Lessons learned from conducting a randomized controlled trial to improve non-adherence to antihypertensive drug treatment.

PURPOSE: Hypertension significantly contributes to cardiovascular diseases and premature deaths. Effective treatment is crucial to reduce cardiovascular risks, but poor adherence to antihypertensive drugs is a major issue. Numerous studies attempted to investigate interventions for identifying non-adherence, but often failed to address the issue effectively. The RHYME-RCT trial sought to bridge this gap by measuring non-adherence by determining antihypertensive drug concentrations in blood through a dried blood spot (DBS) method in patients with resistant hypertension. This measurement was followed by personalized feedback to improve adherence. During the course of this trial several challenges emerged, including selection bias, the gatekeeper role of physicians, the Hawthorne effect and the role of randomization. AIM: This communication aims to inform fellow researchers and clinicians of challenges that can arise when conducting clinical trials to improve adherence and offer insights for refining study designs to avoid these issues in forthcoming adherence studies.

Purpose: High blood pressure is a serious problem that can lead to heart and kidney problems and early deaths. Treating high blood pressure is therefore crucial. Initially, lifestyle changes are recommended, but if they don't work, medications are needed. However, taking these drugs daily can be challenging, and many patients miss doses which is called non-adherence. Despite numerous studies, a perfect solution hasn't been found to solve non-adherence to blood pressure lowering drugs.In the RHYME-RCT study, researchers aimed to improve drug adherence in patients with resistant hypertension. They monitored drug intake by measuring drug concentrations in the blood alongside 24-hour blood pressure monitoring. These data allowed healthcare providers to offer personalized advice to patients. The study encountered some important challenges in its design, including selection bias, where some participants shouldn't have been included or excluded in the study, and the Hawthorne effect, where patients changed their behavior because they knew they were being observed.Aim: This message is to inform fellow scientists and doctors about issues that can arise when conducting clinical trials to improve adherence and to encourage the exchange of ideas between scientists to improve future studies on medication adherence, which is essential for managing conditions like high blood pressure.

Does formative assessment help students to acquire prescribing skills?

PURPOSE: Formative assessments can help motivate students and ease students' learning through feedback. There is a pressing need for improvement of clinical pharmacotherapy (CPT) education since junior doctors make many prescribing errors. The aim of this study was to determine whether a formative assessment with personalized narrative feedback helps medical students to increase their prescribing skills. METHODS: This retrospective cohort study was conducted among masters' medical students at Erasmus Medical Centre, The Netherlands. Students made a formative and a summative skill-based prescription assessment, both during clerkships as part of their regular curriculum. Errors in both assessments were categorized by type and possible consequence and compared with each other. RESULTS: A total of 388 students made 1964 errors in the formative assessment and 1016 in the summative assessment. Most improvements after the formative assessment were seen for mentioning the weight of a child on the prescription (n = 242, 19%). Most new and repeated errors in the summative assessment were missing usage instructions (n = 82, 16% and n = 121, 41%). CONCLUSIONS: This formative assessment with personalized and individual narrative feedback has helped students to increase the technical correctness of their prescriptions. However, errors repeated after the feedback were predominantly errors showing that only one formative assessment has not yet enhanced the clinical prescribing enough.

The effect of combining therapeutic drug monitoring of antihypertensive drugs with personalised feedback on adherence and resistant hypertension: the (RHYME-RCT) trial protocol of a multi-centre randomised controlled trial.

BACKGROUND: Adherence to antihypertensive drugs (AHDs) is important for adequate blood pressure control. Not taking these drugs as prescribed is one of the main underlying causes for resistant hypertension (RH), which in turn leads to an increased risk of cardiovascular events, stroke and kidney damage. Therefore, correct identification of patients that are non-adherent to AHDs is crucial to improve clinical outcome. For this goal, therapeutic drug monitoring is the most reliable method. The primary objective of this trial is to investigate whether monitoring of drug concentrations with a dried blood spot (DBS) sampling method combined with personalised feedback leads to a decrease in prevalence of RH after 12 months due to an increase in adherence. Secondary objectives include the difference over time in the number of required AHDs as well as the defined daily dose (DDD). Lastly, the cost-utility of SoC versus the intervention in RH is determined. METHODS: This is a multi-centre single-blinded randomised controlled trial (RHYME-RCT). First, at an eligibility visit, DBS sampling, to monitor drug concentrations in blood, and a 24-h ambulatory blood pressure measurement (24-h ABPM) are performed simultaneously. Patients with a daytime systolic blood pressure (SBP) > 135 and/or diastolic blood pressure (DBP) > 85 mmHg are randomised to SoC or intervention + SoC. The intervention is performed by the treating physician and includes information on drug concentrations and a comprehensive personalised feedback conversation with the use of a communication tool. The follow-up period is one year with visits at 3, 6 and 12 months randomisation and includes 24-h ABPM and DBS sampling. DISCUSSION: This will be the first trial that focusses specifically on patients with RH without taking into account suspicion of non-adherence and it combines monitoring of AHD concentrations to identify non-adherence to AHDs with a comprehensive feedback to improve non-adherence. Furthermore, if this trial shows positive outcomes for the intervention it can be directly implemented in clinical practice, which would be a great improvement in the treatment of RH. TRIAL REGISTRATION: RHYME-RCT is registered in the Dutch Trial Register on 27/12/2017 (NTR6914) and can be found in the International Clinical Trials Registry Platform.

Case report on postmortem fentanyl measurement after overdose with more than 67 fentanyl patches.

PURPOSE: Fentanyl is an analgesic that is frequently prescribed, which resulted in non-intentional as well as intentional misuse and deaths. Here, we present a postmortem case of a patient who clearly died of a fentanyl overdose due to an extensive number of fentanyl patches combined with oral intake of fentanyl and cocaine. We aimed to show how postmortem analysis can be used to interpret postmortem fentanyl concentrations in unique cases like the one we present. CASE DESCRIPTION: A 23-year-old male was found dead in his bedroom with 67 non-prescribed patches of fentanyl on his body. In the room, there also were fentanyl tablets of 100 µg and cocaine powder, which had possibly also been taken by the deceased. To confirm the cause of death, urine and subclavian blood were retrieved to perform a standard postmortem toxicology screening. The toxicological screening revealed the presence of several drugs, including cocaine, fentanyl, lidocaine and paracetamol. Further analysis of the quantitative postmortem values of fentanyl with ultra-performance liquid chromatography-tandem mass spectrometry revealed a fentanyl concentration of 57.9 µg/L. Considering several issues around postmortem drug analyses, this value seemed to be in line with concentrations found in previously reported postmortem cases. CONCLUSION: We were able to confirm the expected cause of death with an extensive toxicological screening in combination with the circumstantial evidence. We identified fentanyl as most important cause for the fatal outcome in this specific case and simultaneously contributed to the limited availability of knowledge on postmortem fentanyl concentrations.

Acute calcium channel blocker withdrawal-induced cardiac arrest.

Acute withdrawal of calcium channel blockers can lead to the so-called calcium channel blocker withdrawal phenomenon, in particular, when high dosages are used. In the case presented, inadequate drug substitution led to this phenomenon which resulted in a serious course of events. Careful monitoring the process of drug substitution with respect to equal therapeutic dosages is therefore a necessity, especially in vulnerable patients.

Pharmacokinetic and pharmacodynamic considerations in the treatment of the elderly patient with hypertension.

INTRODUCTION: Hypertension is an important risk factor for developing cardiovascular diseases. It is more prevalent in the elderly population. Recently updated American and European guidelines recommend treating every elderly patient with hypertension independent of age, starting with a low dose of antihypertensive drugs. However, little information is available on the optimal dosages of antihypertensive drugs to treat the elderly safely. Areas covered: Comorbidities, co-medication and frailty status can alter the clinical outcome of drug treatment and can cause adverse events in the elderly. Also, due to pharmacokinetic and pharmacodynamic changes the interpatient variability when using antihypertensive drugs is considerable. In this review, an overview is given on the extent to which the previously mentioned parameters are changed in elderly patients and what this means for the exposure to antihypertensive medication. Also, recommendations on the starting dose of the most frequently used antihypertensive drugs are given based on literature data. Expert opinion: We believe that recommendations on starting dosages followed by a stepwise increase of dosages will lead to improved blood pressure control and less adverse drug reactions in the elderly patient. This may improve adherence to antihypertensive therapy.

Personalized immunosuppression in elderly renal transplant recipients.

The number of elderly people has increased considerably over the last decades, due to a rising life expectancy and ageing populations. As a result, an increased number of elderly with end-stage-renal-disease are diagnosed, for which the preferred treatment is renal transplantation. Over the past years the awareness of the elderly as a specific patient population has grown, which increases the importance of research in this group. Elderly patients often receive kidneys from elderly donors while younger donor kidneys are preferentially reserved for younger recipients. Although the rate of acute rejection after transplantation is lower in the elderly, these rejections may lead to graft loss more frequently, as kidneys from elderly donors have marginal reserve capacity. To prevent acute rejection, immunosuppressive therapy is needed. On the other hand, elderly patients have a higher risk to die from infectious complications, and thus less immunosuppression would be preferable. Immunosuppressive treatment in the elderly is complicated further by changes in the pharmacokinetics and pharmacodynamics, with increasing age. Adjustments in standard immunosuppressive regimes are therefore suggested for this population. An unmet need in transplantation medicine is a tool to guide a personalized approach to immunosuppression. Recently several promising biomarkers that identify injury to the graft at an early stage or predict acute rejection have been identified. Unfortunately, none of these biomarkers were tested specifically in the elderly. We believe there is an urgent need to perform clinical trials investigating novel immunosuppressive regimens in conjunction with biomarker studies in this specific population.

Selection and transfer of an IncI1-tet(A) plasmid of Escherichia coli in an ex vivo model of the porcine caecum at doxycycline concentrations caused by crosscontaminated feed.

AIMS: The aim of this study was to investigate the effect of subtherapeutic intestinal doxycycline (DOX) concentrations (4 and 1 mg l-1 ), caused by cross-contamination of feed, on the enrichment of a DOX-resistant commensal Escherichia coli and its resistance plasmid in an ex vivo model of the porcine caecum. METHODS AND RESULTS: A DOX-resistant, tet(A)-carrying, porcine commensal E. coli strain (EC 682) was cultivated for 6 days in the porcine caecum model under different conditions (0, 1 and 4 mg l-1 DOX). EC 682, other coliforms and anaerobic bacteria were enumerated daily. A selection of isolated DOX-resistant coliforms (n = 454) was characterized by rep-PCR clustering, PCR assays (Inc1 and tet(A)) and micro broth dilution susceptibility tests (Sensititre). Both 1 and 4 mg l-1 DOX-enriched medium had a significantly higher selective effect on EC 682 and other resistant coliforms than medium without DOX. Transconjugants of EC 682 were isolated more frequently in the presence of 1 and 4 mg l-1 DOX compared to medium without DOX. CONCLUSIONS: Subtherapeutic intestinal DOX concentrations have the potential to select for DOX-resistant E. coli, and promote the selection of transconjugants in a porcine caecum model. SIGNIFICANCE AND IMPACT OF THE STUDY: Cross-contamination of feed with antimicrobials such as DOX likely promotes the spread of antimicrobial resistance. Therefore, it is important to develop or fine-tune guidelines for the safe use of antimicrobials in animal feed and its storage.

Comprehensive microRNA profiling in acetaminophen toxicity identifies novel circulating biomarkers for human liver and kidney injury.

Our objective was to identify microRNA (miRNA) biomarkers of drug-induced liver and kidney injury by profiling the circulating miRNome in patients with acetaminophen overdose. Plasma miRNAs were quantified in age- and sex-matched overdose patients with (N = 27) and without (N = 27) organ injury (APAP-TOX and APAP-no TOX, respectively). Classifier miRNAs were tested in a separate cohort (N = 81). miRNA specificity was determined in non-acetaminophen liver injury and murine models. Sensitivity was tested by stratification of patients at hospital presentation (N = 67). From 1809 miRNAs, 75 were 3-fold or more increased and 46 were 3-fold or more decreased with APAP-TOX. A 16 miRNA classifier model accurately diagnosed APAP-TOX in the test cohort. In humans, the miRNAs with the largest increase (miR-122-5p, miR-885-5p, miR-151a-3p) and the highest rank in the classifier model (miR-382-5p) accurately reported non-acetaminophen liver injury and were unaffected by kidney injury. miR-122-5p was more sensitive than ALT for reporting liver injury at hospital presentation, especially combined with miR-483-3p. A miRNA panel was associated with human kidney dysfunction. In mice, miR-122-5p, miR-151a-3p and miR-382-5p specifically reported APAP toxicity - being unaffected by drug-induced kidney injury. Profiling of acetaminophen toxicity identified multiple miRNAs that report acute liver injury and potential biomarkers of drug-induced kidney injury.