Clinical efficacy of amlodipine and benazepril hydrochloride tablets in controlling morning blood pressure surge (MBPS) in patients with arteriosclerosis

doi:10.21203/rs.3.rs-4935195/v1

Objective: This prospective, randomized, open-label, parallel-group clinical trial aimed to rigorously evaluate the influence of amlodipine besylate and benazepril hydrochloride tablets on nocturnal blood pressure patterns and morning blood pressure surge in a cohort of patients diagnosed with primary hypertension.

Methods: A total of 294 eligible patients with primary hypertension were randomly assigned to one of two treatment regimens: (1) Bisoprolol amlodipine tablets in the morning (Group A) or (2) Amlodipine besylate and benazepril hydrochloride tablets in the morning(Group B). After 24 weeks of intervention, the following parameters were meticulously compared between the two groups: office blood pressure, morning blood pressure surge, adverse events, 24-hour ambulatory blood pressure monitoring, and major adverse cardiovascular events (MACE). Additionally, the prognostic utility of morning blood pressure surge for predicting future MACE was explored.

Results: A total of 113 and 112 patients in Groups A and B, respectively, successfully completed the 24-week study protocol. Both treatment regimens elicited statistically significant reductions in blood pressure; however, the decrease in diastolic blood pressure was markedly greater in Group B versus Group A (p<0.05). Analysis of the 24-hour ambulatory blood pressure monitoring data revealed an interesting pattern. After 24 weeks, no between-group differences were detected in the variation of daytime ambulatory blood pressure. In contrast, the reductions in nighttime ambulatory systolic and diastolic blood pressure were significantly more pronounced in Group B versus Group A (p<0.05). Furthermore, the morning systolic and diastolic blood pressures were notably higher in Group A versus Group B at the end of the study. Importantly, the magnitude of the morning blood pressure surge was significantly lower in Group B versus Group A (p<0.05). During the subsequent 12-month follow-up period, a total of 42 MACE were observed, with 26 events occurring in Group A and 16 in Group B. Receiver operating characteristic (ROC) curve analysis identified optimal cutoff values for predicting MACE of 27.5 mmHg for morning systolic blood pressure surge (AUC=0.698) and 24.5 mmHg for morning diastolic blood pressure surge (AUC=0.701).

Conclusion: In this population of hypertensive patients, morning blood pressure surge demonstrates moderate prognostic value for future MACE. Importantly, the regimen of administering amlodipine besylate and benazepril hydrochloride tablets in the morning was found to be an effective strategy for improving nocturnal blood pressure, attenuating morning blood pressure surge, and conferring significant long-term cardiovascular benefits.

Health sciences/Cardiology

Health sciences/Health care

hypertension

chronotherapy

morning blood pressure surge

amlodipine

benazepril

Hypertension is a major global public health concern and a potent risk factor for cardiovascular diseases, including stroke, coronary artery disease, heart failure, chronic kidney disease, and aortic and peripheral arterial diseases [1]. Arteriosclerosis represents a comorbidity of hypertension, wherein the occurrence of arteriosclerosis in hypertensive patients leads to intimal thickening, diminished elasticity, vena cava constriction, and consequent target organ ischemia due to vascular stenosis or occlusion [2, 3]. This vascular insufficiency manifests in clinical conditions such as angina pectoris, acute myocardial infarction, chronic heart failure, ischemic stroke, and renal impairment. Blood pressure (BP) exhibits a distinct circadian rhythm, with most populations experiencing a nocturnal decline and a morning surge [2]. The morning period is accompanied by significant neuroendocrine changes, particularly the activation of the sympathetic nervous system, which commonly leads to a rapid increase in BP, known as the morning blood pressure surge (MBPS) [3]. Although MBPS is a physiological phenomenon, growing clinical evidence has shown that the morning period is the time of highest incidence of major cardiovascular events, such as myocardial infarction, sudden cardiac death, or stroke, and is closely associated with MBPS [4]. Therefore, it is essential for hypertensive patients to adhere to a chronotherapeutic approach in medication administration to maintain a normal circadian rhythm of blood pressure.

The ideal antihypertensive drug can sustain its therapeutic effects over 24 hours, preserving the normal circadian BP pattern with a nocturnal BP reduction [5]. The average nighttime BP is considered a predictor of cardiovascular morbidity and mortality, and an attenuated or non-dipping nighttime BP pattern, compared to daytime, is associated with an increased risk of organ damage, particularly left ventricular hypertrophy, congestive heart failure, and myocardial infarction, indicating a poor prognosis for the patient [6, 7]. Current hypertension guidelines recommend that for patients with uncontrolled hypertension on monotherapy, the combination of an angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) with a calcium-channel blocker (CCB) or a thiazide diuretic has a synergistic effect in BP control [8]. Previous studies have shown that the combination of amlodipine/benazepril and benazepril/hydrochlorothiazide have comparable reductions in ambulatory systolic BP, and amlodipine/benazepril has a more pronounced daytime BP-lowering effect compared to benazepril/hydrochlorothiazide [9]. Amlodipine besylate and benazepril hydrochloride tablets, a compound formulation composed of two distinct drug classes, exhibit superior efficacy in blood pressure control compared to monotherapy, while maintaining a commendable safety profile and offering a viable alternative [10]. Amlodipine, classified as a calcium channel blocker, stands as a preferred antihypertensive agent, exerting its influence through the stabilization of blood pressure levels and demonstrating therapeutic efficacy in the management of coronary heart disease [8]. Upon administration, the constituents of the medication facilitate vasodilation of both coronary and peripheral arteries, thereby reducing vascular arterial pressure and effectively achieving blood pressure regulation [9]. Conversely, benazepril contributes to blood pressure reduction and additionally enhances the treatment of coronary heart disease. Functioning as an angiotensin-converting enzyme inhibitor, benazepril inhibits the enzymatic activity of angiotensin-converting enzyme upon elevation of its concentration, leading to diminished vascular resistance and other favorable effects, ultimately culminating in the attainment of optimal blood pressure levels and exerting a regulatory effect [11]. Furthermore, its utility extends to the management of morning blood pressure in hypertensive patients with concomitant arteriosclerosis, as it elicits vasodilatory effects on both venous and arterial vessels, alleviates cardiac workload and peripheral vascular resistance, thereby promoting the recovery of patients with coronary heart disease and engendering a synergistic therapeutic outcome [12]. Thus, in elucidating the optimal paradigm for hypertension medication management, we conducted a comparative analysis of the impact of Bisoprolol amlodipine tablets and Amlodipine besylate and benazepril hydrochloride tablets on dynamic blood pressure and morning blood pressure, thereby providing evidence-based medicine to refine the optimization of hypertension management protocols.

2.1 Study Design

This was a prospective, randomized, open-label, parallel-group study. Participants were recruited from the cardiology outpatient clinic of our hospital between October 2021 and June 2023. A total of 294 eligible patients were enrolled and randomly assigned. The study included two treatment groups: one received bisoprolol amlodipine tablets in the morning (Group A), and the other received amlodipine besylate and benazepril hydrochloride tablets in the morning (Group B). The study protocol was reviewed and consented by the Institutional Ethics Committee of Shaoxing Central Hospital, and all procedures were conducted as per the ethical principles in the Declaration of Helsinki. All participants signed written informed consent before enrollment.

2.2 Inclusion and Exclusion Criteria

Inclusion criteria were: (1) age between 50 and 75 years, regardless of sex; (2) diagnosed with hypertension according to the criteria of ambulatory blood pressure monitoring (ABPM): systolic blood pressure (SBP) > 130 mmHg and diastolic blood pressure (DBP) > 90 mmHg; (3) untreated or with uncontrolled hypertension on monotherapy; and (4) Presence of characteristics of arteriosclerosis, including: a) Carotid atherosclerosis: Carotid ultrasound showing intima-media thickness (IMT) ≥ 0.9 mm or the presence of an atherosclerotic plaque, carotid artery stenosis, or a history of carotid artery revascularization. b) Arteriosclerosis of lower limbs: Presence of arterial plaque in the lower limbs or an ankle brachial index (ABI) < 0.9, lower limb arterial stenosis, or a history of lower limb revascularization. c) Aortic syndrome: Presence of aortic atherosclerosis, aortic intramural hematoma, or a local aortic ulcer. d) Coronary atherosclerosis or coronary heart disease: Detection of coronary artery plaque or stenosis through coronary artery CT or coronary angiography, a history of myocardial infarction or typical angina pectoris, or a history of coronary artery revascularization. e) History of stroke or transient ischemic attack (TIA): Includes both ischemic stroke and TIA. f) Fundus arteriosclerosis: Scheie grade 2 or above in the fundus.

Exclusion criteria were: (1) known or suspected resistant hypertension, hypertensive emergency, or secondary hypertension; (2) concomitant severe cardiovascular or cerebrovascular diseases; (3) allergy to ACEI or CCB components; (4) reverse-dipping hypertension; and (5) severe neurological or psychiatric disorders that would prevent adequate understanding and cooperation.

2.3 Antihypertensive Treatment

All participants underwent a 2-week washout period after enrollment to exclude the influence of prior medications on blood pressure. They were then randomly assigned to receive drugs in the morning (6:30 to 7:30). The initial doses were amlodipine besylate and benazepril hydrochloride tablets 12.5mg (Yangzijiang Pharmaceutical Group Guangzhou Hairui Pharmaceutical Co., Ltd., National Pharmaceutical Approval No. H20110072; compound ingredients: amlodipine 5 mg, benazepril hydrochloride 10 mg); bisoprolol amlodipine tablets 5mg [Approval Number/Production License Number: National Medical Standard HJ20210030; Egis Pharmaceuticals PLC (Hungary)]. These medications were administered during follow-up visits with the aim of achieving a target clinical systolic/diastolic blood pressure below 140/90 mmHg.

2.4 Follow-up and Outcome Measures

During the study, the dynamic blood pressure of each enrolled patient was recorded 24 hours before initiating medication. Following medication administration, sitting blood pressure was measured three times consecutively before meals and emptying the bladder in the morning, and the average of these measurements was recorded on a daily basis for a duration of 8 weeks. After the 24-week intervention period, comprehensive 24-hour ABPM was conducted, with oscillometric measurements obtained every 30 minutes. The 24-hour blood pressure was defined as the overall mean of all readings within the full diurnal cycle. Daytime blood pressure was calculated as the average of values recorded from 8:00 to 22:00, nighttime blood pressure as the mean of readings from 0:00 to 6:00, and morning blood pressure as the mean of measurements from 6:00 to 8:00. The nadir nocturnal blood pressure was defined as the mean of the three readings centered on the lowest nighttime value. The MBPS was calculated as the difference between the highest morning blood pressure and the lowest nighttime blood pressure.

2.5 Follow-up Outcome

All participants were followed closely on a monthly basis, and the occurrence of MACE, including stroke, acute coronary syndrome, cardiovascular mortality, acute decompensated heart failure was meticulously documented.

2.6 Statistical Analysis

Continuous variables are reported as mean ± standard deviation (x̄ ± s) and were compared using independent samples t-test for between-group analyses and paired samples t-test for within-group comparisons over time. Categorical data are expressed as frequencies (percentages, n (%)) and were compared using the chi-square test. For participants experiencing multiple outcome events, only the first event was included in the analysis. Receiver operating characteristic (ROC) curve analysis was employed to evaluate the predictive accuracy of MBPS for MACE, and the optimal cut-off value was determined to assess the specificity and sensitivity of MBPS for MACE prediction. All statistical differences were defined with a probability value of p < 0.05, and were performed using the R software platform (Version 3.6.3).

3.1 Baseline patient characteristics

Among the 294 recruited patients, 59 patients withdrew from the study, including 42 patients with unqualified blood pressure, 5 patients who withdrew informed consent, and 12 patients who could not tolerate coughing. A total of 225 patients were included in the study. After randomization, 113 and 112 patients were assigned to Groups A and B, respectively, and underwent effective repeated ambulatory blood pressure monitoring and were included in the efficacy analysis. At baseline, the two groups were comparable in all basic characteristics, clinical features, and blood pressure parameters. The office SBP and DBP were (155.36 ± 10.36) mmHg and (93.25 ± 7.36) mmHg in Group A, and (154.25 ± 9.62) mmHg and (95.25 ± 8.14) mmHg in Group B, respectively (Table 1).

Table 1

Baseline characteristics of randomized enrollments
	Group A	Group B	t/χ2	P
n	113	112
Age (years)	56.36 ± 11.05	58.19 ± 9.43	1.336	0.183
Men (n, %)	71 (62.83)	65 (58.04)	0.541	0.462
Body mass index (kg/m2)	24.96 ± 2.56	25.17 ± 2.85
Hypertensive course (years)	5.68 ± 1.75	4.72 ± 0.17
Previous antihypertensive treatment (n, %)	59 (52.21)	63 (56.25)	0.369	0.543
Diabetes mellitus (n, %)	6 (5.31)	8 (7.14)	0.324	0.569
Current smoking (n, %)	36 (34.86)	44 (39.29)	1.354	0.245
Outpatient blood pressure (mmHg)
SBP	155.36 ± 10.36	154.25 ± 9.62	0.833	0.406
DBP	93.25 ± 7.36	95.25 ± 8.14	1.933	0.054
Baseline Ambulatory blood pressure (mmHg)
SBP	144.36 ± 11.36	146.18 ± 14.44	1.051	0.294
DBP	87.29 ± 9.36	88.36 ± 11.13	0.781	0.436
Day-SBP	149.30 ± 14.29	148.97 ± 15.27	0.167	0.867
Day-DBP	91.36 ± 9.28	92.25 ± 10.21	0.684	0.494
Night-SBP	134.38 ± 16.27	133.93 ± 15.38	0.213	0.831
Night -DBP	81.24 ± 10.02	79.58 ± 11.22	1.171	0.243

3.2 Changes in outpatient blood pressure

During the follow-up period, office blood pressure was measured every 4 weeks. The blood pressure of both groups significantly decreased after 4 weeks of treatment, but the between-group difference in SBP/DBP was insignificant (p > 0.05). The longitudinal changes in clinical blood pressure during the follow-up period are depicted in Fig. 1. At the completion of the 24-week intervention, the office SBP and DBP in Group A decreased by -28.26 ± 2.04 mmHg and − 11.33 ± 1.83 mmHg, respectively, compared to baseline values. Correspondingly, the office SBP and DBP in Group B decreased by -27.32 ± 1.95 mmHg and − 13.43 ± 2.03 mmHg, respectively, from baseline. The between-group comparison revealed no statistically significant difference in the magnitude of SBP reduction from baseline. In contrast, the decrease in DBP from baseline was significantly greater in Group B versus Group A (p < 0.05). The changes in office SBP and DBP at the end of the 24-week follow-up period are summarized in Table 2.

Table 2

Difference of SBP and DBP from baseline to 24 weeks
	n	ΔSBP	ΔDBP
Group A	113	-28.26 ± 2.04	-11.33 ± 1.83
Group B	112	-27.82 ± 1.95	-13.43 ± 2.03
t		1.654	8.151
P		0.100	< 0.001

3.3 Ambulatory blood pressure profiles

All participants underwent 24-hour ambulatory blood pressure monitoring before enrollment and upon completion of the 24-week treatment period. The changes (Δ) in average ambulatory systolic and diastolic blood pressures (SBP/DBP), as well as the daytime (08:00–22:00) and nighttime (00:00–06:00) ambulatory blood pressure parameters, were calculated between baseline and the end of the study.

At the conclusion of the trial, the between-group comparison revealed no significant differences in the changes of overall 24-hour ambulatory SBP and DBP. However, when the daytime and nighttime ambulatory blood pressure components were analyzed separately, an interesting pattern emerged. The changes in daytime ambulatory SBP and DBP were statistically comparable between the two groups. In contrast, the reductions in nighttime ambulatory SBP and DBP were significantly greater in Group B versus Group A (p < 0.05), as shown in Table 3.

Table 3

Changes in ambulatory blood pressure
	Group A	Group B	t	P
n	113	112
ΔSBP	−12.28 ± 2.11	−12.43 ± 2.27	0.513	0.608
ΔDBP	−9.31 ± 1.76	−8.89 ± 1.68	1.831	0.068
ΔDay-SBP	−12.22 ± 1.89	−12.24 ± 1.83	0.081	0.936
ΔDay-DBP	−7.81 ± 1.87	−8.12 ± 1.71	1.297	0.196
ΔNight-SBP	−13.36 ± 2.33	−14.61 ± 1.47	4.808	< 0.001
ΔNight-DBP	−8.21 ± 1.32	−9.57 ± 1.85	6.352	< 0.001

3.4 Changes in morning blood pressure and morning blood pressure surge

Following the 24-week treatment period, morning blood pressure (measured from 06:00–08:00) and the MBPS were evaluated. The analysis revealed that at the end of the study, the morning SBP and DBP were significantly lower in Group B compared to Group A (p < 0.05). Furthermore, the magnitude of the MBPS-SBP was significantly attenuated in Group B relative to Group A (p < 0.05), as summarized in Table 4.

Table 4

Changes in morning blood pressure and morning blood pressure surge
	n	morning-SBP	morning-DBP	MBPS-SBP	MBPS-DBP
Group A	113	151.32 ± 11.36	88.39 ± 8.93	27.86 ± 1.53	24.54 ± 1.61
Group B	112	145.36 ± 12.41	84.57 ± 9.18	25.16 ± 1.36	21.22 ± 1.52
t		3.758	2.690	13.99	15.90
P		< 0.001	0.008	< 0.001	< 0.001

These findings suggest that the treatment intervention in Group B was particularly effective in mitigating the exaggerated morning blood pressure rise, which is an important determinant of cardiovascular risk.

3.5 Adverse events

Adverse events occurring during the intervention period were recorded. At least one adverse event occurred in 38.67% (87/225) of all patients, and no serious adverse events occurred. The most common adverse events were hyperuricemia, dry cough, dizziness, and hypokalemia. There was no significant difference in the occurrence of adverse events between the two groups, and the proportion of patients with at least one adverse event was also similar between the two groups, indicating similar safety profiles (all p > 0.05), as shown in Table 5.

Table 5

Adverse events
	n	Dizziness	Hyperuricemia	Hypokalemia	dry cough	Others	≥ 1 AEs
Total	225	21	27	20	22	44	87
Group A	113	12	12	9	14	20	46
Group B	112	9	15	11	8	24	41
χ2		0.444	0.410	0.240	1.755	0.497	0.399
P		0.505	0.522	0.625	0.185	0.481	0.528

3.6 MACE event rate and the predictive value of morning blood pressure surge

After 12 months of follow-up, a total of 42 cardiovascular events occurred, including 26 in Group A and 16 in Group B, and the MACE event rate did not differ significantly between the two groups (p > 0.05). ROC curve analysis was used to evaluate the optimal cut-off values and diagnostic performance of MBPS-SBP and MBPS-DBP in predicting MACE events. The optimal cut-off value of MBPS-SBP for predicting MACE events was 27.5, with a specificity of 0.712 and a sensitivity of 0.619, and the AUC was 0.698; the optimal cut-off value of MBPS-DBP for predicting MACE events was 24.5, with a specificity of 0.717 and a sensitivity of 0.607, and the AUC was 0.701. The ROC curves for blood pressure surge predicting MACE events are shown in Fig. 2, and the diagnostic performance is shown in Table 6.

Table 6

Diagnostic efficacy of MBPS-BP in AMCE
	Cut-off value	specificity	sensitivity	AUC
MBPS-SBP	27.5	0.712	0.619	0.698
MBPS-DBP	24.5	0.717	0.607	0.701

The principle of using combination therapy with compound formulations for hypertension is based on the synergistic effects of drugs with different mechanisms of action or their ability to counteract certain adverse reactions. Bisoprolol, a selective β1-adrenergic receptor antagonist, exerts its antihypertensive effect by inhibiting excessive sympathetic nervous system activity, suppressing myocardial contraction, and reducing heart rate. Amlodipine, a dihydropyridine calcium channel blocker, selectively dilates peripheral arteries, lowers peripheral vascular resistance, and produces sustained antihypertensive effects. The combination of these two agents not only achieves additive antihypertensive effects through different mechanisms but also partially mitigates the adverse reflex tachycardia caused by amlodipine, thanks to the properties of bisoprolol. Developing bisoprolol and amlodipine as a compound formulation significantly improves medication adherence in patients and holds important implications for blood pressure control and management in hypertensive individuals. Amlodipine and benazepril are recognized as complementary antihypertensive medications, and their combination significantly reduces the incidence and mortality rates of cardiovascular diseases [8, 9]. Amlodipine besylate and benazepril hydrochloride tablets are commonly used as single-pill combination formulations in clinical practice. Dynamic blood pressure monitoring contributes to clinical guidance and optimization of hypertension management. This study provides amlodipine besylate and benazepril hydrochloride tablets antihypertensive therapy showed significant improvement in nighttime blood pressure and morning blood pressure peaks compared to bisoprolol amlodipine tablets. Moreover, the MBPS is identified as a valuable predictor of MACE. The utilization of single-pill combination therapy is a pivotal approach to enhance therapeutic efficacy and minimize adverse reactions in pharmacological treatment [12]. The findings of this study provide evidence supporting the effectiveness of benazepril, one of the components in the compound drug amlodipine besylate and benazepril hydrochloride tablets, in better controlling nighttime blood pressure. While morning administration is widely adopted, it fails to fully account for the 24-hour circadian rhythm and the consequent fluctuations in blood pressure. As a result, there is an inherent limitation in achieving optimal blood pressure control, particularly during the MBPS [13].

Recognizing this limitation, the utilization of single-pill combination therapy for the management of masked hypertension (MBPS) has garnered considerable attention, although consensus regarding its effectiveness is still pending [14, 15]. Notably, research studies have reported remarkable therapeutic efficacy associated with single-pill combination formulations in terms of reducing MBPS, improving overall blood pressure control, preserving organ function, and preventing cardiovascular events [16].

Furthermore, hypertension, when accompanied by atherosclerosis, can lead to the progression of severe cardiovascular diseases such as coronary heart disease. Consequently, proactive treatment becomes imperative to achieve blood pressure control and enhance patient prognosis [10]. A commonly employed medication in the clinical management of hypertension and coronary heart disease is amlodipine. By acting upon cellular membrane calcium channels in cardiac and smooth muscle cells, it inhibits the transmembrane influx of calcium ions (Ca2+), thereby reducing intracellular Ca2 + concentration. This mechanism elicits vasodilation and lowers blood pressure. Amlodipine also exhibits peripheral small artery and coronary artery dilation properties, alleviates coronary artery spasm, and ameliorates symptoms of angina pectoris in affected individuals [17].

Nevertheless, the therapeutic efficacy of amlodipine as a monotherapy exhibits certain limitations. To address this, amlodipine besylate and benazepril hydrochloride tablets have been developed as a compound formulation. This formulation combines amlodipine with the angiotensin-converting enzyme inhibitor benazepril. The latter exerts its effects by inhibiting the physiological activity of angiotensin-converting enzyme, thereby reducing the production of angiotensin II. Consequently, small artery constriction is impeded, leading to blood pressure reduction [18]. Moreover, benazepril has been reported to control aldosterone secretion, minimize water and sodium retention, and inhibit endothelin production in endothelial cells. These actions contribute to improvements in left ventricular remodeling and diastolic dysfunction [19]. Amlodipine besylate and benazepril hydrochloride tablets exert a synergistic antihypertensive effect, enabling superior blood pressure control, effective management of atherosclerosis progression, simplified medication regimens, and enhanced patient adherence [20]. A prospective, open-label, randomized, and blinded endpoint trial has demonstrated that compared to taking at least one antihypertensive medication at night, single-pill combination therapy for hypertension [18] significantly improves blood pressure variability and reduces the risk of major adverse cardiovascular events. Collectively, the findings of this study underscore the potential of amlodipine besylate and benazepril hydrochloride tablets to achieve superior control of morning and evening blood pressure levels while alleviating MBPS.

Previous investigations have substantiated the highest incidence of myocardial infarction, sudden death, and stroke occurring in the morning. The precise mechanism underlying the augmented cardiovascular events during the morning remains unclear, but it is postulated to be closely associated with elevated morning blood pressure [20]. A cohort study reported that every 1 mmHg increase in morning blood pressure confers a 2.1% increment in the risk of cardiovascular mortality [21].

Mounting evidence suggests that the morning blood pressure surge is closely linked to cardiovascular events, strokes, and renal function impairment [22–25]. This is due to the circadian rhythm pattern, where glomerular filtration rate is maximal during the day and minimal at night, requiring appropriate selection of antihypertensive medications [26]. Studies have shown that single-pill combination formulations of antihypertensive drugs exhibit different pharmacokinetic characteristics depending on the specific combination of medications. For instance, calcium channel blockers such as nifedipine and beta-blockers like propranolol and atenolol can result in higher peak concentrations and shorter time to reach peak concentration in the morning. On the other hand, ACE inhibitors have a longer duration of action [27]. Literature has demonstrated that amlodipine besylate and benazepril hydrochloride tablets can significantly modulate the circadian rhythm, shifting it towards a more physiological nighttime decrease. This is closely associated with the diurnal variations of the renin-angiotensin-aldosterone system and its enhanced activation during nighttime sleep [28]. Furthermore, benazepril, which is present in amlodipine besylate and benazepril hydrochloride tablets, is a third-generation ACE inhibitor that not only effectively lowers blood pressure but also delays and reverses ventricular remodeling, prevents further myocardial hypertrophy, improves endothelial function and cardiac performance, reduces the incidence of arrhythmias, and enhances survival and prognosis [29].

However, it is important to consider medication adherence, as once-daily antihypertensive regimens generally exhibit the highest compliance compared to more frequent dosing schedules.

In conclusion, this study emphasizes the clinical benefits of utilizing single-pill combination formulations in the management of hypertension. The findings highlight the significant role of amlodipine besylate and benazepril hydrochloride tablets in effectively controlling nocturnal blood pressure, alleviating masked hypertension, and ultimately improving long-term prognosis. Future hypertension guidelines should consider integrating chronotherapy principles to maximize treatment efficacy and optimize cardiovascular risk reduction.

Conflict of Interest Disclosures:

The authors declared no potential conflict of interest with respect to the research, authorship, and/or publication of this article.

Funding:

This work was supported by Clinical Research Foundation of Zhejiang Medical Association (2021ZYC-A185).

Author Contribution

Author Contributions:LIqin Zhang and Fang Ren: Conceptualization, Data Analysis, Writing - Original DraftYouying Zhao and Hailiang Ma: Data Collection, Data Analysis, Review & EditingJianyao Shen: Funding Acquisition, Project Administration, manuscript reviewAll authors reviewed the manuscript.

Data Availability

The datasets used and/or analysed during the current study available from the corresponding author on reasonable request.

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No competing interests reported.

Clinical efficacy of amlodipine and benazepril hydrochloride tablets in controlling morning blood pressure surge (MBPS) in patients with arteriosclerosis

Status:

Version 1

Abstract

Figures

Introduction

Materials and Methods

Results

Discussion

Declarations