hypertension is the most common treatable risk factor for stroke , coronary artery disease , heart failure , chronic kidney disease , and aortic and peripheral arterial disease , accounting for about 50% of risk.1 ) the ultimate goal of blood pressure ( bp ) control is to reduce the incidence of target - organ damage and prevent cardiovascular disease or premature death in hypertensive patients . rather , it decreases them by approximately one - third , a meaningful , but clearly suboptimal result.2 ) usual bp , the theoretical true underlying level of blood pressure , is widely considered the main determinant of bp - related vascular risk and of benefit from antihypertensive treatment . the american heart association guidelines3 ) on measurement bp state that it is generally agreed that conventional clinic readings are a surrogate marker for a patient 's true bp and are thought to be the most important component of bp in determining its adverse effects . like this , clinic bp is used as the primary tool for diagnosis and assessment of hypertension and its severity in clinical practice and in current guidelines . also , physicians treat hypertension under the basic assumption that lower is better so long as diastolic bp is sufficient to maintain coronary perfusion . mean bp ( average of several readings of either systolic or diastolic bp ) is clearly important , but other factors , such as variability ( variation in bp with time ) or instability of bp ( transient fluctuations in bp ) might also play a part when most vascular events occur . according to the current paradigm , however , an effective pharmacological regimen is one that provides continuous , indiscriminate bp reduction throughout 24 hours . the results of the monitorizacion ambulatoria para prediccion de eventos cardiovasculares ( mapec , ambulatory blood pressure monitoring for prediction of cardiovascular events ) study challenge conventional understanding , and have the potential to effect important changes in the management of hypertension.4 ) the circadian rhythm of bp was ultimately established by millar - craig et al.5 ) using continuous intra - arterial monitoring . in persons with normal bp or uncomplicated hypertension , bp declines to lowest levels during nighttime sleep ( nocturnal dip ) , rises abruptly with morning awakening ( morning surge ) , and attains near peak or peak values during the first hours of diurnal activity . in the normal dippers , the sleep - time bp mean is lower by 10% to 20% compared to the daytime mean . the timing and amplitude of the natural rhythm of bp is influenced by intrinsic factors ( neurohumoral regulation ) and the extrinsic factors ( physical activity , sleep deprivation or quality , and dietary sodium ) . furthermore , behavioral factors ( mental activity and emotional status ) and lifestyle factors ( alcohol drinking and smoking ) can also affect the natural rhythm of bp.6 ) when hypertension first develops , the normal circadian bp rhythm is preserved . later , as target - organ damage compromises the regulation of systemic bp , the circadian rhythm becomes distorted , with a tendency towards greater variability and excessive morning bp surge . finally , sleep - time bp may increase to produce a non - dipper pattern.5 ) diabetes , post - stroke , congestive heart failure , sleep apnea syndrome , orthostatic hypotension , or medicated hypertension are frequently associated conditions in non - dipper or riser pattern . otherwise , smoking , alcohol drinking , over 60 years of age , cold weather , increased arterial stiffness , impaired baroreflex , or orthostatic hypertension is associated with a morning bp surge pattern.7 ) blood pressure variability ( bpv ) , standard deviation of mean daytime and sleep - time bp , has emerged as a complex phenomenon that includes both short - term ( within minutes or hours ) and long - term ( daily or monthly ) bp changes . in individuals with higher than normal bp , the amplitude of bpv is greater than normal and increases progressively with increasing levels of hypertension.8 ) the prevalence of non - dipper and riser patterns reached 39% and 14% , respectively and high - risk hypertensive patients showed a remarkably high prevalence of circadian bpv abnormalities in a large cohort of treated hypertensive patients from the spanish ambulatory blood pressure monitoring registry.9 ) the timing of onset of cardiovascular events strongly parallels the circadian rhythm of bp . meta - analyses indicate that there is a 40% higher relative risk of acute myocardial infarction , a 29% increased risk of sudden cardiac death , and a 49% higher relative risk of stroke between 6:00 am and 12:00 pm compared with the rest of the day though only limited data directly link the early morning surge and the incidence of cardiovascular events.10,11 ) in one prospective study , for each 10 mm hg increase in baseline early morning systolic bp , the risk of stroke increased by 24% and the change in bp on rising predicted cardiovascular events independently of age and 24-hour systolic bp mean.12 ) however , so far , no clinical trial has been derived to address the relationship between a reduction in the early morning bp and a possible reduction in cardiovascular events . the non - dipper pattern has been associated with increased risk of cardiac , renal , and vascular target - organ damage compared with the dipper pattern13 ) and can be independent of the clinic and 24-hour mean bp values.14,15 ) additionally , patients with hypertension who exhibit a sleep - time bp increase compared with daytime bp have the worst prognosis for stroke and cardiac events.14 ) recently , the mapec study4 ) found that a 13% decrease in cardiovascular risk was observed for every 5 mm hg decline in sleep - time bp , and this risk reduction was independent of changes in other aspects of the circadian bp pattern . also , reduction in the level of bp during sleep and the difference in sleep - waking bp were the most potent predictors of future events . rothwell et al.16 ) reported that visit - to - visit variability in systolic bp was a powerful predictor of stroke and coronary events independent of mean systolic bp in treated hypertensive patients . also , they showed that residual variability in systolic bp on treatment had a poor prognosis and stable hypertension had a better prognosis than episodic hypertension . cross - sectional and longitudinal studies have shown that bpv correlates with vascular events in the general population . the ohasama study,14 ) which examined the prognostic significance of increased bpv in a general population in rural japan , found that increased systolic bpv and decreased heart rate variability were independent predictors of cardiovascular mortality . similarly , higher levels of short - term visit - to - visit variability in systolic bp were associated with increased all - cause mortality in population based study of us adults.17 ) all these results suggest that bpv has an important role in cardiovascular disease and a potentially important impact on the treatment of hypertension . even small reductions in bp for short periods substantially improve cardiovascular outcomes . however , more recent evidence has emphasized the importance of optimal bp control , particularly on patients with high cardiovascular risk because the results are still unsatisfactory : 62% of cerebrovascular disease and 49% of ischemic heart disease can be attributed to suboptimal bp treatment.18 ) bpv is not only associated with the severity of target - organ damage but also has a prognostic value for the subsequent target - organ damage in hypertensive patients.19,20 ) these findings suggest that buffering the enhanced bpv commonly found in hypertensive patients may be an equally important target of antihypertensive treatment . optimal bp control requires strategies that lower bp consistently and fully throughout a 24-hour period , maintain the normal circadian pattern of bp , do not increase bpv , and optimize the patient 's compliance.21 ) the early morning surge in blood pressure is mediated in part by the sympathetic nervous system and through the renin - angiotensin - aldosterone system ( raas ) . otherwise , pathophysiology leading to a loss of decline in sleep - time bp is probably mediated by raas activation and volume excess . therefore , the pathophysiology of the circadian bpv allows us to consider the potential for blockade of systems leading to this abnormal circadian bp profile.6 ) in 1987 , parati et al.19 ) showed that for nearly any level of mean 24-hour bp assessed intra - arterially , subjects with high bp variability had more severe target - organ damage , an observation confirmed by long - term follow - up in the same patients . short - acting antihypertensive agents can cause bpv over a 24-hour period due to the intrinsic fluctuation caused by multiple dosing.21 ) in this regard , antihypertensive drugs with a short - lasting action or with an enhancing effect on bpv should be avoided . control of sleep - time bp and bp during early morning may require agents that have a reasonably long - half life or are administered twice daily . to produce its maximal effects , a drug must be present in appropriate concentration at its sites of action at the right moment . modification of the administration timing of many antihypertensive agents may affect the extent of 24-hour bp control and modify circadian rhythm , including the conversion from a non - dipper to dipper profile . the chronotherapy of hypertension takes into account the bp pattern , potential administration - time determinants of the pharmacokinetics , and dynamics of antihypertensive medications , as a means of enhancing beneficial outcomes and reducing or preventing adverse effects.18 ) accordingly , chronotherapy is a cost - effective means of both individualizing and optimizing the treatment of hypertension and constitutes a new option to optimize bp control and reduce risk . all therapeutic strategies have , in practice , one common element : the administration of antihypertensive medication in a single morning dose ( either at the beginning of the diurnal activity or , more commonly , with breakfast ) , not only with a single prescribed drug , but also with combination therapy . results from a recent study indicate that up to 89% of treated hypertensive patients take all their medication in a single morning dose.22 ) however , this therapeutic approach is theoretically suitable only if all patients have an adequate dipper pattern of bpv and if all prescribed antihypertensive drugs have homogenous efficacy throughout 24-hour.23 ) some antihypertensive agents recommended for once - daily administration are relatively short - acting , and may not provide efficient bp control for the entire time between doses intervals . this problem can not be overcome simply by increasing the dose of a short - acting agent to prolong its action , because the patient would be exposed to the risk of an unacceptably low bp during the time of peak drug effect and the resulting bpv over 24-hour would be greatly amplified . in this regards , a hypertensive patient with dipper pattern should , at least a priori , probably be treated using a strategy consisting of a single morning dosing of an antihypertensive medication ( alone or in combination ) that is known to have a high therapeutic coverage . on the other hand , a hypertensive with non - dipper pattern will need to add a second dose or additional medication at bedtime , or even shift to evening dosing in order to control bp and to normalize the altered 24-hour bp pattern . indeed , normalization of the circadian bp pattern towards a more dipper pattern has already been associated with a significant decrease in plasma fibrinogen , decrease in urinary albumin excretion , better metabolic profile , and better bp control.23 ) however , until recently , these strategies have not yet been shown to alter clinical outcomes . the mapec study24 ) is the first prospective trial to show that bedtime dosing of bp medications lowers the risk of cardiovascular events and death . in this study , patients were enrolled if they had a diagnosis of either untreated hypertension ( based on ambulatory bp monitoring criteria ) or resistant hypertension ( uncontrolled on 3 or more optimally dosed antihypertensive drugs ) . patients were randomly assigned to one of 2 time - of - day dosing groups : morning dosing of all their bp medications ( n = 1,109 ) or dosing of one more bp medications at bedtime ( n = 1,092 ) . ambulatory bp monitoring was conducted once a year or more frequently when medication adjustment occurred . patients were followed for a mean of 5.6 years for the endpoints of cardiovascular events and mortality . throughout the study , patients in the bedtime dosing group had lower mean sleep - time systolic and diastolic bp , a lower prevalence of non - dipping pattern , and a higher prevalence of controlled ambulatory bp . the bedtime dosing group also had a lower risk of total cardiovascular events ( relative risk [ rr ] , 0.39 ; 95% confidence interval [ ci ] , 0.29 to 0.51 ) , major cardiovascular events ( rr , 0.33 ; 95% ci , 0.19 to 0.55 ) , and fewer overall deaths ( 4.16/1000 vs. 2.11/1000 patient - years ; p = 0.008 ) . a subgroup analysis of patients with type 2 diabetes ( n = 448 ) and with chronic kidney disease ( n = 661 ) had similar results.25,26 ) while ambulatory bp monitoring appears to be a better indicator of cardiovascular risk compared with clinic bp monitoring , most physicians still rely on clinic bp for diagnosing and managing hypertension . also , morning bp surge , sleep - time bp , and dipper or non - dipper patterns of bp profiles are usually assessed using ambulatory bp monitoring ; however , there is no consensus on a single definition or on the threshold of pathological conditions . patients who have a long - standing routine of taking their medications in the morning may be resistant to change . pharmacists and nurses , as well as some physicians , may continue recommending morning dosing , which could be confusing for patients . despite the potential benefits of conversion of a non - dipper to a dipper pattern , the safety of bedtime drug administration must be clearly established . bedtime drug administration raises the possibility of nocturnal hypotension , which has been reported to cause both cerebral and myocardial ischemia in susceptible patients . thus , in the ideal situation , changes in administration time should be followed by repeated ambulatory bp monitoring to assess the effects of therapy and rule out an excessive bp fall during the night . although bpv is often unrecognized , bpv and bp instability have important roles in the progression of target - organ damage and in triggering of cardiovascular events . patients with well controlled bp , but high residual variability in systolic bp also have a poor prognosis , despite greater use of add - on drugs . diagnostic strategies should take into account the effect of increased bpv and episodic hypertension on vascular risk . the goals of antihypertensive treatment should consider the reduction of both 24-hour mean bp and its variability . antihypertensive drugs and dosing timing should be chosen to reduce bpv as well as mean bp . bedtime dosing of bp medications is one way to decrease the prevalence of non - dipper patterns and lowers the risk of cardiovascular events and death in hypertensive patients with or without diabetes or chronic kidney disease . thus reduction of bpv might represent a new strategy and target for the treatment of hypertension .
optimizing treatment for hypertension has focused on reducing cardiovascular risk through reduction of mean blood pressure ( bp ) under the basic assumption that lower is better , as long as diastolic bp is sufficient to maintain coronary perfusion . 
 however , antihypertensive therapy as currently practiced does not eliminate all hazards associated with bp elevation . 
 blood pressure variability ( bpv ) correlates closely with target - organ damage independent of mean bp and transient increases in bp are also triggers of vascular events . 
 so far , there is no definitive outcome data relating specific reduction in bpv to decline cardiovascular events or death . 
 thus , the decision whether bpv should be considered a new therapeutic target is left to the clinical judgment of physicians and individualized for each patient . however 
 , new evidence suggests that taking an antihypertensive medication at bedtime significantly affects bpv and lowers the risk of cardiovascular events and death . 
 this strategy may provide a means of individualizing treatment of hypertension according to the circadian bpv of each patient and may be a new option to optimize bp control and reduce risk .