DIAGNOSTIC AND THERAPEUTIC APPLICATIONS OF LIQUID CHROMATOGRAPHY-TANDEM MASS SPECTROMETRY (LC-MS/MS)-BASED URINE ANALYSIS IN THE MANAGEMENT OF NON-ADHERENCE TO ANTIHYPERTENSIVE TREATMENT

Abstract

Non-adherence to medications is widespread in patients with chronic cardiovascular conditions of which hypertension is a prime example. Hypertension affects around 1.5 billion people worldwide, but blood pressure is at target only in the minority of patients despite the presence of cheap and effective medications. One important reason for the lack of desired response to blood pressure lowering therapy is the non-adherence to antihypertensive medications. The recently developed biochemical screening for adherence using urine or blood analysis by liquid chromatography- tandem mass spectrometry (LC-MS/MS) provides a confirmation of presence of the most common antihypertensive medications in a single sample with high precision, sensitivity and specificity. The thesis contemplates the benefits of the objective direct measurement of adherence versus other methods of screening including questionnaires, pharmacy records, electronic monitoring devices and directly observed therapy. It also thoroughly addresses the current methodological, conceptual and interpretational limitations of the biochemical screening for non-adherence to antihypertensive treatment. The diagnostic potential of the test is explored in a retrospective study of 1348 patients attending clinical centers in the UK and the Czech Republic. The prevalence of non-adherence to antihypertensive treatment was high at 41.6% and 31.5% in these two populations, respectively. Non-adherence rates showed a strong and almost linear relationship with the number of prescribed antihypertensive medications, decreased with increasing age, were higher in females and those on diuretics. The therapeutic benefit of the test is demonstrated in a retrospective cohort study of hypertensive patients with uncontrolled blood pressure (BP) who had undergone a biochemical adherence testing. The mean systolic blood pressure (SBP) dropped by 19.5 mmHg and diastolic blood pressure (DBP) by 7.5 mmHg on follow up in the 73 initially non-adherent UK patients after the results of the test were discussed with them. The corresponding figures for 93 initially non-adherent Czech patients were 32.6 mmHg (for SBP) and 17.6 mmHg for (DBP) on follow-up. The biological insights into mechanisms of resistant hypertension are examined through the analysis of associations between the degree of resistance to blood pressure lowering therapy and clinical measures of sympathetic nervous system activity. Resistant hypertension was proposed as a state of the sympathetic nervous system over-activity, but this concept was based on studies that did not exclude non- adherence to antihypertensive treatment objectively. The analysis of 76 patients with resistant hypertension demonstrated that if non-adherence is excluded objectively by biochemical analysis of blood or urine, there is no evidence of heightened activity of sympathetic nervous system. The thesis assesses the overall clinical impact of the biochemical screening for non- adherence to treatment in management of hypertensive patients. It also outlines current and future research directions including multicenter interventional study to assess benefit of the test in improving blood pressure control, a health economic benefit analysis, studies assessing preanalytical factors in urine and pharmacokinetic analysis.

Date of Award	1 Aug 2019
Original language	English
Awarding Institution	The University of Manchester
Supervisor	Bernard Keavney (Supervisor) & Maciej Tomaszewski (Supervisor)