arterial stiffness is an important risk factor for cardiovascular morbidity and mortality   and can be assessed using several methods including pulse pressure ( pp ) , the augmentation index ( ai ) , and pulse wave velocity ( pwv ) . these parameters are readily determined on an outpatient basis and are well correlated with the risk of cardiovascular events [ 13 ] . the cardioankle vascular index ( cavi ) is a novel marker of arterial stiffness that is calculated from the pwv and adjusted according to the bp values . in addition , cavi has been shown to be a biomarker for the evaluation of the severity of arterial fibrosis with higher sensitivity and specificity than pwv . both experimental data and clinical evidence suggest that the renin - angiotensin system ( ras ) contributes to the pathogenesis of a number of cardiovascular diseases . angiotensin ii type 1 receptor blockers ( arbs ) are currently some of the most wildly used antihypertensive drugs . we have demonstrated that losartan , candesartan , and telmisartan improve arterial stiffness as assessed by cavi [ 68 ] . olmesartan ( olm ) significantly decreases cavi in patients with hypertension and diabetes [ 9 , 10 ] , but whether it is more effective alone than together with azelnidipine ( azl ) treatment remains uncertain . the aim of this study was to evaluate the protective effects of olm and add - on azl on arterial stiffness in patients with essential hypertension . arterial stiffness was assessed by measuring cavi , the augmentation index ( ai ) , and the maximum of the carotid intima - media thickness ( max - imt ) . the subjects of the present study were 52 consecutive hypertensive patients with arterial stiffness and untreated hypertension or uncontrollable hypertension treated with medications other than ras inhibitors . in patients without comorbid illness , hypertension was defined as a clinic systolic bp of > 140  mmhg at any time and/or a clinic diastolic bp of > 90  mmhg at any time and/or a systolic bp of > 130  mmhg in the morning and/or a diastolic bp of > 85  mmhg in the morning . in patients with diabetes mellitus and chronic kidney disease , hypertension was defined as a clinic systolic bp of > 130  mmhg at any time and/or a clinic diastolic bp of > 80  mmhg at any time . in patients with metabolic syndrome , hypertension was defined as a clinic systolic bp of > 130  mmhg at any time and/or a clinic diastolic bp of > 85  mmhg at any time . all of the patients were randomly assigned to either a group treated with olm alone ( monotherapy group ) or a group treated with olm combined with azl ( combination therapy group ) . the target bp was defined as < 130/85  mmhg in patients without any complications and < 130/80  mmhg in patients with diabetes mellitus , chronic kidney disease , or metabolic syndrome . patients in the monotherapy group were first treated with 20  mg / day of olm for 4 weeks , and the dose of the olm was subsequently titrated up to 40  mg / day . if the target bp was not achieved , additional antihypertensive medications other than ras inhibitors and calcium channel blockers were added . patients treated with combination therapy were first treated with 20  mg / day of olm for 4 weeks , and 16  mg / day of azl was subsequently added . the dose of the olm was increased up to 40  mg / day until the target bp was attained . additional antihypertensive agents other than ras inhibitors and calcium channel blockers were further added unless the bp fell below the target bp despite treatment with 40  mg / day of olm combined with 16  mg / day of azl . clinical and biological parameters were measured before and 12 months after the start of this study . during the study period , previous medications and therapies other than antihypertensive drugs were continued . the study was approved by the review board of keio university medical school hospital and written informed consent was obtained from every subject . serum levels of creatinine ( cr ) , estimated glomerular filtration rate ( egfr ) , cystatin c , potassium ( k ) , uric acid ( ua ) , triglyceride ( tg ) , high - density lipoprotein cholesterol ( hdl - c ) , low - density lipoprotein cholesterol ( ldl - c ) , glycoalbumin ( ga ) , plasma levels of atrial natriuretic peptide ( anp ) , brain natriuretic peptide ( bnp ) , the active renin concentrations ( arc ) , and aldosterone were measured in venous blood samples . the albumin creatinine ratio ( acr ) was measured in urinary samples drawn on the morning after an overnight fast on the same days as the ankle - brachial index ( abi ) , cardioankle brachial index ( cavi ) , augmentation index ( ai ) , and bp measurements and the maximum of carotid intima - media thickness ( max - imt ) measurements were performed . an oscillometric - based device ( tm-2431 ; a&d co. , tokyo , japan ) the bp was measured every 30 minutes during the day ( between 6:00 am and 10:00 pm ) and every 60 minutes during the night ( between 10:00 pm and 6:00 am ) . the mean values and the standard deviations of the ambulatory bp for each subject were calculated for a 24-hour period . the standard deviation of the ambulatory bp values was recorded as the variability of ambulatory bp in this study . the nocturnal decrease in bp was calculated as the average systolic bp during the day minus the average systolic bp during the night . the morning bp surge was calculated as the highest systolic bp during the first 2 hours after waking minus the lowest systolic bp during the night . the cavi was measured using a vasera vs-1000 vascular screening system ( fukuda denshi co. ltd . , cuffs were applied to bilateral upper arms and ankles , with the subjects lying in a supine position and holding their heads along the midline . ecg electrodes were placed on both wrists , and a microphone for detecting heart sounds was placed over the sternum . the patients rested in this supine position for at least 10 minutes before the start of monitoring . the cavi was calculated using the following formula : 
 ( 1)cavi = a  { ( 2p)ln  ( pspd )  pwv2}+b , 
 
					 where , ps is the systolic blood pressure , pd is the diastolic blood pressure , p is ps  pd ,  is blood density , and a and b are constants . the ai was measured using an automated tonometric device ( hem-9000ai ; omron healthcare co. , ltd . , kyoto , japan ) , as described previously . peripheral pressure waveforms were recorded over 30 seconds from the radial artery at the wrist with the subjects in a sitting position after resting for at least 5 minutes . the ai was calculated using the following formula 
 ( 2)ai  = ( late  systolic  bpdiastolic  bp  ( dbp))(systolic  bpdbp)100  ( % ) . acr was evaluated on the basis of the mean albumin - to - creatinine ratio in three nonconsecutive overnight urine samples . the urinary concentrations of albumin and creatinine were determined using a turbidimetric immunoassay with a superior - microalbumin kit ( dpc co. , tokyo , japan ) and with the jaff reaction using an autoanalyzer . ultrasonography b - mode imaging of the carotid artery was performed using a powervision 6000 machine ( toshiba , tokyo , japan ) at a transducer frequency of 7.5  mhz . each subject was examined while in a supine position . up to 4  cm of the common carotid artery and the carotid bulb intima - media thickness ( imt ) was defined as the distance between the leading edge of the lumen - intima interface and the leading edge of the media - adventitia interface of the far wall . the greatest imt value in the bilateral longitudinal projections was recorded as the max - imt . the mean intraobserver and interobserver coefficients of variation for the maximum imt were 4.3% and 4.7% , respectively . fisher 's exact test was used to analyze sex and the frequency of diabetes mellitus , smoking , and the use of statins . the mann - whitney u test was used to analyze the age and body mass index . the changes in the biological parameters were analyzed using a student t - test and a two - way analysis of variance for repeated measures combined with tukey - kramer posthoc tests . the contributions of changes in variables to changes in cavi were tested using a regression analysis and an analysis of covariance . a p value <  .05 was considered significant . no significant differences were observed in the baseline patient characteristics between the monotherapy group and the combination therapy group , with the exception of the serum k level ( table 1 ) . during the 12-month treatment period , the clinic systolic bp , the clinic diastolic bp , the 24-hour ambulatory systolic bp , the 24-hour ambulatory diastolic bp , the daytime systolic bp , the daytime diastolic bp , and the nighttime systolic bp decreased significantly both after the monotherapy and combination therapy , the nighttime diastolic bp decreased significantly after combination therapy whereas it did not change significantly after monotherapy . the nocturnal decrease reduced significantly after monotherapy whereas it did not change significantly after combination therapy . no significant changes in the morning sbp surge or the sbp variability were seen during the 12-month observation period in either group . figure 1 shows the changes in primary outcomes including acr , anp , bnp , abi , max - imt , and arterial stiffness as assessed by cavi and ai in both groups . the cavi decreased significantly from 8.4  0.2 to 7.8  0.2 after combination therapy , whereas it did not change significantly after monotherapy . the ai decreased significantly after both monotherapy and combination therapy , from 83.8  2.8 to 71.9  3.7 , and from 75.2  4.3 to 68.8  3.3 , respectively . the acr , anp , bnp , and max - imt did not change significantly in either group . during the 12-month observation period , the serum ldl - c level decreased significantly from 127  6 to 109  8  mg / dl after combination therapy whereas a significant change was not observed after monotherapy ( figure 2 ) . the plasma aldosterone level decreased significantly after both monotherapy and combination therapy , from 205  23 to 155  20  pg / dl , from 194  18 to 125  9  pg / dl , respectively , but no significant difference was observed between the two groups . during the 12-month observation period , the reduction in cavi , abi , and serum ldl - c level was significantly greater after the combination therapy than the monotherapy after adjustment by the baseline value ( figures 3 and 4 ) . an ancova analysis to examine whether the changes in the ldl - c , plasma aldosterone , abi , ai , clinical bp , 24-h bp , daytime bp , and nighttime bp affected the change in cavi during the combination therapy ( table 3 ) . the changes in the abi and clinic sbp contributed significantly to the decrease in cavi after combination therapy . the present study demonstrates that olm plus azl significantly improve the cavi in hypertensive patients , which reflects arterial stiffness . although the reduction in the cavi in the combination therapy group was correlated with clinic sbp , the beneficial effect of olm and azl on arterial stiffness was independent of bp changes . there was no significant difference in the reduction of brachial systolic bp between the two treatments . it has been shown that the combination of olm and azl has beneficial effects on the properties of the cardiovascular system . stimulation of the angiotensin ii type 1 receptor results in stimulation of l - type calcium channels and induces the influx of extracellular calcium through calcium channels . the l - type calcium channel blocker ( ccb ) azl enhances the effect of arbs on vascular remodeling independently of blood pressure . moreover , azl has been implicated in augmenting the inhibitory effect of arb compared with other l - type ccbs such as nifedipine and amlodipine . coadministration of azl and olm synergistically blunts oxidative stress partly through the inhibition of akt activity and exerts antiatherogenic actions by inhibiting vsmc migration and vascular remodeling . combination therapy has a beneficial effect on central systolic bp and arterial stiffness , and enhances the effects of monotherapy with these drugs in treating atherosclerosis [ 1417 ] . the combination of azl with olm acts to prevent hypertensive heart failure with preserved systolic function in a rat model of this disease . combination therapy produces a greater reduction in cardiac fibrosis by inhibiting the increase in elastolytic activity induced by activation of nadph oxidase [ 18 , 19 ] . simultaneous treatment with exercise and olm plus azl produces renal protective effects in the rat model . this suggests that the treatment may affect macrophage infiltration to the glomerulus , fibroblast accumulation in the glomerulus , mesangial activation , and podocyte differentiation . combination therapy protects against cyst enlargement in polycystic kidney disease by suppressing interstitial inflammation , fibrosis , and oxidative stress through upregulating enos expression during the course of the disease . taken together , the combination of olm plus azl provides additional cardiovascular protective effects on arterial stiffness resulting in an improvement in the cavi . since arterial stiffness is a powerful and independent risk factor for mortality in cardiovascular events , olm plus azl could be a first - line antihypertensive drug . the ai is another marker of arterial stiffness and reflects the central aortic pressure [ 23 , 24 ] . vascular stiffening causes an increase in the amplitude and early return of the reflected wave during systole , with augmentation of the central systolic bp and a resultant increase in ai . we have shown that arbs decrease the ai [ 7 , 8 ] but there has not been any prior study focusing on the effect of olm on ai . in the present study , olm produced a reduction in the ai whereas azl has been previously shown to cause a significant reduction in ai in combination with arbs . this was confirmed in the present study indicating that combination therapy results in a reduction in ai . since there was not any difference in the decrease in the ai between the two therapies , the reduction could be explained by the vascular protective effects of the olm . in this study a significant reduction in the serum ldl - c levels after the combination therapy was observed . this improvement in the serum ldl - c levels can be attributed to azelnidipine , since olm monotherapy did not produce a decrease in the serum ldl - c levels . a previous study showed that the antioxidant effect of azelnidipine may have participated in the reduction of plasma malondialdehyde - modified ldl ( mda - ldl ) levels . the antioxidant effect of azl possibly participated in the reduction of plasma mda - ldl levels [ 28 , 29 ] . in this respect , combination therapy would be preferable for hypertensive patients with comorbid dyslipidemia . in the present study this confirms previous reports that show that the incidence of adverse events is similar in the combination and the monotherapy groups . these include that the trial population was comparatively small and the observation period was relatively short . a longer observation with a larger number of subjects might more clearly elucidate the beneficial and adverse effects of olm and azl . therefore , further studies are needed to confirm the benefits and safety of olm and azl therapy . in conclusion , the combination treatment with olm and azl compared with olm monotherapy produces beneficial effects on arterial stiffness as assessed by cavi , as well as by the level of ldl - c , despite a similar reduction of bp . since these markers are known to influence the future risk for cardiovascular events in hypertensive patients , the combination of olm and azl could well be a reasonable antihypertensive management for the treatment of hypertensive patients .
background / aims . 
 arterial stiffness is an independent risk factor for cardiovascular morbidity and mortality . 
 this study was conducted to determine the effect of olmesartan ( olm ) and azelnidipine ( azl ) on arterial stiffness using the cardio - ankle vascular index ( cavi ) , which is a novel blood pressure ( bp)-independent marker for arterial stiffness in hypertensive patients . methods . 
 fifty - two consecutive hypertensive patients were randomly assigned either to a group treated with olm monotherapy or to a group treated with olm and azl combination therapy . 
 clinical and biological parameters were measured before and 12 months after the start of this study . results . both therapies significantly and similarly reduced bp , augmentation index , and plasma aldosterone levels . 
 the combination therapy significantly decreased cavi and serum low - density lipoprotein ( ldl - c ) levels and these reductions were significantly greater than those produced with monotherapy . 
 no significant differences in metabolic parameters were observed between the two therapies . conclusion . 
 the combination therapy with olm and azl had beneficial effects on arterial stiffness assessed by cavi , ldl - c , and metabolism , despite the similar bp reduction , compared with olm monotherapy . 
 since these markers are known to influence the future risk of cardiovascular events , combination therapy with olm and azl could be a useful choice for treating hypertensive patients .