Non-achievement of therapeutic range of antihypertensive drug concentration in a triple combination as a cause of ineffective control of primary arterial hypertension: ambiguous results of a cross-sectional clinical trial in routine clinical practice

INTRODUCTION: High blood pressure (BP) is one most important risk factor for coronary heart disease, stroke, chronic kidney disease, and dementia. Despite a wide range of pharmacological and non-pharmacological treatments, BP control can be achieved in less than 50% of cases, therefore, the development of new methods to improve the effectiveness of arterial hypertension (AH) treatment is urgent. One possible approach is monitoring antihypertensive drug (AHD) for their correspondence to the therapeutic range (TR).

AIM: To analyze the effect of serum concentrations of lisinopril, indapamide and amlodipine on blood pressure parameters in patients with stage III essential hypertension taking these drugs in a triple combination.

METHODS: A cross-sectional clinical study included 147 patients with stage III essential hypertension who were simultaneously receiving the three studied AHDs (lisinopril, amlodipine, indapamide); mean age (63.7±11.0) years; 44% were men; 54% of patients had uncontrolled hypertension. Using high-performance liquid chromatography with tandem mass spectrometry (Ultimate 3000 chromatograph and TSQ Fortis mass spectrometer (ThermoFisher, USA)) the concentrations of AHDs in blood serum were analyzed: steady-state concentration (C_0h) and 2 hours after administration of AHDs (C_2h). Using univariate and then multivariate regression analysis, the existence of a relationship between the mean level of daytime and nighttime blood pressure, pharmacokinetic parameters (C_0h, C_2h, achievement of TR) and general clinical criteria (age, gender, body weight, creatinine clearance) was determined.

RESULTS: The proportion of patients with C0h below TR was: 8.2% for lisinopril, 27.9% for amlodipine, 69.4% for indapamide, 8.8% for simultaneous indapamide and amlodipine, and 0.7% for the three simultaneous AHDs. The proportion of patients with non-achievement of the target BP level was the following: with C_0h of lisinopril within the TR (n=135) — 56.0%, with C_0h of lisinopril below the TR (n=12) — 33.0%, with C_0h of amlodipine within the TR (n=106) — 57.0%, with C_0h of amlodipine below the TR (n=41) — 49.0%, with C_0h of indapamide within the TR (n=45) — 44.0%, with C_0h of indapamide below the TR (n=102) — 59.0%, with C_0h of indapamide and amlodipine simultaneously below the TR (n=13) — 85.0%, with C_0h of the three drugs simultaneously below the TR (n=1) — 1 out of 1. According to the results of multiple regression analysis, a significant factor influencing the level of daytime SBP was age, daytime DBP — age and non-achievement of the TR of amlodipine and indapamide C_0h; of nighttime SBP — body weight, of nighttime DBP — age and non-achievement of the TR of amlodipine and indapamide C_0h.

CONCLUSION: A high prevalence of subtherapeutic serum concentrations of indapamide and amlodipine has been recorded. Non-achievement of the TR level of both amlodipine and indapamide is associated with higher diastolic blood pressure with no significant effect on systolic blood pressure. The problem of poor hypertension control cannot be explained solely by serum antihypertensive drug concentrations — no convincing, unambiguous correlation has been established.