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The purpose of this study was to elucidate the therapeutic effect of different antihypertensive drugs (amlodipine and perindopril) on hypertension induced by apatinib and bevacizumab. Sixty patients with hypertension treated with apatinib or bevacizumab were selected and divided into two groups: one group was treated with amlodipine and the other group was treated with perindopril. Before and after treatment, the dynamic blood pressure (BP) measurement (systolic BP [SBP] and diastolic BP [DBP]), echocardiography (left ventricular end-diastolic diameter, interventricular septal thickness [IVST], left ventricular posterior wall thickness [LVPWT], and left atrial diameter [LAD]), and detection of nitric oxide (NO) content in venous blood were performed. In the amlodipine group, the 24hSBP, 24hSSD, 24hSCV, daytime mean SBP (dSBP), daytime mean SSD (dSSD), daytime mean SBP CV, night mean SBP (nSBP), night mean SSD, 24hDBP, 24hDSD, 24 h DBP CV, daytime mean DBP (dDBP), daytime mean DSD (dDSD), daytime mean DBP CV, night mean DBP (nDBP), LAD, and LAD index (LADi) after treatment were all lower than before treatment, while NO was higher than before treatment (all P < 0.05). In the perindopril group, the 24hSBP, dSBP, nSBP, 24hDBP, dDBP, nDBP, LAD, LADi, IVST, LVPWT, and left ventricular mass index (LVMI) after treatment were lower than before treatment, and NO level after treatment was higher than before treatment (all P < 0.05). After treatment, the 24hSBP, 24hSSD, dSBP, dSSD, nSBP, 24hDBP, 24hDSD, dDBP, dDSD, nDBP, night mean DSD, and NO were all lower while the LAD, LADi, IVST, LVPWT, and LVMI were higher in the amlodipine group than those in the perindopril group (all P < 0.05). Our study suggests that the SBP and DBP variability of amlodipine in the treatment of hypertension induced by apatinib and bevacizumab is slightly better than that of perindopril, but the effect of perindopril in improving endothelial function indices NO and echocardiographic data is better than that of amlodipine.
Keywords: Amlodipine, antihypertensive drugs, apatinib, bevacizumab, blood pressure variability, hypertension, perindopril
How to cite this URL:
Zhao W, Liu L, Chen L. Comparison of antihypertensive drugs amlodipine and perindopril on blood pressure variability after long-term treatment of hypertension induced by apatinib and bevacizumab. Chin J Physiol [Epub ahead of print] [cited 2023 May 29]. Available from: https://www.cjphysiology.org/preprintarticle.asp?id=377108 |
| Introduction | |  |
Hypertension is a significant adverse event resulting from anti-angiogenic antitumor drugs, and elevated blood pressure (BP) not only leads to the cessation of antitumor therapy but also aggravates the occurrence of cardiovascular events.[1] Apatinib, as a novel and selective tyrosine kinase inhibitor of vascular endothelial growth factor receptor-2, is known as the second anti-angiogenic drug approved in the treatment of gastric cancer in China.[2] However, in the course of apatinib treatment, some subsequent adverse events, especially hypertension, can result in dose reduction or termination of drug therapy in some well-responding patients.[3] Bevacizumab, as a recombinant humanized monoclonal antibody targeting VEGF, has been approved by the U.S. Food and Drug Administration for the therapy of diverse metastatic cancers.[4] Nevertheless, hypertension is usually observed in the course of bevacizumab treatment, and the high-grade toxicity of hypertension can limit treatment and further results in other cardiovascular complications.[5] Over the last decade, the improved hypertension awareness, treatment, and control in some regions contribute to diminish in adverse cardiovascular outcomes, but further efforts to expand these developments are still recommended.
Antihypertensive therapy includes the use of angiotensin receptor blockers (ARBs), calcium channel blockers (CCBs), angiotensin-converting enzyme inhibitors (ACEIs), as well as thiazide diuretics.[6],[7] These aforesaid prescribed drugs can be administered alone, or make a combined treatment with other drugs to increase treatment adherence.[8] Amlodipine is a commonly prescribed long-term acting dihydropyridine CCB, which has long been recommended as an antihypertensive agent for hypertension therapy.[9] Perindopril is defined as a prodrug that is hydrolyzed into the active metabolite perindoprilat, which suppresses ACE at the levels of plasma and tissue.[10] There are articles demonstrating that the combination of perindopril and amlodipine has successfully reduced BP in patients with ischemic heart disease, coronary artery disease, as well as hypertension.[11],[12],[13],[14] Specifically, the administration of the perindopril and amlodipine combination exhibits an outstanding impact on the reduction of systolic BP (SBP), diastolic BP (DBP), mean BP, pulse pressure, as well as heart rate.[15] In clinical practice, BP measurements offer superior results, reproducibility, and assessment of the influence of antihypertensive drugs.[16] The clinical implications of BP variability (BPV) are obvious in terms of hypertension diagnosis because of the challenges related to making a precise diagnosis in clinical practice with traditional methods.[17] Perindopril and amlodipine have been researched in some large and outcome-based randomized clinical trials, and both of them are independently related to diverse ameliorative long-term cardiovascular outcomes.[18] However, this study aimed to compare two antihypertensive agents, amlodipine and perindopril, on BPV after long-term treatment for apatinib- and bevacizumab-induced hypertension. We first used dynamic BP measurement and echocardiography to evaluate the efficacy and BPV of amlodipine and perindopril treatments, accompanied with determination of plasma levels of nitric oxide (NO) of patients.
| Materials and Methods | | |
Ethical approval
The study for clinical samples got approval from the Ethics Committee of The Fourth Hospital of Hebei Medical University (approval number: 20210321), and the informed consent was acquired from all the participants.
Participants
From June 2021 to December 2021, 60 hospitalized patients who had treated with apatinib or bevacizumab for tumors that caused hypertension in our hospital were enrolled for experimentations. All the cases were confirmed as malignant tumors by relevant examination, involving 15 kinds of tumors, including gastric cancer, lung cancer, breast cancer, esophageal cancer, rectal cancer, and cervical cancer. Baseline BP levels were within the normal range before application of antitumor agents. The basic information of the patients is listed in [Table 1].
Inclusion criteria: (1) Normal BP was measured in patients before the administration of apatinib or bevacizumab. (2) Patients had normal spirit and were able to complete the study.
Exclusion criteria: (1) Patients were accompanied with cerebrovascular disease, coronary revascularization, myocardial infarction, congestive heart failure, unstable angina pectoris, serious uncorrected aortic or mitral valve stenosis, stable angina pectoris, hypertrophic obstructive myocardiopathy, severe renal impairment, atrial fibrillation or atrial flutter, ventricular rhythm disorders, cardiogenic shock, second- or third-degree atrioventricular block, as well as symptomatic orthostatic hypotension. (2) Patients were known to have contraindications or allergic reactions to either of the study drugs.
Research technique
Patients receiving antitumor therapy should take 500 mg of apatinib (specification: 250 mg/tablet; National Medicine Permission Number: H20140103; Jiangsu Hengrui Pharmaceuticals Co., Ltd., Jiangsu, China) or 7.5 mg/kg of bevacizumab (specification: 100 mg/tablet; Roche, Basel, Switzerland; dissolved in 100 mL of 0.9% sodium chloride) intravenously at the same time every day at 30 min after meals until they have intolerable adverse reactions. Before treatment, the patients should be informed that the use of apatinib or bevacizumab may lead to elevated BP. In case of headache, dizziness, blurred vision, and other hypertension symptoms, the doctors should be informed in time to monitor the dynamic BP.
BP was measured after 4 weeks of apatinib or bevacizumab. The patients whose BP ranged from 140 mmHg ≤ SBP <180 mmHg and 90 mmHg ≤ DBP <110 mmHg[19] were randomly divided into a perindopril group and an amlodipine group (n = 30). Dynamic BP (dynamic SBP and DBP), echocardiography, and venous blood collection were measured in the two groups. Patients in the perindopril group took perindopril at 30 min after meals (one tablet daily, specification: 4 mg/tablet; National Medicine Permission Number: H20034053; SERVIER (Tianjin) Pharmaceutical Co., Ltd., Tianjin, China); patients in the amlodipine group took amlodipine at 30 min after meals (two tablets daily, specification: 2.5 mg/tablet; National Medicine Permission Number: H10950224; Pfizer Inc., New York, USA).
Evaluation indicators
Dynamic BP (dynamic SBP and DBP), echocardiography, and venous blood collection were reviewed for 8 weeks after taking perindopril or amlodipine.
Dynamic blood pressure monitoring
The 24-h BP was monitored by MK-WABP non-invasive portable dynamic BP monitor (all patients underwent dynamic BP monitoring for 24 h, once every 30 min automatically from 6:00 to 22:00, and once every hour from 22:00 to 6:00 on the next day. The number of effective BP monitoring within 24 h shall not be <80% of the total number of measurements). For patients, the strenuous exercise was avoided and maintained emotional stability during testing, followed by the measurement of 24 h mean SBP (24h SBP), 24 h mean DBP (24h DBP), 24 h SBP standard deviation (24hSSD), 24 h DBP standard deviation (SD) (24hDSD), daytime mean SBP (dSBP), daytime mean DBP (dDBP), daytime mean SSD (dSSD), daytime mean DSD (dDSD), night mean SBP (nSBP), night mean DBP (nDBP), night mean SSD (nSSD), and night mean DSD (nDSD). The SD and coefficient of variation (CV) were taken as indicators of BPV. CV was calculated as the standard deviation of BP/mean of BP × 100 (%). The 24 h SBP CV (24hSCV), 24 h DBP CV (24hDCV), daytime mean SBP CV (dSCV), daytime mean DBP CV (dDCV), night mean SBP CV (nSCV), and night mean DBP CV (nDCV) were calculated.
Biochemical index detection
The cubital vein blood was harvested from all patients on an empty stomach in the morning after taking perindopril or amlodipine for 8 weeks. Next, the cubital vein blood was placed in a plastic centrifuge tube containing 20% ethylenediaminetetraacetic acid salt, mixed, and centrifuged at 3000 r/min for 10 min to isolate the serum. Serum NO concentration was measured by the NO assay kit (nitrate reductase method, Nanjing Jiancheng Bioengineering Institute, Nanjing, China).
Echocardiography
A HP7500 color Doppler echocardiography machine was implemented to evaluate the left ventricular end-diastolic diameter (LVDd), interventricular septal thickness (IVST), left ventricular posterior wall thickness (LVPWT), and left atrial diameter (LAD), with three consecutive cardiac cycles measured and averaged. According to the Devereux formula, the left ventricular mass (LVM) was calculated with 0.8 × 1.04 [(LVDd + IVS + LVPW)3 − LVDd3] + 0.6; LVM index (LVMI) was calculated with LVM/body surface area (BSA, m2).[20] The LAD index (LADi, mm/m2) was calculated with LAD/BSA, where BSA (m2) was calculated with 0.0061 × height (cm) + 0.0128 × weight (kg) − 0.1529.[21] The examination was performed by the same trained sonographer, and the test results were recorded in detail.
Statistics
All data were statistically analyzed using the statistical software SPSS 21.0 (IBM SPSS Statistics, Chicago, IL, USA). Measurement data, depicted with mean ± standard deviation, were analyzed by paired t-test (for comparison before and after treatment within a group) or unpaired t-test (for intergroup comparison). Enumeration data, shown as percentage or rate, were performed using Fisher's exact test. Statistical significance was interpreted as P < 0.05.
| Results | | |
General condition
No difference was witnessed in age, gender, height, weight, body mass index, blood glucose, cholesterol, triglycerides, high-density lipoprotein cholesterol, as well as low-density lipoprotein cholesterol in patients between the amlodipine and the perindopril groups (all P > 0.05) [Table 1].
Comparison of the systolic blood pressure parameters
Before treatment, there were no significant differences in the 24hSBP, 24hSSD, 24hSCV, dSBP, dSSD, dSCV, nSBP, nSSD, and nSCV in the perindopril group and the amlodipine group (all P > 0.05). In the amlodipine group, the 24hSBP, 24hSSD, 24hSCV, dSBP, dSSD, dSCV, nSBP, and nSSD after treatment were all lower than before treatment (all P < 0.05); nSCV exhibited no difference before and after treatment (P > 0.05). In the perindopril group, the 24hSBP, dSBP, and nSBP after treatment were lower than before treatment (all P < 0.05), and the 24hSSD, 24hSCV, dSSD, dSCV, nSSD, and nSCV presented no statistical differences before and after treatment (all P > 0.05). After treatment, the 24hSBP, 24hSSD, dSBP, dSSD, and nSBP were all lower in the amlodipine group than those in the perindopril group (all P < 0.05). No statistical significance was observed in 24hSCV, dSCV, nSSD, and nSCV between the two groups (all P > 0.05) [Table 2]. | Table 2: Comparison of systolic blood pressure parameters between the two groups (x̄±standard deviation)
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Comparison of the diastolic blood pressure parameters
Before treatment, no difference was witnessed in the 24hDBP, 24hDSD, 24hDCV, dDBP, dDBP, dDSD, dDCV, nDBP, and nDCV of patients between the perindopril group and the amlodipine group (all P > 0.05). In the amlodipine group, the 24hDBP, 24hDSD, 24hDCV, dDBP, dDSD, dDCV, and nDBP after treatment were lower than before treatment (all P < 0.05); nDSD and nDCV exhibited no difference before and after treatment (both P > 0.05). In the perindopril group, the 24hDBP, dDBP, and nDBP after treatment were lower than before treatment (all P < 0.05), and the 24hDSD, 24hDCV, dDSD, dDCV, nDSD, and nDCV presented no statistical differences before and after treatment (all P > 0.05). After treatment, the 24hDBP, 24hDSD, dDBP, dDSD, nDBP, and nDSD were all higher in the perindopril group than those in the amlodipine group (all P < 0.05). There were no differences in the 24hDCV, dDCV, and nDCV between the perindopril group and the amlodipine group (all P > 0.05) [Table 3]. | Table 3: Comparison of diastolic blood pressure parameters between the two groups (x̄±standard deviation)
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Comparisons of serum nitric oxide levels and echocardiographic data
Before treatment, no difference was witnessed in the NO level and LAD, LADi, LVDd, IVST, LVPWT, and LVMI between the perindopril group and the amlodipine group (all P > 0.05). In the amlodipine group, there exhibited elevated NO level and reduced LAD and LADi after treatment (all P < 0.05), and no changes were observed in LVDd, IVST, LVPWT, and LVMI (all P > 0.05). In the perindopril group, there exhibited elevated NO level and reduced LAD, LADi, IVST, LVPWT, and LVMI after treatment (all P < 0.05), and no changes were observed in LVDd (P > 0.05). After treatment, the NO level was higher and the LAD, LADi, IVST, LVPWT, and LVMI were lower in the perindopril group than those in the amlodipine group (all P < 0.05), and the LVDd between the two groups was not statistically significant (P < 0.05) [Table 4]. | Table 4: Comparisons of serum nitric oxide levels and echocardiographic data in both groups
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| Discussion | | |
As reported, hypertension is a frequent adverse event caused by the VEGF-targeted agent. VEGF antagonism contributes to a reduction in NO release from endothelial cells, thus resulting in vasoconstriction and enhanced peripheral vascular resistance, ultimately contributing to hypertension.[22],[23] Since the application of antihypertensive agents does not restrain antitumor activity of VEGF inhibitors, which should be considered as the first-line treatment of hypertension induced by bevacizumab or apatinib.[5],[24] Based on the current treatment guidelines, ACEI, ARB, and CCB are central to pharmacological treatment for hypertension,[25],[26] and different classes of antihypertensive agents can lower BP through various mechanisms of action.[27] Evidence has shown that perindopril and amlodipine meet the selection criteria for the core antihypertensive drugs.[28] In view of this, we conducted this research to discuss the therapeutic effect of different antihypertensive drugs (amlodipine and perindopril) on hypertension induced by apatinib and bevacizumab.
BP is an indicator of the human health status, and routine measurement of it contributes to the early detection of cardiovascular diseases. Conventional BP measurement techniques are either invasive or cuff based and are therefore not applicable for continuous measurement.[29] Dynamic BP measurements show stronger prognostic evidence because they can identify patients with hypertension easily, as well as those with BPV.[30],[31] The BPV stands for a dynamic and distinctive physiologic characteristic of the cardiovascular system function, and its size varies greatly when an individual faces daily challenges, which also depends on the characteristic responsiveness of its cardiovascular control mechanisms.[32] In addition, the ventricular and atrial dimensions offer a novel avenue to increase the current diagnostic criteria. Several related parameters, such as LVDd, IVST, LVPWT, and LVMI, have been revealed to be linked with diastolic dysfunction.[33],[34] Furthermore, NO is the main endothelial relaxing factor, and its reduced bioavailability is linked to hypertension.[35] Based on this, in our work, the dynamic BP measurement, echocardiography, and detection of NO content in venous blood were performed before and after treatment.
As previously described, perindopril plays a positive role in inflammation, thrombosis, ischemia, atherosclerosis, endothelial function, platelet aggregation, cardiovascular structure and function, as well as albuminuria.[36] Besides, perindopril may partially ameliorate the peripheral edema through its pharmacodynamic effects, which is usually a dose-limiting side effect of amlodipine.[37] Treatment of amlodipine treatment in hypertensive patients diminishes the LVMI and LVPWT but has no impact on the LVDd.[38] An article has found that after statistical adjustment for clinical and demographic confounding factors, hypertensive medication with amlodipine correlates to a reduced risk of dementia development in comparison to medication without CCBs.[39] These findings imply that perindopril and amlodipine improve apatinib- and bevacizumab-induced hypertension to some extent. In our study, we found that in the amlodipine group, the 24hSBP, 24hSSD, 24hSCV, dSBP, dSSD, dSCV, nSBP, nSSD, 24hDBP, 24hDSD, 24hDCV, dDBP, dDSD, dDCV, nDBP, LAD, and LADi after treatment were all lower than before treatment, while NO was higher than before treatment. In the perindopril group, the 24hSBP, dSBP, nSBP, 24hDBP, dDBP, nDBP, LAD, LADi, IVST, LVPWT, and LVMI after treatment were lower than before treatment, and NO level after treatment was higher than before treatment. After treatment, the 24hSBP, 24hSSD, dSBP, dSSD, nSBP, 24hDBP, 24hDSD, dDBP, dDSD, nDBP, nDSD, and NO were all lower while the LAD, LADi, LVDd, IVST, LVPWT, and LVMI were higher in the amlodipine group than those in the perindopril group. Based on these findings of our research, we came to a conclusion that BPV of amlodipine is slightly better than that of perindopril. In hypertension, endothelial dysfunction occurs and NO production decreases. Therefore, we observed the effect of different antihypertensive drugs (perindopril and amlodipine) on NO in hypertensive patients. The results of this study showed that perindopril and amlodipine increased plasma NO levels, and other researchers obtained similar results when exploring the effects of different antihypertensive drugs on NO in hypertensive patients.[40],[41] In our study, we found that the plasma levels of NO in the perindopril group were significantly higher than that of the amlodipine group, but the lowering BP effect of perindopril was less than amlodipine.
| Conclusion | | |
We highlight that the systolic and diastolic BPV of amlodipine in the treatment of hypertension induced by apatinib and bevacizumab is slightly better than that of perindopril, but the effect of perindopril in improving endothelial function indices NO and echocardiographic data is better than that of amlodipine. Specifically, 8-week treatment with amlodipine significantly reduces BP and BPV, while perindopril does not show a significant lowering BP effect on hypertension induced by apatinib or bevacizumab. Furthermore, the effects of perindopril on elevating plasma NO levels and reducing LVMI are better than those of amlodipine. Based on the evidence, the combination of amlodipine and perindopril may produce a more efficient outcome for hypertension patients. This shows that amlodipine and perindopril can be used as a clinical drug for treating hypertension, but there are some differences in their treatment effects, and the treatment mode should be decided according to the personal situation of the patients.
Financial support and sponsorship
This study was supported by the Public Health Foundation of Hebei Province of China (No. 20211245).
Conflicts of interest
There are no conflicts of interest.
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Correspondence Address:
Lanbo Liu,
Department of Cardiovascular Medicine, The Fourth Hospital of Hebei Medical University, No. 12 Jiankang Road, Shijiazhuang 050000, Hebei
China
 Source of Support: None, Conflict of Interest: None DOI: 10.4103/cjop.CJOP-D-22-00158
[Table 1], [Table 2], [Table 3], [Table 4] |
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