Effect of long-term adherence to clopidogrel on the VASP-PRI after elective coronary stent implantation: a randomized controlled study.

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.

The Importance of Assessing Drug Exposure and Medication Adherence in Evaluating Investigational Medications: Ensuring Validity and Reliability of Clinical Trial Results.

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.

Treatment Adherence and Adherence Patterns of Tofacitinib and Self-Injectable TNFi Use in People with Rheumatoid Arthritis.

OBJECTIVE: To 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). METHODS: Eligible 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. RESULTS: Of 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. CONCLUSION: We 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.

Cost-effectiveness of a nurse-based intervention (AIMS) to improve adherence among HIV-infected patients: design of a multi-centre randomised controlled trial.

BACKGROUND: Non-adherence to HIV-treatment can have a negative impact on patients treatment success rates, quality of life, infectiousness, and life expectancy. Few adherence interventions have shown positive effects on adherence and/or virologic outcomes. The theory- and evidence-based Adherence Improving self-Management Strategy (AIMS) is an intervention that has been demonstrated to improve adherence and viral suppression rates in a randomised controlled trial. However, evidence of its cost-effectiveness is lacking. Following a recent review suggesting that cost-effectiveness evaluations of adherence interventions for chronic diseases are rare, and that the methodology of such evaluations is poorly described in the literature, this manuscript presents the study protocol for a multi-centre trial evaluating the effectiveness and cost-effectiveness of AIMS among a heterogeneous sample of patients. METHODS/DESIGN: The study uses a multi-centre randomised controlled trial design to compare the AIMS intervention to usual care from a societal perspective. Embedded in this RCT is a trial-based and model-based economic evaluation. A planned number of 230 HIV-infected patients are randomised to receive either AIMS or usual care. The relevant outcomes include changes in adherence, plasma viral load, quality of life, and societal costs. The time horizon for the trial-based economic evaluation is 12-15 months. Costs and effects are extrapolated to a lifetime horizon for the model-based economic evaluation. DISCUSSION: The present multicentre RCT is designed to provide sound methodological evidence regarding the effectiveness and cost-effectiveness of a nurse-based counselling intervention (AIMS) to support treatment adherence among a large and heterogeneous sample of HIV-infected patients in the Netherlands. The objective of the current paper is to describe the trial protocol in sufficient detail to allow full evaluation of the quality of the study design. It is anticipated that, if proven cost-effective, AIMS can contribute to improved evidence-based counselling guidelines for HIV-nurses and other health care professionals. TRIAL REGISTRATION: The study has been registered on clinicaltrials.gov (Identifier: NCT01429142).

Innovative ICT solutions to improve treatment outcomes for depression: the ICT4Depression project.

Depression is expected to be the disorder with the highest disease burden in high-income countries by the year 2030. ICT4Depression (ICT4D) is a European FP7 project, which aims to contribute to the alleviation of this burden by making use of depression treatment and ICT innovations. In this project we developed an ICT-based system for use in primary care that aims to improve access as well as actual care delivery for depressed adults. Innovative technologies within the ICT4D system include 1) flexible self-help treatments for depression, 2) automatic assessment of the patient using mobile phone and web-based communication 3) wearable biomedical sensor devices for monitoring activities and electrophysiological indicators, 4) computational methods for reasoning about the state of a patient and the risk of relapse (reasoning engine) and 5) a flexible system architecture for monitoring and supporting people using continuous observations and feedback via mobile phone and the web. The general objective of the ICT4D project is to test the feasibility and acceptability of the ICT4D system within a pilot study in the Netherlands and in Sweden during 2012 and 2013.

Uptake, retention, and outcomes in a demonstration project of pre-exposure prophylaxis among female sex workers in public health centers in Senegal.

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.

Linear and loglinear structural mean models to evaluate the benefits of an on-demand dosing regimen.

BACKGROUND: Structural mean models can be used to estimate treatment efficacy when drug exposure varies. We applied structural mean model to evaluate the clinical benefits of a proton pump inhibitor prescribed to be taken as needed to alleviate epigastric pain. We also investigated a new diagnostic approach to evaluate model assumptions. METHODS: All patients were suffering from nonerosive reflux disease or functional ulcer-like dyspepsia and were prescribed a proton pump inhibitor to be taken as needed for relief of epigastric pain. The primary endpoint was a score variable that expresses the magnitude of gastro-intestinal symptoms at 8 weeks after randomization. We developed linear and loglinear versions of the structural mean models to derive an unbiased estimator of the reduction in symptom score as a function of exposure to the test drug. Semi-parametric models based on splines and corresponding simultaneous confidence bands identified the presence of potential interactions between drug exposure and baseline covariates. RESULTS: The on-demand dosing regimen generated a wide range of drug exposure. Application of SMM showed that the potential treatment-induced reduction in symptom score was much greater than the average treatment reduction observed in this population of patients. Our diagnostic tool was useful for detecting the interaction between drug exposure and baseline covariates. LIMITATIONS: Analysis could only be performed over the first 2 months after randomization because, afterwards, many patients dropped out from the placebo group. CONCLUSIONS: The structural mean model approach allows one to estimate treatment efficacy in the presence of variable drug exposure. Similar results were obtained using linear and loglinear structural mean model.

Real-World Adherence to Oral Methotrexate Measured Electronically in Patients With Established Rheumatoid Arthritis.

OBJECTIVE: To assess methotrexate (MTX) adherence using the Medication Event Monitoring System (MEMS) and characterize associations with adherence in patients with rheumatoid arthritis (RA). METHODS: Eligible 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. RESULTS: Overall, 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). CONCLUSION: Even 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.

"White coat compliance" limits the reliability of therapeutic drug monitoring in HIV-1-infected patients.

PURPOSE: To analyze the extent of improved adherence preceding a clinic visit ("white coat compliance") in a clinical trial and its potential impact on the utility of therapeutic drug monitoring (TDM). METHOD: In this randomized, open-label trial, 190 antiretroviral-naïve, HIV-1-infected subjects received lopinavir/ritonavir capsules, once or twice daily, with tenofovir DF and emtricitabine (both once daily) for 96 weeks. Lopinavir/ritonavir compliance was assessed using MEMS. RESULTS: 178 subjects (107 once daily, 71 twice daily) had plasma samples collected for lopinavir concentration resulting in 768 visits with pharmacokinetic (PK) assessment. The results were not used to provide feedback or recommend dose changes. For 239 (31%) of these visits, drug intake was perfect 1-3 days before PK sampling, whereas compliance during the remainder of the inter-PK visit period was < or = 95%. This phenomenon was noted in 66% of subjects, more frequently among twice-daily than once-daily subjects (85% vs. 54%; p < .0001), and may have led to determination of "therapeutic" drug levels despite overall adherence < or = 95%. The opposite phenomenon (>95% compliance reported during the inter-PK visit period, yet a dose missed the day before PK sampling) was observed for 1% of PK visits and clustered in 5% of subjects. CONCLUSIONS: In a substantial portion of visits and a majority of subjects, a white coat compliance pattern was observed. Drug concentration results obtained at these visits could deliver unreliable estimates of long-term drug exposure.

Effect of Adherence-enhancing Interventions on Adherence to Tyrosine Kinase Inhibitor Treatment in Chronic Myeloid Leukemia (TAKE-IT): A Quasi-experimental Pre-Post Intervention Multicenter Pilot Study.

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.

Identifying Tyrosine Kinase Inhibitor Nonadherence in Chronic Myeloid Leukemia: Subanalysis of TAKE-IT Pilot Study.

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 theory-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.

Comparative Long-Term Effect of Three Anti-P2Y12 Drugs after Percutaneous Angioplasty: An Observational Study Based on Electronic Drug Adherence Monitoring.

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).

Management of patients with uncontrolled arterial hypertension--the role of electronic compliance monitoring, 24-h ambulatory blood pressure monitoring and Candesartan/HCTZ.

BACKGROUND: Incomplete drug regimen compliance (DRC) and white-coat hypertension are two of several possible causes of uncontrolled hypertension. Therefore the aim of the present study was to compare DRC in hypertensives treated with combination therapy whose blood pressures (BP) were controlled vers. uncontrolled after 4 weeks of self-monitored BP measurement. To observe the consequences in uncontrolled patients of switching one drug of the combination therapy to candesartan/HCTZ (16 mg/12.5 mg) with and without a compliance intervention program. METHODS: Self-and ambulatory-monitoring of BP were done with upper arm oscillometric devices. Patients' dosing histories were compiled electronically (MEMS, AARDEX). Patients with office blood pressure (OBP) >140/90 mmHg despite combination therapy were begun on MEMS monitoring and self BP measurement for 4 weeks of run-in. Of 62 such patients, 18 (29%) patients were normotensive according to self BP measurement and ambulatory BP measurement at 4 weeks (Group A); in the remaining 44 still uncontrolled patients, candesartan/HCTZ was substituted for one of the combination therapy drugs, with half these patients receiving passive compliance monitoring (B) and half a DRC intervention program (C). All groups were then followed for 8 weeks. RESULTS: DRC before week 4 was significantly higher in A than in the uncontrolled patients (B&C). DRC was stable during run-in A, but declined in B and C. DRC after week 4 was not different in the three groups and stayed constant over time. DRC during weekends was lower than during weekdays in all groups. In group A no significant change in blood pressure was observed with all three methods of BP measurements. In groups B and C significant reductions of systolic and diastolic BP were observed for ABPM and SBPM. After the change to candesartan/HCTZ in B&C ambulatory 24-h-BP (ABPM) was normalized in 39% of patients. CONCLUSION: Normalization of BP was associated with superior drug regimen compliance in previously uncontrolled patients treated with a combination drug regimen. Switching still-uncontrolled patients to candesartan/HCTZ significantly improved BP control and stabilized a declining DRC.

Successful projection of the time course of drug concentration in plasma during a 1-year period from electronically compiled dosing-time data used as input to individually parameterized pharmacokinetic models.

Pharmacokinetic studies rely on blood sampling at times relative to predefined dosing intervals. Intensive sampling is often done under direct observation of dose taking, which, though costly, virtually eliminates uncertainty about actual dosing times. In contrast, the sparse sampling done in population pharmacokinetic studies relies on patient-reported times of dosing, the accuracy of which the authors sought to assess by adding electronic monitoring to the usual patient reporting of dosing times. The study involved 35 antiretroviral-naive, human immunodeficency virus-infected patients and was designed to assess the safety, tolerability, pharmacokinetics, and antiviral activity of prescribed lopinavir/ritonavir (800/200 mg qd or 400/100 mg bid), stavudine, and lamivudine. The present research reports the pharmacokinetic analysis that results from taking into account the patients' actual dosing histories. Intensive sampling for plasma lopinavir concentrations was done at week 3, and 4 additional predose (trough) concentrations were measured during the next 12 months. Convergence was achieved by fitting a simple 1-compartment pharmacokinetic model, with first-order absorption and elimination, to the sparse sampling data, using electronic monitoring-reported times. In contrast, convergence was not achieved using the simple model when steady state was assumed, and the times for the last qd dose or the last 2 bid doses, as reported by the patient, were used as model input. Estimated individual pharmacokinetic parameters were then combined with electronic dosing histories to project each patient's internal drug exposure over long periods of time. This strategy may provide a basis for greatly increasing the informational yield and utility of conventional therapeutic drug monitoring.

Clinical benefits of an adherence monitoring program in the management of secondary hyperparathyroidism with cinacalcet: results of a prospective randomized controlled study.

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 (P = 0.04). The mean cinacalcet taking adherence improved by 10.8% in the IC group and declined by 5.3% in the UC group (P = 0.02). 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 (P = 0.03). 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.

Impact of supportive measures on drug adherence in patients with essential hypertension treated with valsartan: the randomized, open-label, parallel group study VALIDATE.

OBJECTIVE: The majority of treated hypertensive patients do not achieve target blood pressure (BP) levels of less than 140/90 mmHg. One key reason is inadequate adherence with the prescribed drug regimen. Dosing regimens are either not executed as prescribed (noncompliance) or patients stop taking the medication (nonpersistence). It has been demonstrated that adherence with angiotensin receptor antagonists such as valsartan is high due to the tolerability profile of this drug class. The present study was designed to evaluate whether drug adherence could further be improved by the use of supportive measures. DESIGN AND METHODS: Twenty-eight centers were randomized to provide pharmacological treatment with or without a set of supportive measures (e.g. structured physician-patient interaction, printed information about hypertension, reminder stickers, 24 h timer, and home BP measurement device). Two hundred and two patients with grade 1 hypertension (BP at baseline 149.8 +/- 6.2/93.9 +/- 4.4 mmHg) who were either newly diagnosed or who had not been treated for at least 1 year were included in this trial. All patients entered the 34-week treatment phase with valsartan 160 mg daily. Titration to valsartan 160 mg/hydrochlorothiazide 12.5 mg was allowed if necessary. Drug adherence was assessed by electronic monitors (Medication Event Monitoring System). RESULTS: Patients treated with a valsartan-based therapy receiving supportive measures as compared with the standard care group demonstrated an initially higher level of adherence with a maximum absolute difference of 7.8% (P = 0.041). This difference did not persist over the observation period but faded with time. In parallel, execution of the dosing regimen (compliance) was also improved in the intervention group during the early months of treatment but this effect also disappeared by the end of the observation period. In contrast, persistence in the two groups slowly but continuously separated over time. Estimated absolute difference in persistence at the end of the 34-weeks study between the two groups was 7.6% (95.9 vs. 88.3%) reflecting a 66% lower hazard of discontinuation in the intervention group (P = 0.073). BP control improved more in patients with the supportive measures. CONCLUSION: Drug adherence improved initially with the use of supportive measures. However, this effect faded with time mainly because of the short-lived improvement in the quality of execution (compliance) achieved. In contrast, a longer lasting effect of the chosen supportive measures on persistence could be demonstrated, which, however, at least under the conditions of the present study, did not translate into a persistent improvement of medication adherence.

Estimation of the comparative therapeutic superiority of QD and BID dosing regimens, based on integrated analysis of dosing history data and pharmacokinetics.

Once-daily dosing almost invariably shows a slightly higher percentage of prescribed doses taken than does twice-daily dosing. Many pharmaceutical scientists, regulators, and prescribers have considered this finding to signify the therapeutic superiority of once-daily dosing. The therapeutically more relevant question, however, is not the percentage of prescribed doses taken but the comparative impact of missed doses on the pharmacologic effects of a drug under the two dosing regimens. A key point in this regard is that the pharmacokinetic equivalent of a single missed once-daily dose is 2-3 sequentially omitted twice-daily doses. Thus, an important parameter in comparing the two regimens is the probability of two or three twice-daily doses being sequentially omitted, versus the probability of missing a single once-daily dose. Our data indicate that the probability of sequential omission of 2-3 twice daily doses is half the probability of omission of a single once-daily dose. For that reason, a twice-daily regimen could prove to be superior to a once-daily regimen in maintaining drug concentrations within a therapeutically desirable range. A more important consideration, however, is to maintain not just the concentration of drug in plasma, but the drug's therapeutic action. The duration of therapeutic drug action following a last-taken dose is not only drug-specific, but also, for some drug, dependent on the pharmacodynamic properties. Judging the comparative superiority of one dosing regimen over another requires knowledge of the drug's duration action after a last-taken dose, plus knowledge of the comparative probabilities of the various patterns of dose omission. When applied to HIV protease inhibitors, a twice-daily regimen appears to be better than an once-daily regimen in maintaining therapeutically effective drug actions.

Decreased adherence to antiretroviral therapy observed prior to transient human immunodeficiency virus type 1 viremia.

BACKGROUND: To identify potential causes and clinical implications of transient increases in plasma viral load (hereafter, "blips"). METHODS: M99-056 and M02-418 were prospective, randomized trials evaluating the safety and efficacy of lopinavir/ritonavir (LPV/r) capsules administered twice per day or once per day to subjects infected with human immunodeficiency virus-1 (HIV-1). Plasma viral load was measured every 4 weeks (from baseline through week 24, excluding week 12 and week 20 in M02-418), every 8 weeks (from week 24 through week 48), and every 12 weeks (from week 48 through week 96). Blips were defined by 1 plasma viral load measurement of between 50-1000 copies/mL, immediately preceded and immediately followed by a measurement of <50 copies/mL. A medication event monitoring system was used to record the date and time subjects administered a dose of LPV/r. RESULTS: Of 228 subject enrolled, event monitor data were available for 223 (98%) subjects (92 of whom received twice-daily LPV/r therapy, and 131 of whom received once-daily therapy). Viral load blips (median plasma viral load, 82 copies/mL [range, 51-858 copies/mL]) were identified in 60 (27%) of the subjects (21 in the LPV/r twice-daily group and 39 in the LPV/r once-daily group). Neither the baseline plasma viral load nor the CD4(+) T cell count were associated with blips. During the week prior to a blip, the mean number of days that the subject administered the prescribed number of doses was lower than the number during a matched period for the same subject during which a blip did not occur (5.55 vs. 6.22 days; P = .007). Blips were not associated with virologic failure or the development of drug resistance. CONCLUSIONS: Blips were associated with decreased adherence, but not with virologic failure or development of drug resistance in these studies of LPV/r. TRIAL REGISTRATION: Clinicaltrials.gov identifier: NCT00043966 .