be determined. This study aimed to evaluate correlates of TKI NA using EM and test the diagnostic accuracy of subjective adherence measures. Patients and Methods: CML patients receiving a TKI for any duration were enrolled at 4 hematology institutes, and adherence was measured for 4 months. EM adherence was the reference adherence measure, expressed as the percentage of days with the drug taken as prescribed. Subjective adherence was measured using the Basel Assessment of Adherence to Immunosuppressive Medications Scale (BAASIS) self-report and clinician-reported visual analog scale (VAS) at 2 time points. Baseline t heory-derived correlates of NA were identified using single and multiple regression analysis. The diagnostic accuracy of BAASIS and clinician-reported VAS was tested against an exploratory EM NA cutoff of < 95%. Results: The median EM adherence (n = 55) was 97.5% (range, 48-100%), while the 25th percentile was 92.1%. Lack of membership in a CML patient support group, living alone, and third-line treatment were associated with EM NA on multiple regression analysis. The BAASIS self-report (n = 94) had a sensitivity of 67% and a specificity of 71% for diagnosing NA, while clinician-reported VAS (n = 89) had a sensitivity of 78% and specificity of 42%. Conclusion: A quarter of patients had potentially clinically meaningful NA. These NA correlates and the BAASIS provide a basis for identifying nonadherent patients who can be targeted by interventions.

BACKGROUND:Nonadherence to tyrosine kinase inhibitors (TKIs) in chronic myeloid leukemia (CML) has been associated with inferior outcomes. Scarce evidence exists on the effectiveness of adherence-enhancing interventions. The present pilot study evaluated the feasibility and effectiveness of an intervention to improve TKI adherence in adult CML patients. PATIENTS AND METHODS:Using a quasi-experimental pre-post intervention design, we included a convenience sample of 58 CML patients (median age, 60.5 years; interquartile range, 19) receiving TKI treatment in 4 hematology institutes in Israel (median previous treatment duration, 34 months; interquartile range, 60). Of the 58 patients, 36 (62%) were receiving first-line treatment. TKI adherence was assessed using electronic monitoring for 7 months (4 months for the baseline assessment and for 3 months after the intervention) and defined as the percentage of days with dosing taken as prescribed. The multilevel intervention combined training of health care workers and multiple behavioral change techniques (eg, motivational interviewing, feedback on electronic monitoring printouts, behavioral change techniques tailored to reasons for nonadherence). The baseline and postintervention adherence were compared using generalized estimating equation models. RESULTS:The median baseline electronically monitored adherence (n = 55) was 97.5% (range, 48%-100%). The odds of taking the drug daily as prescribed were 58% greater after intervention (odds ratio, 1.58; 95% confidence interval [CI], 1.16-2.15). Adherence improved by only 1.5% overall (95% CI, 0.1%-2.8%) but by 8.5% (i.e. from 71.2% average adherence before intervention, to 79.6% after; P = .04) in a subgroup of 10 nonadherent patients (baseline adherence < 90%). CONCLUSION:TKI adherence improved with our pilot intervention, mainly in patients with suboptimal baseline adherence.

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).

been through the copyediting, typesetting, pagination and proofreading process which may lead to differences between this version and the Version of Record. Please cite this article as doi: 10.1111/bcp.13071 This article is protected by copyright. All rights reserved. Title page “Effect of long-term adherence to clopidogrel on the VASP-PRI after elective coronary stent implantation: a randomized controlled study” Running head: Long-term drug adherence and clopidogrel responsiveness after elective coronary stenting

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.

Medication non-adherence (MNA) to tyrosine kinase inhibitors (TKIs) occurs in around 30% of chronic myeloid leukemia (CML) patients and is associated with adverse outcomes. There are no proven strategies for identifying patients at risk for non-adherence in CML, while data on electronically measured adherence are rare.

Introduction: Medication non-adherence (MNA) to tyrosine kinase inhibitors TKIs occurs in around 30% of chronic myeloid leukemia (CML) patients and is associated with adverse outcomes (Noens, 2009; Marin, 2010). Data on adherence-enhancing interventions (AEIs) in CML are scarce and an improvement in dose implementation has yet to be shown.

Background/Aims. One of the causes of uncontrolled secondary hyperparathyroidism (sHPT) is patient’s poor drug adherence. We evaluated the clinical benefits of an integrated care approach on the control of sHPT by cinacalcet. Methods. Prospective, randomized, controlled, multicenter, open-label study. Fifty hemodialysis patients on a stable dose of cinacalcet were randomized to an integrated care approach (IC) or usual care approach (UC). In the IC group, cinacalcet adherence was monitored using an electronic system. Results were discussed with the patients in motivational interviews, and drug prescription adapted accordingly. In the UC group, drug adherence was monitored, but results were not available. Results. At six months, 84% of patients in the IC group achieved recommended iPTH targets versus 55% in the UC group (). The mean cinacalcet taking adherence improved by 10.8% in the IC group and declined by 5.3% in the UC group (). Concomitantly, the mean dose of cinacalcet was reduced by 7.2 mg/day in the IC group and increased by 6.4 mg/day in the UC group (). Conclusions. The use of a drug adherence monitoring program in the management of sHPT in hemodialysis patients receiving cinacalcet improves drug adherence and iPTH control and allows a reduction in the dose of cinacalcet.