Combined Use of Angiotensin Receptor Blockers and Calcium Channel Blockers in High-risk Hypertensive Populations: An Observational Study

Summary

This protocol evaluates the effects of ARB-CCB combination in high-risk hypertensive patients, comparing it with monotherapy to assess improvements in blood pressure control, vascular and cardiac function, and cardiovascular outcomes.

Abstract

This observational matched cohort study evaluated the combined use of angiotensin receptor blockers (ARBs) and calcium channel blockers (CCBs) in high-risk hypertensive patients to optimize treatment strategies. A total of 330 high-risk hypertensive patients treated between 2018 and 2024 were identified from the cardiovascular department database. Propensity score matching was applied to balance baseline characteristics, yielding three matched groups (n = 110 each): ARB monotherapy (valsartan 80 mg once daily), CCB monotherapy (amlodipine 5 mg once daily), and combination therapy (valsartan/amlodipine 80/5 mg once daily). Data were collected through medical record review, ambulatory blood pressure monitoring, vascular and cardiac ultrasound, electrocardiography, pulse wave velocity measurement, and SF-36 questionnaires. Primary outcomes were cardiovascular and cerebrovascular events and blood pressure control; secondary outcomes included vascular function, cardiac performance, arterial elasticity, and quality of life. All procedures followed standardized protocols, and adverse events were systematically recorded. The findings suggest that the combination therapy was associated with advantages in blood pressure control and vascular outcomes, though further prospective studies are warranted to confirm these observations.

Introduction

Hypertension refers to a state where blood exerts persistently higher-than-normal pressure on blood vessel walls during circulation. In 2023, the European Society of Hypertension issued its 2023 guidelines for managing arterial hypertension, which define hypertension as an office blood pressure reading of ≥140/90 mmHg¹. The European Society of Hypertension Guidelines for Arterial Hypertension define hypertension in a manner that aligns with international standards set by organizations such as the World Health Organization and the European Society of Cardiology, based on existing evidence^2,3,4. The World Health Organization's 1990–2019 study on 30–79-year-olds showed that the number of hypertensive patients in this age bracket doubled⁵. A 2020 analysis of the Global Burden of Disease Study found that high systolic blood pressure (SBP) was the leading modifiable risk factor for death globally in both sexes, accounting for 5.25 million deaths among women and 5.60 million among men⁶. Despite significant advancements in the understanding and research of hypertension in recent years, as well as continuous innovations in corresponding diagnostic and therapeutic technologies, hypertension continues to be a major factor contributing to deaths related to cardiovascular diseases⁷. Hypertension exerts diverse negative impacts on the body, causing damage to vital organs like the heart, brain, kidneys, and retina⁸. Proper management of hypertension is crucial for enhancing patient outcomes and alleviating the societal medical burden.

Lifestyle interventions serve as the foundation for hypertension management, encompassing low-salt diets, smoking cessation, alcohol restriction, regular exercise, and weight control⁹. However, relying solely on lifestyle interventions often fails to achieve ideal blood pressure control, making pharmacological therapy a crucial component of hypertension treatment. In clinical practice, calcium channel blockers (CCBs) and angiotensin receptor blockers (ARBs) are frequently employed as blood pressure-lowering medications¹⁰. Other commonly used antihypertensive agents include diuretics and beta-blockers; however, these are often associated with metabolic side effects or are preferred in patients with specific comorbidities, such as diabetes or chronic kidney disease, where ARBs and CCBs offer a more favorable safety profile. Nevertheless, for individuals with high-risk hypertension, like those having multiple chronic conditions or organ damage, traditional monotherapy often falls short of achieving optimal blood pressure reduction and may fail to comprehensively improve vascular and cardiac functions¹¹. Moreover, with in-depth research into the pathophysiological mechanisms of hypertension, there is a growing recognition that hypertension treatment should not be limited to merely lowering blood pressure values but should also focus on improving multidimensional indicators such as vascular endothelial function, cardiac function, arterial elasticity function, and quality of life¹². Contemporary guidelines, including the 2023 ESH guidelines, recommend initial combination therapy for most patients with hypertension, particularly with single-pill combinations, to achieve prompt and sustained blood pressure control. In high-risk populations—such as those with diabetes, chronic kidney disease, or target organ damage—combination therapy becomes even more critical due to the greater challenges in achieving optimal outcomes. Although combination therapy is now widely endorsed by guidelines and supported by extensive clinical evidence, the optimal regimen for specific high-risk subgroups remains an area of ongoing investigation.

ARBs block angiotensin II receptors to relax blood vessels and lower blood pressure¹³. It also protects organs by reducing myocardial hypertrophy, proteinuria, and renal function decline¹⁴. Valsartan is a widely used ARB that not only has a marked antihypertensive effect but also provides multifaceted protection to the cardiovascular system¹⁵. Studies have shown that valsartan can improve myocardial remodeling, reduce ventricular hypertrophy, and decrease cardiomyocyte apoptosis and necrosis, thereby effectively preventing the occurrence of cardiomyopathy¹⁶. Valsartan is widely used for treating mild to moderate essential hypertension, heart failure, diabetes, and renal insufficiency¹⁷. When combined with other antihypertensive drugs, valsartan can further enhance the antihypertensive effect. CCBs are drugs that lower blood pressure by blocking calcium ion entry into smooth muscle cells of blood vessels¹⁸. They are divided into dihydropyridine and non-dihydropyridine types based on their mechanism and pharmacokinetics. Among them, dihydropyridine CCBs, such as amlodipine, are characterized by rapid onset and significant antihypertensive effects, with no adverse impacts on glucose and lipid metabolism, making them widely used in clinical practice¹⁹. Amlodipine primarily acts by selectively targeting L-type calcium channels, reducing calcium ion influx, thereby dilating peripheral arteries, decreasing peripheral vascular resistance, and achieving an antihypertensive effect²⁰. ARBs and CCBs have complementary mechanisms in lowering blood pressure: ARBs inhibit the renin-angiotensin-aldosterone system, while CCBs promote vasodilation via calcium channel blockade. Their combination may enhance the antihypertensive effect through complementary mechanisms and may provide additional protection to the heart and blood vessels. High-risk hypertensive patients, due to their comorbid conditions or target organ damage, face greater challenges in blood pressure control and a higher risk of cardiovascular events. Recently, fixed-dose combinations containing three or more components (polypills) have emerged as a strategy to improve adherence; however, the ARB + CCB dual combination remains a foundational and well-tolerated approach with proven synergistic effects, particularly suitable for initiating combination therapy in high-risk populations. Moreover, the combination of ARBs and CCBs has been shown to mitigate the dose-dependent ankle edema commonly associated with dihydropyridine CCBs, potentially improving tolerability and adherence.

Despite recommendations for combination therapy, its efficacy and safety in high-risk populations remain understudied, and identifying the optimal regimen for this group is an unmet clinical need. This study aims to evaluate the efficacy and clinical value of ARB (valsartan) and CCB (amlodipine) combination therapy in high-risk hypertensive patients, with a focus on its effects on blood pressure control, vascular/cardiac function, CVD event rates, and quality of life—ultimately providing evidence to optimize treatment regimens for this vulnerable population.

Protocol

This study was conducted in accordance with the principles of the Declaration of Helsinki and was approved by the Ethics Committee of Taixing People's Hospital Affiliated to Yangzhou University. All data used were de-identified and accessed from a secure, encrypted database. The study was retrospective in nature and did not involve any additional interventions or direct patient contact; thus, informed consent was waived by the ethics committee. The detailed study flowchart is shown in Figure 1.

Patient selection and grouping
Screening of eligible patients
Electronic medical records were extracted from the electronic medical record (EMR) database of the Cardiovascular Department of Taixing People's Hospital Affiliated to Yangzhou University between January 2018 and January 2024. Patients with a treatment duration of less than 12 months (minimum follow-up period for outcome assessment) were excluded.

The following inclusion criteria were applied: age ≥ 18 years; diagnosis of essential hypertension; systolic blood pressure (SBP) ≥ 140 mmHg and/or diastolic blood pressure (DBP) ≥ 90 mmHg; presence of at least one high-risk factor, including diabetes, chronic kidney disease, or evidence of target organ damage (e.g., left ventricular hypertrophy, carotid atherosclerosis, proteinuria); and availability of complete clinical records, including blood pressure measurements, medication history, and adverse event reports.

Patients were excluded based on the following criteria: secondary hypertension (e.g., Cushing's syndrome, primary aldosteronism, pheochromocytoma); contraindications to angiotensin receptor blockers or calcium channel blockers; pregnancy or lactation; concurrent use of medications that significantly affect blood pressure or interact with ARBs or CCBs; treatment duration of less than 12 months; or life expectancy of less than 12 months (e.g., advanced malignancy).

Propensity score matching
Propensity scores were calculated based on key baseline variables, including age, gender, BMI, blood pressure, lipid profile, renal function, and comorbidities. Logistic regression was used to generate propensity scores. Patients were matched in a 1:1:1 ratio without replacement using nearest-neighbor matching with a caliper width of 0.2 of the standard deviation of the propensity score.

Balance across groups was assessed using standardized mean differences (SMDs) before and after matching. An SMD < 0.1 was considered indicative of adequate balance. Additionally, baseline characteristics were compared using one-way ANOVA for continuous variables and chi-square tests for categorical variables. Pre-matching imbalances were observed for several covariates (age, SBP, and prevalence of diabetes), all of which were well balanced after matching (SMD < 0.1 for all covariates; Table 1). The matched cohorts demonstrated no statistically significant differences in baseline characteristics (P > 0.05 for all comparisons), confirming adequate balance across the three groups.

Group assignment
Matched patients were assigned to one of three groups (n = 110 each): ARB monotherapy group (valsartan 80 mg once daily), CCB monotherapy group (levamlodipine besylate 5 mg once daily), and combination therapy group (valsartan/amlodipine 80/5 mg once daily).

Data collection and measurement procedures
Blood pressure measurement
Ambulatory blood pressure monitoring was performed using a validated oscillometric device. The cuff was placed on the non-dominant arm at heart level, and cuff size was selected according to arm circumference (small, standard, or large adult cuff) per device specifications. The device was programmed to record measurements every 30 min during daytime (06:00–22:00) and every 60 min at night (22:00–06:00). Patients maintained a log of activities and medication times. Data were downloaded after 24 h using the manufacturer's software, and mean SBP and DBP were calculated. Recordings with <70% valid readings or no nighttime readings were excluded.

Vascular endothelial function assessment
Carotid intima-media thickness (CIMT) was measured using a color Doppler ultrasound system equipped with a 7.5–12 MHz linear array transducer. Patients were positioned supine with the neck slightly extended and rotated contralaterally. Ultrasound gel was applied, and the common carotid artery was scanned 1 cm proximal to the bifurcation. Images were captured in longitudinal view, and CIMT was measured using built-in electronic calipers at the far wall. Three measurements were averaged for each side, and the intra-observer coefficient of variation was maintained at <5%.

Flow-mediated dilation (FMD) of the brachial artery was measured using the same ultrasound system. A blood pressure cuff was inflated on the forearm to 50 mmHg above SBP for 5 min, after which the cuff was released, and the brachial artery diameter was recorded at 60 s post release. FMD was calculated as the percentage increase from baseline diameter. All scans were performed by a single trained sonographer and reviewed by a cardiologist blinded to the group assignment.

Cardiac function evaluation
Cardiac function was assessed using a cardiac function analyzer and transthoracic echocardiography with a 2.5–5.0 MHz phased-array transducer. Left ventricular ejection time (LVET) and pre-ejection period (PEP) were measured using simultaneous electrocardiography and phonocardiography. Isovolumetric contraction time (ICT) was derived from pulsed-wave Doppler recordings. Ejection fraction (EF) was calculated using Simpson's biplane method from apical four- and two-chamber views. All measurements were performed by a trained sonographer and reviewed by a cardiologist, and three consecutive cardiac cycles were averaged for each parameter.

Arterial elasticity measurement
Brachial-ankle pulse wave velocity (baPWV) was measured using an automated arteriosclerosis detection device. Cuffs were placed simultaneously on both arms and ankles, and the device automatically recorded pulse waves using oscillometric sensors. baPWV was calculated by the device software as the distance between the brachial and ankle sites divided by the pulse wave transit time. Measurements were performed in a temperature-controlled room (22–24 °C) after a 10-minute rest, and values were accepted only when the coefficient of variation between left and right measurements was <10%.

Quality-of-life assessment
The Short Form-36 Health Survey (SF-36) was administered to each patient at baseline and after 12 months. Surveys were completed independently or with minimal assistance from study personnel. Each domain was scored according to the SF-36 manual, with total scores ranging from 0 to 100. Incomplete surveys (>10% missing items) were excluded.

Adverse event recording
The composite outcome of cardiovascular and cerebrovascular events included non-fatal myocardial infarction, non-fatal stroke, hospitalization for unstable angina, coronary revascularization, and cardiovascular death. Events were identified from hospital discharge summaries, electrocardiograms, cardiac biomarker results, and imaging reports. All potential events were adjudicated by two independent cardiologists blinded to group assignment, and any disagreement was resolved by consensus with a third cardiologist. Events were coded using the Medical Dictionary for Regulatory Activities (MedDRA) terminology, version 24.0. Severity was classified as mild, moderate, or severe based on documented clinical impact and intervention required.

Statistical analysis
Data were analyzed. Continuous variables (e.g., SBP, DBP, CIMT) were assessed for normality using the Kolmogorov–Smirnov test with Lilliefors significance correction. Normally distributed variables were reported as mean ± SD, and between-group comparisons were performed using one-way ANOVA followed by post hoc Tukey's test for pairwise comparisons. Within-group changes from baseline were analyzed using paired t-tests. Non-normally distributed variables were reported as median (IQR) and compared using the Kruskal–Wallis H test. Categorical data (e.g., event counts) were presented as n (%) and compared using chi-square tests; Fisher's exact test was used for 2 × 2 tables with expected cell counts < 5. A two-tailed P value < 0.05 was considered statistically significant for all analyses. Given the exploratory nature of this retrospective study and the predefined primary and secondary outcomes, no adjustments were made for multiple comparisons, and findings should therefore be interpreted with caution.

Sample size was determined by the availability of eligible patients after applying inclusion and exclusion criteria and performing propensity score matching. A post hoc power analysis was conducted using G*Power software. Based on the observed incidence of cardiovascular and cerebrovascular events (combination group: 1.82%; ARB group: 8.18%; CCB group: 10.00%) and a two-sided alpha level of 0.05, the achieved power for the primary clinical outcome was 86.4%, indicating that the sample size (n = 110 per group) was sufficient to detect significant differences among the three groups.

Results

Table 1 shows that there were no statistically significant differences in the baseline characteristics among the three groups regarding gender, age, body mass index (BMI), lipid profile indicators [triglycerides (TG), total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C)], fasting blood glucose (FBG), serum creatinine (CREA), blood urea nitrogen (BUN), and uric acid (UA) levels (P > 0.05). This indicates that the basic characteristic...

Discussion

In the clinical practice of cardiovascular disease prevention and treatment, hypertension management has consistently been a core component. In high-risk patients with conditions like diabetes, chronic kidney disease, or organ damage, blood pressure control directly affects cardiovascular and cerebrovascular risks and overall prognosis. This study explores the combined effects of ARBs and CCBs in high-risk hypertensive patients using a observational matched cohort study design. The aim is to provide a robust basis for op...

Materials

List of materials used in this article

Name	Company	Catalog Number	Comments
Ambulatory Blood Pressure Monitor	I.E.M. GmbH, Germany	Mobil-O-Graph NG
Automated Arteriosclerosis Detection Device	Omron Healthcare Co., Ltd., Japan	BP-203RPE III
Cardiac Function Analyzer	Nihon Kohden Corporation, Japan	CardioFax ECG-2150
Color Doppler Ultrasound Diagnostic System	Philips Healthcare, USA	EPIQ 7
G*Power	Heinrich Heine University Düsseldorf, Germany	Version 3.1.9.7
Levamlodipine Besylate Tablets (5 mg)	Zhejiang Anglikang Pharmaceutical Co., Ltd.	H20083459
SPSS Statistics	IBM Corp., USA	Version 25.0
Valsartan and Amlodipine Tablets (80/5 mg)	Beijing Novartis Pharma Co., Ltd.	J20150135
Valsartan Capsules (80 mg)	Beijing Novartis Pharma Co., Ltd.	H20040217