Amlodipine-Benazepril Therapy for Blood Pressure Variability and Prognosis in Elderly Patients with Postprandial Hypotension

Summary

This study aimed to evaluate the effects of amlodipine-benazepril combination therapy on blood pressure variability, vascular and renal function, and clinical outcomes in elderly patients with hypertension and postprandial hypotension.

Abstract

Postprandial hypotension (PPH), a common but underdiagnosed condition in elderly hypertensive patients, is associated with increased cardiovascular risk and mortality. Blood pressure variability (BPV), another independent prognostic factor, is often exacerbated in this population due to impaired autonomic function. This single-center retrospective study evaluated the effects of amlodipine-benazepril combination therapy compared with monotherapy in 150 patients aged ≥65 years diagnosed with hypertension and PPH. Patients were assigned to three groups (amlodipine-benazepril, amlodipine, or benazepril), and outcomes included the incidence of PPH after 4 weeks, 24 h ambulatory BPV at 6 months, changes in carotid intima-media thickness (cIMT), Crouse plaque score, renal function, left ventricular mass index (LVMI), and major adverse cardiovascular events (MACE) over 12 months. The combination therapy group demonstrated a lower incidence of PPH, greater reductions in BPV, improved vascular and renal parameters, and fewer MACE compared with either monotherapy group. No severe adverse events were reported. These findings provide preliminary evidence that amlodipine-benazepril combination therapy may enhance hemodynamic stability and organ protection in elderly patients with PPH. However, given the retrospective, single-center design, the results should be interpreted with caution, and larger prospective studies are warranted.

Introduction

Hypertension remains a major global health burden and a leading cause of cardiovascular disease and mortality, particularly in the elderly population¹. With increasing age, the prevalence of hypertension escalates, often coexisting with age-related syndromes such as postprandial hypotension (PPH)². PPH is defined as a decline of ≥20 mmHg in systolic blood pressure (SBP) within two hours after a meal, or a drop to <90 mmHg in those with premeal SBP ≥ 100 mmHg, often accompanied by symptoms such as dizziness, syncope, or visual disturbances³. It has important clinical consequences, including increased risks of falls, cognitive impairment, and cardiovascular events. Recent epidemiological evidence indicates that PPH is highly prevalent in China, affecting approximately 20-30% of community-dwelling elderly adults, with higher rates reported in those with concomitant hypertension or diabetes^2,3. A large population-based study from China further confirmed that hypertension is a major predictor of PPH, underscoring both the burden of this disorder and the importance of targeted antihypertensive management⁴. Despite its frequency and prognostic importance, PPH remains under-recognized and inadequately managed in routine practice.

The pathophysiology of PPH is multifactorial. Age-associated autonomic dysfunction and impaired baroreflex sensitivity limit compensatory vasoconstriction following meal-induced splanchnic vasodilation^2,5. Additional contributors include reduced arterial compliance, diminished plasma volume, and nutrient-mediated hormonal responses such as insulin- or GLP-1-driven vasodilation^4,6. Importantly, the fall in postprandial blood pressure is driven by meal ingestion, and nutrient-gut interactions play a central role. The rate of gastric emptying^7,8, the composition of ingested nutrients⁹, and the subsequent digestion and absorption of macronutrients along different segments of the small intestine critically determine the magnitude and timing of the hemodynamic response. Furthermore, nutrient exposure in distinct intestinal regions stimulates gut hormone secretion that modulates vascular tone and splanchnic blood flow¹⁰. Emerging studies also implicate gut-nutrient interactions: dietary macronutrient composition and gut microbiome-derived metabolites, particularly short-chain fatty acids, modulate vascular tone and may influence both postprandial hemodynamics and 24 h blood pressure variability (BPV)¹¹. Moreover, observational studies have shown that PPH-related blood pressure fluctuations are most pronounced after breakfast and are temporally associated with increased cardiovascular events, including myocardial infarction and stroke^2,12. These findings highlight the complex interplay of vascular, neural, and metabolic factors in PPH.

BPV itself has become recognized as an independent prognostic marker beyond mean blood pressure levels¹³. Excessive BPV is associated with left ventricular hypertrophy, renal impairment, cognitive decline, and major adverse cardiovascular events (MACE)^14,15. Elderly patients with both hypertension and PPH exhibit particularly pronounced BPV, owing to impaired autonomic regulation, altered circadian rhythms, and polypharmacy^16,17. Effective therapeutic strategies should therefore target both stabilization of postprandial hemodynamics and reduction of BPV.

Various pharmacological approaches for PPH have been explored, including acarbose, caffeine, fludrocortisone, and midodrine^18,19. However, these agents often yield inconsistent results, have limited evidence in elderly cohorts, or pose tolerability concerns such as fluid retention or supine hypertension. Among antihypertensive strategies, thiazide diuretics and β-blockers may worsen postprandial hypotension by reducing plasma volume or blunting compensatory heart rate responses^20,21,22. In contrast, renin-angiotensin system blockers (ACE inhibitors, ARBs) and calcium channel blockers (CCBs) exert vascular protective effects while improving arterial compliance and BPV^23,24. Combination regimens of CCBs with ACE inhibitors have consistently demonstrated superior blood pressure control and end-organ protection compared with monotherapy²⁵. Amlodipine-benazepril is a well-established fixed-dose combination that targets complementary mechanisms-calcium-mediated vasoconstriction and renin-angiotensin-aldosterone system activation^25,26. Clinical trials have shown that this regimen provides more consistent blood pressure reduction, lowers BPV, and reduces cardiovascular risk in hypertensive populations. Yet, its specific role in elderly patients with PPH has not been adequately investigated^27,28.

Elderly patients represent an especially suitable population for such intervention because they often have impaired baroreflex sensitivity, vascular stiffening, and multiple comorbidities that exacerbate BPV and increase susceptibility to PPH. In this high-risk group, a therapeutic approach that simultaneously stabilizes baseline blood pressure and attenuates postprandial drops may confer substantial clinical benefits.

Based on this rationale, we conducted a retrospective cohort study to evaluate the effects of amlodipine-benazepril therapy compared with monotherapy on PPH incidence, blood pressure variability, vascular and renal parameters, and cardiovascular outcomes in elderly hypertensive patients.

Protocol

This study was a retrospective, non-interventional analysis involving no prospective patient enrollment or biological sampling. In accordance with institutional guidelines for retrospective medical record research, the ethics committee of Beilun District People's Hospital formally waived the requirement for ethical approval and informed consent. All procedures were conducted following the Declaration of Helsinki (2013 version).

Study design overview
This was a single-center, retrospective cohort study evaluating the effects of amlodipine-benazepril combination therapy versus monotherapy in elderly patients with hypertension and PPH. Electronic medical records (EMRs) were reviewed for patients treated in the Cardiology Department between November 1, 2022, and October 31, 2023. Patients were assigned to treatment groups based on the antihypertensive regimen documented at the time of discharge or outpatient follow-up. Follow-up data were collected at 4 weeks, 6 months, and 12 months post treatment initiation.

Patient identification and eligibility criteria
The hospital EMR system was queried using ICD-10 codes I10 (essential hypertension) and R55.1 (postprandial hypotension). Only patients aged 65 years or older with at least one documented blood pressure reading within 2 h after breakfast were included. The diagnosis of PPH was based on at least one of the following: (1) a systolic blood pressure (SBP) decrease of ≥20 mmHg within 120 minutes post-meal; (2) a postprandial SBP <90 mmHg when premeal SBP ≥100 mmHg; or (3) typical symptoms including dizziness, blurred vision, or near-syncope within 2 h postprandially. To ensure accuracy, blood pressure values had to be measured using validated automated oscillometric sphygmomanometers with regular calibration.

Patients were excluded if they had any of the following: (1) known allergy or intolerance to amlodipine or benazepril; (2) severe renal dysfunction defined as eGFR ≤ 30 mL∙min^-1∙1.73 m^-2, calculated using the CKD-EPI formula; (3) confirmed bilateral renal artery stenosis by Doppler ultrasound or CT angiography; or (4) baseline serum potassium exceeding 5.4 mmol/L.

Treatment assignment and medication administration
Eligible patients were retrospectively categorized into three treatment groups (n = 50 each). All medications were dispensed through the hospital pharmacy. Group A (Combination Group) received amlodipine 5 mg plus benazepril 10 mg once daily, orally. Group B received amlodipine 10 mg once daily, and Group C received benazepril 20 mg once daily. Patients were instructed to take medication with 150-200 mL of warm water within 30 minutes after breakfast. A registered nurse or clinical pharmacist provided instruction on administration timing and adherence expectations. Drug adherence was monitored through review of medication refill logs and notes from nursing follow-up interviews.

Clinical data collection and monitoring
Baseline data included demographic details, smoking history, and comorbidities (e.g., coronary artery disease, diabetes, dyslipidemia). Blood pressure, heart rate, and anthropometric data (weight, height, body mass index) were measured by trained nurses using standardized protocols.

Vascular ultrasound was performed with a 7.5 MHz linear array transducer. Longitudinal scans of the distal common carotid artery were obtained to measure intima-media thickness (cIMT) at three predefined sites, and the Crouse plaque score was recorded by summing discrete plaque thicknesses.

Cardiac ultrasound was performed using transthoracic echocardiography with a phased-array transducer. Parasternal long-axis and apical four-chamber views were recorded to assess LVMI, LVPWT, and IVST. All parameters were measured in triplicate, and the mean value was used in analysis. To minimize inter-observer variability, two independent sonographers (each with >5 years of experience) analyzed a random 15% sample of studies. Inter-observer intraclass correlation coefficients (ICC) for cIMT and LVMI exceeded 0.90, confirming high reproducibility. Discrepancies were resolved by consensus review. Ultrasound images were required to demonstrate clear intima-media interface with <0.1 mm variance across three contiguous sites, and echocardiographic views had to achieve optimal endocardial border delineation for LVMI calculation. Studies not meeting these benchmarks were repeated or excluded.

Blood samples were drawn from the antecubital vein after an 8-12 h overnight fast using standard vacutainer tubes. Serum was separated by centrifugation at 1,000 × g for 10 min at 4 °C, aliquoted, and analyzed on automated clinical chemistry analyzers. Serum creatinine was measured using enzymatic assays. Urine was collected as a first-morning midstream specimen and analyzed for microalbumin and creatinine using immunoturbidimetry and colorimetry, respectively. The urinary albumin-to-creatinine ratio (ACR) was calculated.

Postprandial blood pressure monitoring
Postprandial BP was assessed at week 4 under standardized conditions. After consuming a hospital-provided meal (approx. 450 kcal: 60% carbohydrate, 25% fat, 15% protein), patients were placed in a supine position in a quiet room. SBP and DBP were measured at 15, 30, 60, and 120 min using the same validated oscillometric monitor. All measurements were taken by nurses certified in cardiovascular monitoring, and calibration checks were performed prior to each session. To ensure reproducibility, all sphygmomanometers underwent monthly calibration against a mercury reference standard, and daily zero-checks were performed before use. Patients were instructed to remain resting and avoid caffeine or physical activity for 2 h postprandially. In typical PPH patients, the expected curve demonstrates a progressive SBP decline peaking at 30-60 min, with partial recovery by 120 min. Absence of this pattern or paradoxical BP increase triggered protocol deviation review.

Ambulatory blood pressure monitoring (ABPM)
At month 6, 24 h ABPM was performed using ambulatory monitors configured to record BP every 15 min during the day (06:00-22:00) and every 30 min at night (22:00-06:00). The cuff was placed on the non-dominant arm, and patients were instructed to maintain regular daily activities but avoid excessive motion during readings. ABPM devices were calibrated quarterly using manufacturer-recommended procedures against a mercury sphygmomanometer to minimize drift. Each monitor underwent validation with three consecutive reference readings before patient assignment. Data were analyzed to extract average BP values, BP variability (SD), and nocturnal dipping patterns. A minimum of 70 valid readings (including at least 14 nighttime values) was required for inclusion.

Assessment of longitudinal outcomes
At month 6, cIMT, plaque scores, serum creatinine, urinary ACR, and echocardiographic parameters were re-measured using the same equipment and procedures. At month 12, clinical follow-up was conducted by reviewing EMRs and conducting structured telephone interviews. MACE was defined as cardiovascular death, nonfatal myocardial infarction, stroke, or hospitalization for heart failure. Each potential MACE was adjudicated independently by two senior cardiologists blinded to group allocation, with discrepancies resolved by consensus.

Data management and statistical analysis
All study data were anonymized and stored on encrypted hospital servers with access restricted to study personnel. Double data entry and audit trails were implemented to ensure data integrity. Statistical analyses were performed. Normality was tested using the Shapiro-Wilk method. Continuous variables were presented as mean ± standard deviation or median (IQR) and compared using one-way ANOVA (with post-hoc Bonferroni correction) or Kruskal-Wallis tests as appropriate. Categorical variables were compared using chi-square or Fisher's exact tests. Binary logistic regression was used to identify factors independently associated with PPH at week 4. Time-to-event analysis for MACE was performed using Kaplan-Meier curves and Cox proportional hazards regression. For multiple pairwise comparisons of continuous variables, Bonferroni correction was applied following ANOVA or Kruskal-Wallis tests, and adjusted P values are reported where applicable. Statistical significance was set at two-tailed P < 0.05.

Results

Baseline characteristics
A total of 150 elderly hypertensive patients with PPH were enrolled and randomly assigned to three treatment groups (Figure 1): amlodipine-benazepril group (n = 50), amlodipine group (n = 50), and benazepril group (n = 50). Baseline demographic and clinical characteristics were well balanced across groups, with no statistically significant differences (all P > 0.05, Table 1). In addition to demographic features, basel...

Discussion

This retrospective cohort study proposes a novel therapeutic strategy using amlodipine-benazepril combination therapy to manage BPV and PPH in elderly hypertensive patients (Figure 6). Our findings demonstrated that the fixed-dose combination significantly reduced the incidence of PPH after 4 weeks, lowered 24 h BPV at 6 months, and improved vascular, renal, and cardiac parameters more effectively than either monotherapy. Furthermore, the combination group showed a lower rate of MACE over 12...

Materials

List of materials used in this article

Name	Company	Catalog Number	Comments
24 h ambulatory BP monitor	Schiller	BR-102 plus	ABPM with SD and circadian analysis; ABPM device; validated, calibrated quarterly
Amlodipine besylate tablets	Jiangsu Hengrui	H20000405	5 mg and 10 mg oral tablets
Benazepril hydrochloride tablets	Novartis Pharma	H20040289	10 mg and 20 mg oral tablets
Blood pressure monitor (automated)	Omron	HEM-7136	Validated oscillometric upper-arm model; validated oscillometric device; RRID: not available
Carotid ultrasound system	Mindray	DC-70	High-resolution B-mode scanner; linear array transducer, 7.5 MHz
Echocardiography machine	Philips	Affiniti 50	Used for LVMI and cardiac remodeling; phased-array transducer, used for LVMI/IVST
SPSS statistical software	IBM	SCR_002865	Version 23.0 for data analysis
Urine microalbumin test kit	Roche Diagnostics	6545225	Immunoturbidimetric assay