ARBs are some of the major first line antihypertensive drugs due to their BP lowering effect, and they are widely used in hypertensive comorbidities such as atherosclerosis, diabetes mellitus and heart failure, due to their target organ protective role.[28–30] As a new nonpeptide ARB, allisartan isoproxil has displayed good safety and antihypertensive effects.[14,31] One recent study assessed the effects of allisartan isoproxil on essential hypertensive patients at low-medium risk; after the 8-week follow-up, the SBP and DBP of the allisartan isoproxil and placebo groups were decreased 14.5/10.4 and 8.3/7.7 mm Hg, respectively, and no deaths or serious adverse events were observed. In the present study, with nifedipine as the control, the SBP and DBP were decreased 19.88/17.96 and 9.69/10.86 mm Hg after the 6-month study, indicating that allisartan isoproxil has a powerful BP lowering effect with a good safety profile for essential hypertensive patients.
Compared with other traditional antihypertensive drugs, the major advantage of ARBs is their heart protecting effects. Left ventricular hypertrophy (LVH) is an independent risk factor for cardiovascular disease,[33,34] and a growing body of evidence has confirmed the role of ARBs in reversing LVH in hypertensive patients.[33,34] Yasunari et al compared valsartan and amlodipine on LVH and found that, after the 8-month intervention, LVMI was reduced 16% vs 1.2%, respectively, which indicated the apparent LVH-reversing effects of ARBs on hypertensive patients. A reanalysis of Val-HeFT study demonstrated that valsartan can both improve the LVEF and LVEDD in heart failure patients and can gain the most antiremodeling effect and clinical benefit. In the present study, we found that allisartan isoproxil significantly reduced the LVEDD, IMST, LVPWT, and LVMI after the 6-month intervention, which was consistent with the previous study.[33–35]
Endothelial dysfunction is one of the most important initiating and maintenance risk factors of hypertension.[39,40] In patients with essential hypertension, endothelial dysfunction is characterized by the impaired basal and agonist-dependent release of NO; meanwhile, vasoconstriction to endogenous ET is increased. ARBs can increase NO availability and reduce the synthesis of ET by reducing the production of oxygen free radicals and inhibiting the activation of RAS; then, it can decrease BP and reduce the incidence of related cardiovascular diseases.[39,40] In the present study, we found that allisartan isoproxil could significantly improve endothelial dysfunction by reducing the serum level of ET and increase the serum level of NO, consistent with the the related study.[39,40]
Sustained high BP often leads to stiffness of the large arteries. The increased stiffness, in turn, aggravates hypertension by increasing SBP, inducing arterial lesions, and leading to the formation of atherosclerosis. Epidemiological studies have strongly suggested that artery stiffness is associated with excess morbidity and mortality independent of other cardiovascular risk factors.[42,43] A previous study has demonstrated that losartan improved artery stiffness in essential hypertensive patients compared with atenolol, which may be related to inhibiting RAS. In the present study, after the 6-month follow-up, the parameters of artery stiffness in the allisartan group, including carotid IMT and IMCSA and ba-PWV, were all significantly decreased, which may be a possible mechanism of its heart and renal protecting effects.
There were 2 major novel findings in the present study. First, as a new ARB drug, there are not enough clinical studies to demonstrate its BP lowering effect. Although Li's study elucidated the structural features, BP lowering efficacy, safety and tolerability, and adverse drug reaction of allisartan isoproxil, it was a placebo-controlled study, and there were no comparisons with other antihypertensive drugs. Therefore, we further investigated the BP lowering effect using nifedipine as a control and found that allisartan isoproxil not only had as powerful a BP lowering effect as nifedipine, but had target organ protective effects after the 6-month intervention. The second finding was that allisartan isoproxil can ameliorate left ventricular remodeling, decrease 24-hour urinary MA, and improve vascular endothelial dysfunction and artery stiffness, indicating that it is a heart, renal and vascular protective drug.
Several limitations should be acknowledged in the present study. First, this trial was a double-blinded, single-center study, which may have led to systematic bias in BP measurements. Second, the measurements of BP were taken in the office, rather than ambulatory or home BP monitoring data, which may be different from the participants’ usual family BP. Third, in order to better demonstrate the BP lowering effect, we selected nifedipine as the control group, which may be less desirable than using an angiotensin II type 1 receptor antagonist as the control drug. Fourth, in order to enroll participants with good compliance, we recruited a relatively old population and a small sample; thus, to extrapolate the results to a more general population, further large sample, multicenter clinical study are needed.
Yu-Ming Li orcid: 0000-0003-1981-8120.
. Carrick D, Haig C, Maznyczka AM, et al. Hypertension, microvascular pathology, and prognosis after an acute myocardial infarction. Hypertension 2018;72:720–30.
. Mendy A. Association of urinary nitrate with lower prevalence of hypertension and stroke and with reduced risk of cardiovascular mortality. Circulation 2018;137:2295–7.
. Nielsen PM, Grimm D, Wehland M, et al. The combination of valsartan and sacubitril in the treatment of hypertension and heart failure—an update. Basic Clin Pharmacol Toxicol 2018;122:9–18.
. Yan Z, Wang Y, Li S, et al. Hypertension control in adults with CKD in China: baseline results from the Chinese Cohort Study of Chronic Kidney Disease (C-STRIDE). Am J Hypertens 2018;31:486–94.
. Benjamin EJ, Virani SS, Callaway CW, et al. Heart disease and stroke statistics—2018 update: a report from the American Heart Association. Circulation 2018;137:e67–492.
. Whelton PK, Carey RM, Aronow WS, et al. 2017 ACC/AHA/AAPA/ABC/ACPM/AGS/APhA/ASH/ASPC/NMA/PCNA Guideline for the Prevention, Detection, Evaluation, and Management of High Blood Pressure
in Adults: Executive Summary: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. J Am Coll Cardiol 2018;71:2199–269.
. Lu Z, Chen Y, Li L, et al. Combination therapy of renin-angiotensin system inhibitors plus calcium channel blockers versus other two-drug combinations for hypertension: a systematic review and meta-analysis. J Hum Hypertens 2017;31:1–3.
. Uijl E, Danser AHJ. Renin-angiotensin-aldosterone system parameters as biomarker in heart failure patients with preserved ejection fraction: focus on angiotensinogen. Am J Hypertens 2018;31:175–7.
. Park H, Kim HK, Jeong MH, et al. Clinical impacts of inhibition of renin-angiotensin system in patients with acute ST-segment elevation myocardial infarction who underwent successful late percutaneous coronary intervention. J Cardiol 2017;69:216–21.
. Ruiz-Rosado JD, Lee YU, Mahler N, et al. Angiotensin II receptor I blockade prevents stenosis of tissue engineered vascular grafts. FASEB J 2018;32:6822–32.
. Eguchi S, Kawai T, Scalia R, et al. Understanding angiotensin II type 1 receptor signaling in vascular pathophysiology. Hypertension 2018;71:804–10.
. Savina NM. Prevention of cardiovascular complications in patients with arterial hypertension while use of angiotensin II receptor antagonists. Possibilities of candesartan. Kardiologiia 2016;56:63–7.
. Tadevosyan A, Maclaughlin EJ, Karamyan VT. Angiotensin II type 1 receptor antagonists in the treatment of hypertension in elderly patients: focus on patient outcomes. Patient Relat Outcome Meas 2011;2:27–39.
. Wu MY, Ma XJ, Yang C, et al. Effects of allisartan, a new AT(1) receptor blocker, on blood pressure
and end-organ damage in hypertensive animals. Acta Pharmacol Sin 2009;30:307–13.
. Amini H, Ahmadiani A, Moazenzadeh M. Pharmacokinetics of losartan and its active metabolite EXP3174 in healthy Iranian subjects. Clin Drug Investig 2004;24:619–23.
. Zhao Q, Wei J, Zhang H. Effects of quercetin on the pharmacokinetics of losartan and its metabolite EXP3174 in rats. Xenobiotica 2018;1–6.
. Li H, Liu L, Xie L, et al. Effects of berberine on the pharmacokinetics of losartan and its metabolite EXP3174 in rats and its mechanism. Pharm Biol 2016;54:2886–94.
. Sun J, Yang GH, Liu JX, et al. Discordance between VASP phosphorylation and platelet aggregation in defining high on-clopidogrel platelet reactivity after ST-segment elevation myocardial infarction. Clin Appl Thromb Hemost 2018;24:47–54.
. Yang GH, Zhou X, Ji WJ, et al. Effects of a low salt diet on isolated systolic hypertension: a community-based population study. Medicine (Baltimore) 2018;97:e0342.
. Jafary FH. Devereux formula for left ventricular mass—be careful to use the right units of measurement. J Am Soc Echocardiogr 2007;20:783.
. Schulte-Altedorneburg G, Droste DW, Felszeghy S, et al. Accuracy of in vivo carotid B-mode ultrasound compared with pathological analysis: intima-media thickening, lumen diameter, and cross-sectional area. Stroke 2001;32:1520–4.
. Yamaki M, Sato T, Fujii H. Lower ankle-brachial index is associated with poor sleep quality in patients with essential hypertension
. Am J Cardiovasc Dis 2015;5:77–82.
. Takase H, Dohi Y, Toriyama T, et al. Brachial-ankle pulse wave velocity predicts increase in blood pressure
and onset of hypertension. Am J Hypertens 2011;24:667–73.
. Oluwatowoju IO, Ajuluchukwu JN, Afonja OA. Clinical usefulness of a timed overnight (8 hours) Urine Albumin (microalbumin) excretion in monitoring treatment in benign essential hypertension
. Niger Postgrad Med J 2014;21:177–80.
. Nessler J, Nessler B, Kitlinski M, et al. Concentration of BNP, endothelin 1, pro-inflammatory cytokines (TNF-alpha, IL-6) and exercise capacity in patients with heart failure treated with carvedilol. Kardiol Pol 2008;66:144–51. discussion 52-3.
. Bellien J, Iacob M, Remy-Jouet I, et al. Epoxyeicosatrienoic acids contribute with altered nitric oxide and endothelin-1 pathways to conduit artery endothelial dysfunction in essential hypertension
. Circulation 2012;125:1266–75.
. Zhong B. How to calculate sample size in randomized controlled trial? J Thorac Dis 2009;1:51–4.
. Zheng H, Li N, Ding Y, et al. Losartan alleviates hyperuricemia-induced atherosclerosis in a rabbit model. Int J Clin Exp Pathol 2015;8:10428–35.
. Jin H, Zhang HN, Hou XL, et al. Clinical study of double dose of valsartan combined with tacrolimus in treatment of diabetic nephropathy. Eur Rev Med Pharmacol Sci 2016;20:174–9.
. Marinsek M, Sinkovic A. Ramipril and losartan exert a similar long-term effect upon markers of heart failure, endogenous fibrinolysis, and platelet aggregation in survivors of ST-elevation myocardial infarction: a single centre randomized trial. Biomed Res Int 2016;2016:9040457.
. Li Y, Li XH, Huang ZJ, et al. A randomized, double blind, placebo-controlled, multicenter phase II trial of Allisartan Isoproxil
in essential hypertensive population at low-medium risk. PLoS One 2015;10:e0117560.
. Thomopoulos C, Parati G, Zanchetti A. Effects of blood pressure
-lowering on outcome incidence in hypertension: 5. Head-to-head comparisons of various classes of antihypertensive drugs - overview and meta-analyses. J Hypertens 2015;33:1321–41.
. Yasunari K, Maeda K, Watanabe T, et al. Comparative effects of valsartan versus amlodipine on left ventricular mass and reactive oxygen species formation by monocytes in hypertensive patients with left ventricular hypertrophy. J Am Coll Cardiol 2004;43:2116–23.
. Kucukler N, Kurt IH, Topaloglu C, et al. The effect of valsartan on left ventricular myocardial functions in hypertensive patients with left ventricular hypertrophy. J Cardiovasc Med (Hagerstown) 2012;13:181–6.
. Wong M, Staszewsky L, Latini R, et al. Severity of left ventricular remodeling defines outcomes and response to therapy in heart failure: valsartan heart failure trial (Val-HeFT) echocardiographic data. J Am Coll Cardiol 2004;43:2022–7.
. Thomopoulos C, Parati G, Zanchetti A. Effects of blood-pressure-lowering treatment on outcome incidence. 12. Effects in individuals with high-normal and normal blood pressure
: overview and meta-analyses of randomized trials. J Hypertens 2017;35:2150–60.
. Menne J, Izzo JL Jr, Ito S, et al. Prevention of microalbuminuria in patients with type 2 diabetes and hypertension. J Hypertens 2012;30:811–8. discussion 18.
. Asselbergs FW, Diercks GF, Hillege HL, et al. Effects of fosinopril and pravastatin on cardiovascular events in subjects with microalbuminuria. Circulation 2004;110:2809–16.
. Ghiadoni L, Virdis A, Magagna A, et al. Effect of the angiotensin II type 1 receptor blocker candesartan on endothelial function in patients with essential hypertension
. Hypertension 2000;35:501–6.
. Suzuki R, Fukuda N, Katakawa M, et al. Effects of an angiotensin II receptor blocker on the impaired function of endothelial progenitor cells in patients with essential hypertension
. Am J Hypertens 2014;27:695–701.
. Benetos A, Laurent S, Asmar RG, et al. Large artery stiffness in hypertension. J Hypertens Suppl 1997;15:S89–97.
. Vriz O, Bertin N, Ius A, et al. Carotid artery stiffness and development of hypertension in people with paraplegia and no overt cardiovascular disease
: a 7-year follow-up study. J Cardiovasc Echogr 2017;27:132–40.
. Blacher J, Safar ME. Large-artery stiffness, hypertension and cardiovascular risk in older patients. Nat Clin Pract Cardiovasc Med 2005;2:450–5.
. Park JB, Intengan HD, Schiffrin EL. Reduction of resistance artery stiffness by treatment with the AT(1)-receptor antagonist losartan in essential hypertension
. J Renin Angiotensin Aldosterone Syst 2000;1:40–5.
. Cadeddu C, Piras A, Mantovani G, et al. Protective effects of the angiotensin II receptor blocker telmisartan on epirubicin-induced inflammation, oxidative stress, and early ventricular impairment. Am Heart J 2010;160:487.e1–7.
. Dahiya R, Shultz SP, Dahiya A, et al. Relation of reduced preclinical left ventricular diastolic function and cardiac remodeling in overweight youth to insulin resistance and inflammation. Am J Cardiol 2015;115:1222–8.
. Zhang C, Tan Y, Guo W, et al. Attenuation of diabetes-induced renal dysfunction by multiple exposures to low-dose radiation is associated with the suppression of systemic and renal inflammation. Am J Physiol Endocrinol Metab 2009;297:E1366–77.
. Li JJ, Chen JL. Inflammation may be a bridge connecting hypertension and atherosclerosis. Med Hypotheses 2005;64:925–9.