Adrian G. Stanley

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.

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.

OBJECTIVE: Increased arterial stiffness is a risk factor for cardiovascular disease and is a feature associated with diabetes. Pulse wave velocity (PWV) is an accepted index of arterial stiffness and augmentation index (AI) derived from radial applanation tonometry has been advocated as a measurement of arterial stiffness. This study compares the relationship between PWV and AI in people with and without diabetes. DESIGN AND METHODS: A total of 66 people with diabetes and 66 age-matched non-diabetic controls were studied. Central aortic pressure waves were generated using applanation tonometry over the radial artery and used to calculate AI. Carotid-femoral PWV (PWVcf) was measured simultaneously. RESULTS: Relative to controls, diabetes was associated with increased pulse pressure (PP) and PWVcf (P < 0.01). In contrast, AI did not differ between groups even after adjustment for heart rate. This observation remained consistent irrespective of diabetes type, arterial site, and the presence or absence of antihypertensive therapy. Multiple regression analysis revealed diabetes to be a significant determinant of PWVcf, but not AI. CONCLUSIONS: PP and PWVcf are increased in people with diabetes, but this is not associated with increased AI. These findings conclusively demonstrate that AI is not a reliable measure of arterial stiffness in people with diabetes.

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.

BACKGROUND AND AIMS: Visit-to-visit systolic blood pressure variability (BPV) is an important predictor of cardiovascular (CV) outcomes. The long-term effect of a period of blood pressure (BP) control, but with differential BPV, is uncertain. Morbidity and mortality follow-up of UK participants in the Anglo-Scandinavian Cardiac Outcomes Trial-Blood Pressure-Lowering Arm has been extended for up to 21 years to determine the CV impact of mean systolic blood pressure (SBP) control and BPV during the trial, and amongst those allocated to amlodipine- and atenolol-based treatment. METHODS: Eight thousand five hundred and eighty hypertensive participants (4305 assigned to amlodipine ± perindopril-based and 4275 to atenolol ± diuretic-based treatment during the in-trial period (median 5.5 years) were followed for up to 21 years (median 17.4 years), using linked hospital and mortality records. A subgroup of participants (n = 2156) was followed up 6 years after the trial closure with a self-administered questionnaire and a clinic visit. In-trial mean SBP and standard deviation of visit-to-visit SBP as a measure of BPV, were measured using >100 000 BP measurements. Cox proportional hazard models were used to estimate the risk [hazard ratios (HRs)], associated with (i) mean with SBP and BPV during the in-trial period, for the CV endpoints occurring after the end of the trial and (ii) randomly assigned treatment to events following randomization, for the first occurrence of pre-specified CV outcomes. RESULTS: Using BP data from the in-trial period, in the post-trial period, although mean SBP was a predictor of CV outcomes {HR per 10 mmHg, 1.14 [95% confidence interval (CI) 1.10-1.17], P < .001}, systolic BPV independent of mean SBP was a strong predictor of CV events [HR per 5 mmHg 1.22 (95% CI 1.18-1.26), P < .001] and predicted events even in participants with well-controlled BP. During 21-year follow-up, those on amlodipine-based compared with atenolol-based in-trial treatment had significantly reduced risk of stroke [HR 0.82 (95% CI 0.72-0.93), P = .003], total CV events [HR 0.93 (95% CI 0.88-0.98), P = .008], total coronary events [HR 0.92 (95% CI 0.86-0.99), P = .024], and atrial fibrillation [HR 0.91 (95% CI 0.83-0.99), P = .030], with weaker evidence of a difference in CV mortality [HR 0.91 (95% CI 0.82-1.01), P = .073]. There was no significant difference in the incidence of non-fatal myocardial infarction and fatal coronary heart disease, heart failure, and all-cause mortality. CONCLUSIONS: Systolic BPV is a strong predictor of CV outcome, even in those with controlled SBP. The long-term benefits of amlodipine-based treatment compared with atenolol-based treatment in reducing CV events appear to be primarily mediated by an effect on systolic BPV during the trial period.