| BackgroundHypertension is one of the most common chronic diseases. It is an independent risk factor for cardiovascular and cerebrovascular diseases and is associated with increasing mortality. With the accelerated aging of China’s population, the number of hypertensive patients continues to increase. It is estimated that approximately200million people have hypertension in China. The early signs of hypertension include changes in the structure and function of arterial walls and decreased vascular compliance and elasticity. The2010guidelines on hypertension prevention and treatment of China indicate that in hypertension treatment, blood pressure needs to be controlled within a normal range and potential atherosclerosis needs to be impeded or reversed.Previous studies have demonstrated that hypertension can cause endothelial dysfunction and a thickening of the vascular endothelial membrane, leading to the formation of atherosclerotic plaques. In recent years, a large number of animal experiments and clinical studies[1.2,3] have revealed that in addition to lowering blood pressure, different antihypertensive drugs also improve the structure and function of arteries in varying degrees. At present, the literature regarding the different effects of different antihypertensive drugs on vascular structure and function is limited, and the conclusions of these studies are also inconsistent. Additionally, these studies included small numbers of patients. Moreover, a meta-analysis or a large-scale, prospective clinical study has yet to be performed.ObjectiveThe method of systematic analysis commonly used in international evidence-based medicine was adopted. Hypertensive patients receiving different antihypertensive drug treatments, such as calcium channel blockers (CCBs), angiotensin-converting enzyme inhibitors (ACEIs), and angiotensin Ⅱreceptor antagonists (ARBs), were included in this analysis. The brachial-ankle pulse wave velocity (baPWV) was used to compare the effects of different antihypertensive drugs on vascular function among these patients. In addition, intravascular ultrasound (IVUS) was used to detect the changes of arterial plaque volume in patients with hypertension or coronary heart disease after antihypertensive drug treatment to understand the effects of antihypertensive drugs on vascular structure.In this analysis, the following questions were addressed:1) Could different antihypertensive drugs improve vascular compliance or stiffness in hypertensive patients?2) Was there a significant difference in the effects of different antihypertensive drugs on vascular function in hypertension patients?3) Were the effects of antihypertensive drugs on vascular function independent of their blood pressure-lowering effects?4) Could antihypertensive drugs reduce arterial plaque volume in patients with hypertension or coronary heart disease? MethodsbaPWV was used as the basic indicator of vasodilation and vasoconstriction. IVUS was used to detect changes in arterial plaque volume, which reflected the changes in vascular structure. RevMan5.0software was adopted for the meta-analysis.I. The effects of antihypertensive drugs on vascular functionAccording to the principle of evidence-based medicine, the controlled clinical trials database of the Cochrane library and the PubMed and Embase databases were systematically searched between December1966and January2012. The keyword "antihypertensive therapy" was used to search for treatment strategies; the keywords "hypertension","blood pressure", OR "arterial stiffness" and "arterial compliance" OR "brachial-ankle pulse wave velocity" was used to search for included diseases; and the keyword "randomized controlled trials","trial","clinical trial","random allocation","double-blind method", OR "single-blind method" was used to search for randomized controlled trials (RCTs). All searched literature was written in English. Randomized, blind, and controlled studies were included. Meanwhile, the keywords "vascular stiffness","vascular compliance","brachial-ankle pulse wave velocity", and "hypertension" were used to search the CNKI Network, Chinese National Digital Library, and Wanfang database between January1979and January2012. All included literature was further screened manually. The objectives of this analysis were to compare the effects of different antihypertensive drugs on arterial stiffness in hypertensive patients, provide a basis for further optimization of hypertension treatment strategies, and therefore further benefit hypertensive patients through antihypertensive therapy. The inclusion criteria were as follows:(1) primary hypertension patients;(2) either CCBs and ACEIs were used independently as an intervention in the same study; and (3) the use of baPWV as the indicator of vascular function. The exclusion criteria were as follows:(1) animal experiments or non-original literature;(2) patients with secondary hypertension;(3) patients with normal blood pressure;(4) the concomitant use of antihypertensive drugs;(5) baPWV was not used as the indicator of vascular stiffness; and (6) a lack of a control in the study.ResultsThe difference in the effects of ACEIs and CCBs on vascular function in hypertensive patients1) The evaluation of the quality of the included literature revealed that all studies were randomized, but none described whether blinded assessment and allocation concealment were used. In addition, no patient was lost to follow-up or early dropout. Thus, the quality of the literature was not high, but the baselines were comparable without the need for sensitivity analysis. Three studies were class B, and one study was class C.2) A total of833relevant articles were retrieved using the previously mentioned search strategy and data collection methods. The studies that compared the effects of ACEIs and CCBs on hypertensive patients were screened, and the47studies that met the criteria were all RCTs. After papers were read in their entirety and further screened according to the inclusion criteria and data integrity, four RCTs with a total of226patients were included[12-15] in this analysis. The included studies reported the changes of the patients’baPWV, systolic and diastolic blood pressure, and pulse pressure before and after treatment. They also reported the levels of various biochemical and physiological indicators, including body mass index, waistline size, and total cholesterol, triglyceride, and serum creatinine levels.3) The results of literature heterogeneity analysis and meta-analysis revealed literature heterogeneity (Q=54.80, P<0.001), and thus, the random effects model was adopted for further analysis. The post-treatment PWV data were merged into (135.01[95%CI (59.87,210.16)]. The results of the Z-test were Z=3.52and P=0.0004(p<0.05), suggesting a significant difference. Thus, there was a significant difference between the effects of the two classes of drugs on vascular stiffness, and ACEIs were superior to CCBs.4) The included studies also reported changes in systolic and diastolic blood pressure. The results demonstrated that CCBs were superior to ACEIs in lowering both systolic (-4.73[95%CI (-9.35,-0.12)](p<0.04)) and diastolic blood pressure (-10.42[95%CI (-19.16,-1.69)](p<0.02)).5) There was no significant difference in the pulse pressure-lowering effects between CCBs and ACEIs (-6.12[95%CI (-2.3,14.55)](p<0.15)).The difference in the effects of ARB and CCBs on vascular function in hypertensive patients1) The evaluation of the quality of the included literature revealed that all studies were randomized, but none described whether blinded assessment and allocation concealment were used. In addition, no patient was lost to follow-up or early dropout. Thus, the quality of the literature was not high, but the baselines were comparable without the need for sensitivity analysis. Four studies were class B, and one study was class C.2) A total of833relevant articles were retrieved using the previously mentioned search strategy and data collection methods. The studies that compared the effects of ARB and CCBs on hypertensive patients were screened, and the51studies that met the criteria were all RCTs. After papers were read in their entirety and further screened according to the inclusion criteria and data integrity, four RCTs with a total of298patients were included in this analysis. The included studies reported the changes of the patients’baPWV, systolic and diastolic blood pressure, and pulse pressure before and after treatment. They also reported the levels of various biochemical and physiological indicators, including body mass index, waistline size, and total cholesterol, triglyceride, and serum creatinine levels.3) The results of literature heterogeneity analysis and meta-analysis revealed literature heterogeneity (Q=269.90, P<0.001,), and thus, the random effects model was adopted for further analysis. The post-treatment PWV data were merged into (APWV,211.07,[95%CI (94.09～328.04)]). The results of the Z-test were Z=3.54and p<0.05, suggesting a significant difference. Thus, there was a significant difference between the effects of the two classes of drugs on vascular stiffness, and ARB was superior to CCBs.4) The included studies also reported changes in systolic and diastolic blood pressure. The results demonstrated that CCBs were superior to ARB in lowering both systolic (ΔSBP,-2.71[95%CI (-3.40,-2.01)](p<0.001)) and diastolic blood pressure (ΔDBP,-6.46[95%CI (-10.15,-2.78)](p<0.001))The difference in the effects of RAS-blockers and CCBs on vascular function in hypertensive patients1) A total of833relevant articles were retrieved using the previously mentioned search strategy and data collection methods. The studies that compared the effects of RAS-blockers and CCBs on hypertensive patients were screened, and the98papers that met the criteria were all RCTs. After papers were read in their entirety and further screened according to the inclusion criteria and data integrity,7RCTs with a total of528patients were included in this analysis. The included studies reported the changes of the patients’baPWV, systolic and diastolic blood pressure, and pulse pressure before and after treatment. They also reported the levels of various biochemical and physiological indicators, including body mass index, waistline size, and total cholesterol, triglyceride, and serum creatinine levels. 2) The evaluation of the quality of the included literature revealed that all studies were randomized, but none described whether blinded assessment and allocation concealment were used. In addition, no patient was lost to follow-up or early dropout. Thus, the quality of the literature was not high, but the baselines were comparable without the need for sensitivity analysis. Five studies were class B, and two study was class C.3) The results of literature heterogeneity analysis and meta-analysis revealed literature heterogeneity (Q=928.99, P<0.001), and thus, the random effects model was adopted for further analysis. The post-treatment PWV data were merged into (ΔPWV,160.15,95%(57.10～263.21)). The results of the Z-test were Z=3.05and p<0.05, suggesting a significant difference. Thus, there was a significant difference between the effects of the two classes of drugs on vascular stiffness, and RAS-blockers was superior to CCBs.The difference in the effects of ARB and ACEI on vascular function in hypertensive patients1) A total of833relevant articles were retrieved using the previously mentioned search strategy and data collection methods. The studies that compared the effects of ARB and ACEI on hypertensive patients were screened, and the51studies that met the criteria were all RCTs. After papers were read in their entirety and further screened according to the inclusion criteria and data integrity,3RCTs with a total of130patients were included in this analysis. The included studies reported the changes of the patients’CaPWV.3RCTs with a total of111patients were included in this analysis reported the changes of the patients’baPWV.2) Systolic and diastolic blood pressure, and pulse pressure were reported before and after treatment, and the levels of various biochemical and physiological indicators, including body mass index, waistline size, and total cholesterol, triglyceride, and serum creatinine levels were reported too.3) The evaluation of the quality of the included literature revealed that all studies were randomized, but none described whether blinded assessment and allocation concealment were used. In addition, no patient was lost to follow-up or early dropout. Thus, the quality of the literature was not high, but the baselines were comparable without the need for sensitivity analysis. Two studies were class A. Three studies were class B, and one study was class C.4) Take CaPWV as the basic indicator:The results of literature heterogeneity analysis and meta-analysis revealed literature heterogeneity (Q=6.53, P=0.04) and thus, the random effects model was adopted for further analysis. The post-treatment data were merged into (ΔCaPWV,-0.03,[95%CI (-1.14～1.08)]).The results of the Z-test were Z=0.05, P=0.96, suggesting no significant difference between them.5) Take baPWV as the basic indicator:The results of literature heterogeneity analysis and meta-analysis revealed literature no heterogeneity(Q=2.29, P=0.32)and thus the fixed effects model was adopted for further analysis. The post-treatment data were merged into (AbaPWV,-113.53,[95%CI (-152.21～-74.84)]).The results of the Z-test were Z=5.75, P<0.001, Thus, there was a significant difference between the effects of the two classes of drugs on vascular stiffness, and ACEI was superior to ARB.6) The included studies also reported changes in systolic and diastolic blood pressure. The results demonstrated that there were no difference between ACEI and ARB.in lowering both systolic (ΔSBP,2.09[95%CI (-2.50,6.67)](p=0.37)) and diastolic blood pressure (ADBP,1.75[95%CI (-1.55,5.04)](P=0.30)).Ⅱ. The effects of antihypertensive drugs on vascular structureAccording to the principle of evidence-based medicine, the controlled clinical trials database of the Cochrane library and the PubMed and Embase databases were systematically searched between December1966and January2012. The keyword "antihypertensive agent","antihypertensive drugs","hypotensive agent", OR "hypotensor" was used to search for treatment strategies; the keyword "hypertension" OR "blood pressure" was used to search for included diseases; the keyword "intravascular ultrasound" was used to search for detection methods, and the keyword "randomized controlled trials","trial","clinical trial","random allocation","double-blind method", OR "single-blind method" was used to search for RCTs. All targeted papers were written in English. Randomized, blind methods and controlled studies were included in this analysis. Meanwhile, the keywords "intravascular ultrasound" and "hypertension" were used to search the CNKI Network, Chinese National Digital Library, and Wanfang database between January1979and January2012. All included literature was further screened manually. The objectives of this analysis were to compare the effects of different antihypertensive drugs on patient vascular structure, provide a basis for further optimization of hypertension treatment strategies, and further benefit hypertension patients through antihypertensive therapy.The inclusion criteria were as follows:(1) patients with coronary heart disease or hypertension;(2) the use of antihypertensive drugs as an intervention; and (3) IVUS was used to detect the changes of coronary plaque volume. The exclusion criteria were as follows:(1) animal experiments and non-original literature;(2) patients with secondary hypertension;(3) patients with normal blood pressure;(4) IVUS was not used to detect the changes of vascular plaque volume; and (5) a lack of a control in the study. The changes of patient arterial plaque volume, systolic and diastolic blood pressure, and pulse pressure in the included studies were analyzed.RevMan5.0software was adopted for statistical analysis. Heterogeneity was analyzed via the Z-score and the chi-squared test. Heterogeneity was present if P<0.1. The method of further systematic analysis was selected according to the results of the heterogeneity test. If P>0.1, suggesting no data heterogeneity, then the fixed effects model was adopted for further analysis. If P<0.1, suggesting the presence of data heterogeneity, then the random effects model was adopted for further analysis. The number of patients, the mean, and the standard deviation were all derived from the original literature. P<0.05indicated a significant difference, and P<0.01indicated a very significant difference.ResultsA total of9044English articles and10Chinese articles were retrieved. After screening, it was found that only two articles, both written in English, used IVUS to detect the changes of arterial plaque volume after antihypertensive drug treatment in hypertensive patients. Both studies were prospective, double-blind, and randomized. However, all comparisons were conducted using the before-and after-treatment data of the same patients. There was no negative control. A total of269patients were included in these studies.Three studies used IVUS to detect the changes of arterial plaque volume after antihypertensive drug treatment in patients with coronary artery disease. All three studies were prospective, double-blind, randomized, and controlled. A total of672patients were enrolled. The baseline conditions and the basic treatment between patient group and control group were consistent in all studies.The effects of antihypertensive drugs on the vascular structure of hypertensive patients1) General information of the included studies:Hypertensive patients were enrolled in the studies. IVUS was used to detect the changes of arterial plaque volume, systolic and diastolic blood pressure, heart rate, tricuspid gradient, and the levels of low-density lipoprotein-cholesterol, high-density lipoprotein-cholesterol, hemoglobin Alc, C-reactive protein, monocyte chemoattractant protein1, and fasting blood sugar before and after antihypertensive drug treatment.2) The quality of both included studies was class A, but neither study included a negative control. In both studies, the before-and after-treatment data of the same patients were compared.3) Only descriptive analysis was performed for these two studies due to the small sample size. The results indicated that the arterial plaque volume of patients was significantly reduced after antihypertensive drug treatment.The effects of antihypertensive drugs on the vascular structure of patients with coronary heart disease1) Patients with coronary heart disease were enrolled in the studies. IVUS was used to detect the changes of artery plaque volume, systolic and diastolic blood pressure, heart rate, and pulse pressure before and after antihypertensive drug treatment.2) The quality of two of the included studies was class A, whereas that of the remaining study was class B.3) Heterogeneity analysis and meta-analysis revealed data homogeneity (Q=0.13, P=0.94), and thus, the fixed effects model was adopted for further analysis. The after-treatment PV data was merged into (-0.70,[95%CI (-1.70,0.30)]). The results of the Z-test were Z=1.36and P=0.17, suggesting an insignificant effect of antihypertensive drug treatment on arterial plaque volume in patients with coronary heart disease.ConclusionsMeta-analysis was performed to analyze the RCTs in which the effects of different antihypertensive drugs on vascular stiffness or compliance were compared. The results revealed a significant difference in the effects of different antihypertensive drugs on vascular function. Meta-analysis was also performed to analyze the RCTs in which IVUS was used to detect the changes of atherosclerotic plaque volume after antihypertensive drug treatment. The results suggested that antihypertensive drugs could reduce the arterial plaque volume in hypertensive patients but had no significant effect on that in patients with coronary artery disease.The effects of antihypertensive drugs on vascular function1) There was a significant difference between the effects of different antihypertensive drugs on vascular function.2) ARBs were superior to CCBs in improving vascular stiffness.3) ACEIs were superior to CCBs in improving vascular stiffness.4) ACEIs were superior to ARBs in improving vascular stiffness.5) The aforementioned effects had no relation with the antihypertensive effects of the antihypertensive drugs.The effects of antihvpertensive drugs on vascular structure1) Arterial plaque volume was significantly reduced after antihypertensive drug treatment in hypertensive patients.2) There was no significance change of arterial plaque volume in patients with coronary heart disease after antihypertensive drug treatment.Limitations and ProspectsThe limitations of this systematic analysis of studies were as follows:(1) The majority of the included studies did not mention the basis of determining the necessary sample size. Moreover, the sample size was insufficient. Both would affect the efficacy of this analysis.(2) While analyzing the effects of antihypertensive drugs on vascular function, the included studies used different drugs such as CCBs, ACEIs, and ARBs at different doses and for different lengths of time.(3) The included studies did not mention whether allocation concealment was implemented.(4) Some included studies were not fully blind, which could result in operation bias and measurement bias.(5) There were few studies on patients with early primary hypertension; therefore, patients with primary hypertension accompanied by diabetes, renal dysfunction, or coronary heart disease were included in this analysis, which may increase the number of confounding factors and thus affect the changes of PWV. However, overall, the quality of the included studies is acceptable, and their argument strength is satisfactory.(6) While analyzing the effects of antihypertensive drugs on the vascular structure of hypertension patients, the conclusions were unconvincing due to the small number of included studies and their lack of negative controls.The results of this analysis indicated that both ACEIs and ARBs were superior to CCBs in improving arterial stiffness in patients with primary hypertension, and ACEIs were superior to ARBs. In addition, antihypertensive drugs could reduce arterial plaque volume in hypertensive patients, which was consistent with the results of previous studies in which vascular intima-media thickness was measured by a two-dimensional method. However, the effects of antihypertensive drugs on arterial plaque volume were insignificant in patients with coronary heart disease. Therefore, it is deduced that ACEI treatment in patients with early hypertension can improve vascular structure and function, thus providing the basis for the rational selection of antihypertensive drugs for hypertension patients. The quality of the studies and the number of patients enrolled included in this analysis are insufficient; therefore, the aforementioned conclusions may be biased. In the future, randomized controlled clinical trials that enroll a large number of patients and involve multiple centers are warranted to confirm the results of this analysis. |
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