Prashanth Patel

High rates of non-adherence to antihypertensive treatment revealed by high-performance liquid chromatography-tandem mass spectrometry (HP LC-MS/MS) urine analysis

Objectives Non-adherence to therapy is an important cause of suboptimal blood pressure control but few practical tools exist to accurately and routinely detect it. We used a simple urine-based assay to evaluate the prevalence of antihypertensive treatment non-adherence and its impact on blood pressure in a specialist hypertension centre. Methods 208 hypertensive patients (125 new referrals, 66 follow-up patients with inadequate blood pressure control and 17 renal denervation referrals) underwent assessment of antihypertensive drug intake using high-performance liquid chromatography-tandem mass spectrometry (HP LC-MS/MS) urine analysis at the time of clinical appointment. A total of 40 most commonly prescribed antihypertensive medications (or their metabolites) were screened for in spot urine samples. Results Overall, 25% of patients were totally or partially non-adherent to antihypertensive treatment (total non-adherence 10.1%, partial non-adherence 14.9%). The highest prevalence of partial and total non-adherence was among follow-up patients with inadequate blood pressure control (28.8%) and those referred for consideration of renal denervation (23.5%), respectively. There was a linear relationship between blood pressure and the numerical difference in detected/prescribed antihypertensive medications—every unit increase in this difference was associated with 3.0 (1.1) mm Hg, 3.1 (0.7) mm Hg and 1.9 (0.7) mm Hg increase in adjusted clinic systolic blood pressure, clinic diastolic blood pressure (DBP) and 24 h mean daytime DBP (p=0.0051, p=8.62×10−6, p=0.0057), respectively. Conclusions Non-adherence to blood pressure lowering therapy is common, particularly in patients with suboptimal blood pressure control and those referred for renal denervation. HP LC-MS/MS urine analysis could be used to exclude non-adherence and better stratify further investigations and intervention.

Risk Factors for Nonadherence to Antihypertensive Treatment

Nonadherence to antihypertensive treatment is a critical contributor to suboptimal blood pressure control. There are limited and heterogeneous data on the risk factors for nonadherence because few studies used objective-direct diagnostic methods. We used high-performance liquid chromatography-tandem mass spectrometry of urine and serum to detect nonadherence and explored its association with the main demographic- and therapy-related factors in 1348 patients with hypertension from 2 European countries. The rates of nonadherence to antihypertensive treatment were 41.6% and 31.5% in the UK and Czech populations, respectively. Nonadherence was inversely related to age and male sex. Each increase in the number of antihypertensive medications led to 85% and 77% increase in nonadherence (P<0.001) in the UK and Czech populations, respectively. The odds of nonadherence to diuretics were the highest among 5 classes of antihypertensive medications (P⩽0.005 in both populations). The predictive model for nonadherence, including age, sex, diuretics, and the number of prescribed antihypertensives, showed area under the curves of 0.758 and 0.710 in the UK and Czech populations, respectively. The area under the curves for the UK model tested on the Czech data and for the Czech model tested on UK data were calculated at 0.708 and 0.756, respectively. We demonstrate that the number and class of prescribed antihypertensives are modifiable risk factors for biochemically confirmed nonadherence to blood pressure–lowering therapy. Further development of discriminatory models incorporating these parameters might prove clinically useful in assessment of nonadherence in countries where biochemical analysis is unavailable.

Screening for non-adherence to antihypertensive treatment as a part of the diagnostic pathway to renal denervation

Renal denervation is a potential therapeutic option for resistant hypertension. A thorough clinical assessment to exclude reversible/spurious causes of resistance to antihypertensive therapy is required prior to this procedure. The extent to which non-adherence to antihypertensive treatment contributes to apparent resistance to antihypertensive therapy in patients considered for renal denervation is not known. Patients (n=34) referred for renal denervation entered the evaluation pathway that included screening for adherence to antihypertensive treatment by high-performance liquid chromatography-tandem mass spectrometry-based urine analysis. Biochemical non-adherence to antihypertensive treatment was the most common cause of non-eligibility for renal denervation—23.5% of patients were either partially or completely non-adherent to prescribed antihypertensive treatment. About 5.9% of those referred for renal denervation had admitted non-adherence prior to performing the screening test. Suboptimal pharmacological treatment of hypertension and ‘white-coat effect’ accounted for apparently resistant hypertension in a further 17.7 and 5.9% of patients, respectively. Taken together, these three causes of pseudo-resistant hypertension accounted for 52.9% of patients referred for renal denervation. Only 14.7% of referred patients were ultimately deemed eligible for renal denervation. Without biochemical screening for therapeutic non-adherence, the eligibility rate for renal denervation would have been 38.2%. Non-adherence to antihypertensive treatment and other forms of therapeutic pseudo-resistance are by far the most common reason of ‘resistant hypertension’ in patients referred for renal denervation. We suggest that inclusion of biochemical screening for non-adherence to antihypertensive treatment may be helpful in evaluation of patients with ‘resistant hypertension’ prior to consideration of renal denervation.

How to screen for non-adherence to antihypertensive therapy

The quality of assessment of non-adherence to treatment in hypertensive is poor. Within this review, we discuss the different methods used to assess adherence to blood-pressure-lowering medications in hypertension patients. Subjective reports such as physicians’ perceptions are inaccurate, and questionnaires completed by patients tend to overreport adherence and show a low diagnostic specificity. Indirect objective methods such as pharmacy database records can be useful, but they are limited by the robustness of the recorded data. Electronic medication monitoring devices are accurate but usually track adherence to only a single medication and can be expensive. Overall, the fundamental issue with indirect objective measures is that they do not fully confirm ingestion of antihypertensive medications. Detection of antihypertensive medications in body fluids using liquid chromatography–tandem mass spectrometry is currently, in our view, the most robust and clinically useful method to assess non-adherence to blood-pressure-lowering treatment. It is particularly helpful in patients presenting with resistant, refractory or uncontrolled hypertension despite the optimal therapy. We recommend using this diagnostic strategy to detect non-adherence alongside a no-blame approach tailoring support to address the perceptions (e.g. beliefs about the illness and treatment) and practicalities (e.g. capability and resources) influencing motivation and ability to adhere.

Biochemical Screening for Nonadherence Is Associated With Blood Pressure Reduction and Improvement in Adherence

We hypothesized that screening for nonadherence to antihypertensive treatment using liquid chromatography-tandem mass spectrometry–based biochemical analysis of urine/serum has therapeutic applications in nonadherent hypertensive patients. A retrospective analysis of hypertensive patients attending specialist tertiary care centers was conducted in 2 European countries (United Kingdom and Czech Republic). Nonadherence to antihypertensive treatment was diagnosed using biochemical analysis of urine (United Kingdom) or serum (Czech Republic). These results were subsequently discussed with each patient, and data on follow-up clinic blood pressure (BP) measurements were collected from clinical files. Of 238 UK patients who underwent biochemical urine analysis, 73 were nonadherent to antihypertensive treatment. Their initial urinary adherence ratio (the ratio of detected to prescribed antihypertensive medications) increased from 0.33 (0–0.67) to 1 (0.67–1) between the first and the last clinic appointments. The observed increase in the urinary adherence ratio in initially nonadherent UK patients was associated with the improved BP control; by the last clinic appointment, systolic and diastolic BPs were ≈19.5 and 7.5 mm Hg lower than at baseline (P=0.001 and 0.009, respectively). These findings were further corroborated in 93 nonadherent hypertensive patients from Czech Republic—their average systolic and diastolic BPs dropped by ≈32.6 and 17.4 mm Hg, respectively (P<0.001), on appointments after the biochemical analysis. Our data show that nonadherent hypertensive patients respond to liquid chromatography–tandem mass spectrometry-based biochemical analysis with improved adherence and significant BP drop. Such repeated biochemical analyses should be considered as a therapeutic approach in nonadherent hypertensive patients.

The effect of multiple analysers on the biochemical diagnosis of myocardial infarction using a contemporary troponin-I assay.

Background The measurement of cardiac troponin is central for the diagnosis of myocardial infarction (MI). It is recommended that a coefficient of variation of ≤10% is achieved at the diagnostic threshold and significant change between serial measurements reported. Many modern laboratories use multiple analysers linked by automation where samples are randomly assigned to an analyser. It is therefore important to consider the combined effect of all analysers on the analytical performance of troponin measurement. Method The performance of a contemporary troponin-I (cTn-I) assay run on three analysers, linked by an automated track, was undertaken across a range of cTn-I concentrations. The data for the three analysers were aggregated to obtain the combined analytical coefficient of variation (CVA) and reference change values (RCVs). Results The CVA improved with increasing concentration and calculated RCVs ranged from 67.2% (±13 ng/L) to 32% (±160 ng/L) between cTn-I values 20 ng/L and 500 ng/L. Although there were significant differences in cTn-I measurement between analysers around the diagnostic threshold (P < 0.05), the CVA was 13.6%. Conclusions We demonstrate that there are significant differences between the performances of analysers which can impact the biochemical criteria for the diagnosis of MI. We also show that the RCV varies according to baseline cTn-I values and that reporting a single RCV across the analytical range of cTn-I may not be appropriate.

Measurements of Antihypertensive Medications in Blood and Urine

Biochemical detection of antihypertensive medications in blood and urine is a recent addition to the diagnosis of therapeutic non-adherence. The biochemical analysis by high performance liquid chromatography-tandem mass spectrometry (LC-MS/MS) provides a direct, objective and robust confirmation of the presence or absence of prescribed antihypertensive medications in bodily fluids. This chapter covers the laboratory principles and the clinical aspects of the biochemical screening for therapeutic non-adherence in management of hypertension.

Design and rationale of the Ready to Reduce Risk (3R) Study: A randomised controlled trial of a group educational intervention with telephone and text messaging support to improve medication adherence for the primary prevention of cardiovascular disease (Preprint)

Background Poor adherence to cardiovascular medications is associated with worse clinical outcomes. Evidence for effective education interventions that address medication adherence for the primary prevention of cardiovascular disease is lacking. The Ready to Reduce Risk (3R) study aims to investigate whether a complex intervention, involving group education plus telephone and text messaging follow-up support, can improve medication adherence and reduce cardiovascular risk. Objective This protocol paper details the design and rationale for the development of the 3R intervention and the study methods used. Methods This is an open and pragmatic randomized controlled trial with 12 months of follow-up. We recruited participants from primary care and randomly assigned them at a 1:1 frequency, stratified by sex and age, to either a control group (usual care from a general practitioner) or an intervention group involving 2 facilitated group education sessions with telephone and text messaging follow-up support, with a theoretical underpinning and using recognized behavioral change techniques. The primary outcome was medication adherence to statins. The primary measure was an objective, novel, urine-based biochemical measure of medication adherence. We also used the 8-item Morisky Medication Adherence Scale to assess medication adherence. Secondary outcomes were changes in total cholesterol, blood pressure, high-density lipoprotein, total cholesterol to high-density lipoprotein ratio, body mass index, waist to hip ratio, waist circumference, smoking behavior, physical activity, fruit and vegetable intake, patient activation level, quality of life, health status, health and medication beliefs, and overall cardiovascular disease risk score. We also considered process outcomes relating to acceptability and feasibility of the 3R intervention. Results We recruited 212 participants between May 2015 and March 2017. The 12-month follow-up data collection clinics were completed in April 2018, and data analysis will commence once all study data have been collected and verified. Conclusions This study will identify a potentially clinically useful and effective educational intervention for the primary prevention of cardiovascular disease. Medication adherence to statins is being assessed using a novel urine assay as an objective measure, in conjunction with other validated measures. Trial Registration International Standard Randomized Controlled Trial Number ISRCTN16863160; http://www.isrctn.com/ISRCTN16863160 (Archived by WebCite at http://www.webcitation.org/734PqfdQw) International Registered Report Identifier (IRRID) DERR1-10.2196/11289

Fluctuating Amylase in a Female Child with Epilepsy and Global Developmental Delay and Absence of Pancreatitis

Amylase is an enzyme produced by both the pancreas and salivary glands to digest carbohydrates. The enzyme is used as a marker for acute pancreatitis however amylase may also be raised in salivary gland disease and other intra-abdominal conditions. We report a case of raised and fluctuating amylase concentrations in the absence of pancreatic or salivary gland disease. Whilst amylase levels fluctuated, serum lipase remained in the normal range and radiological investigation showed no evidence of pancreatitis.

How do specialist trainee doctors acquire skills to practice patient-centred care? A qualitative exploration.

Objectives The importance of patient-centred care (PCC) has been increasingly recognised. However, there is limited work exploring what doctors actually understand by PCC, and how they perceive they acquire PCC skills in the workplace. The objectives of our study were to explore (1) what UK doctors, in specialist training, perceive to be the essential components of PCC, (2) if/how they acquire these skills, (3) any facilitators/barriers for engaging in PCC and (4) views on their PCC training. Design Qualitative study using in-depth individual semi-structured interviews with UK specialist trainees. Interview transcripts were thematically analysed. Setting and participants Thirty-one specialist trainee doctors, with at least 4 years postgraduate experience, were interviewed. Participants worked in various medical specialities within the Medical Directorate of an acute hospital in the East Midlands of England. Results Interview data were transcribed verbatim and categorised into three main themes. The first theme was ‘Understanding PCC’ where the doctors gave varied perspectives on what they understood by PCC. Although many were able to highlight key components of PCC, there were also some accounts which demonstrated a lack of understanding. The second theme was ‘Learning PCC skills: A work in progress’. Learning to be patient-centred was perceived to be an ongoing process. Within this, trainee doctors reported ‘on-the-job’ learning as the main means of acquiring PCC skills, but they also saw a place for formal training (eg, educational sessions focussing on PCC, role play). ‘Delivering PCC: Beyond the physician’ referred to the many influences the doctors reported in learning and delivering PCC including patients, the organisation and colleagues. Observing consultants taking a patient-centred approach was cited as an important learning tool. Conclusions Our findings may assist clinical educators in understanding how trainee doctors perceive PCC, and the factors that influence their learning, thereby helping them shape PCC skills training.