Artemio Mojón

INFLUENCE OF CIRCADIAN TIME OF HYPERTENSION TREATMENT ON CARDIOVASCULAR RISK: RESULTS OF THE MAPEC STUDY

Clinical studies have documented morning-evening, administration-time differences of several different classes of hypertension medications in blood pressure (BP)-lowering efficacy, duration of action, safety profile, and/or effects on the circadian BP pattern. In spite of these published findings, most hypertensive subjects, including those under combination therapy, are instructed by their physicians and pharmacists to ingest all of their BP-lowering medications in the morning. The potential differential reduction of cardiovascular (CVD) morbidity and mortality risk by a bedtime versus upon-awakening treatment schedule has never been evaluated prospectively. The prospective MAPEC study was specifically designed to test the hypothesis that bedtime chronotherapy with ≥1 hypertension medications exerts better BP control and CVD risk reduction than conventional therapy, i.e., all medications ingested in the morning. A total of 2156 hypertensive subjects, 1044 men/1112 women, 55.6 ± 13.6 (mean ± SD) yrs of age, were randomized to ingest all their prescribed hypertension medications upon awakening or ≥1 of them at bedtime. At baseline, BP was measured at 20-min intervals from 07:00 to 23:00 h and at 30-min intervals at night for 48 h. Physical activity was simultaneously monitored every min by wrist actigraphy to accurately determine the beginning and end of daytime activity and nocturnal sleep. Identical assessment was scheduled annually and more frequently (quarterly) if treatment adjustment was required. Despite lack of differences in ambulatory BP between groups at baseline, subjects ingesting medication at bedtime showed at their last available evaluation significantly lower mean sleep-time BP, higher sleep-time relative BP decline, reduced prevalence of non-dipping (34% versus 62%; p < .001), and higher prevalence of controlled ambulatory BP (62% versus 53%; p < .001). After a median follow-up of 5.6 yrs, subjects ingesting ≥1 BP-lowering medications at bedtime exhibited a significantly lower relative risk of total CVD events than those ingesting all medications upon awakening (0.39 [0.29–0.51]; number of events 187 versus 68; p < .001). The difference between the treatment-time groups in the relative risk of major events (including CVD death, myocardial infarction, ischemic stroke, and hemorrhagic stroke) was also highly statistically significant (0.33 [0.19–0.55]; number of events: 55 versus 18; p < .001). The progressive decrease in asleep BP and increase in sleep-time relative BP decline towards a more normal dipping pattern, two novel therapeutic targets requiring proper patient evaluation by ambulatory BP, were best achieved with bedtime therapy, and they were the most significant predictors of event-free survival. Bedtime chronotherapy with ≥1 BP-lowering medications, compared to conventional upon-waking treatment with all medications, more effectively improved BP control, better decreased the prevalence of non-dipping, and, most importantly, significantly reduced CVD morbidity and mortality. (Author correspondence: rhermida@uvigo.es)

Decreasing sleep-time blood pressure determined by ambulatory monitoring reduces cardiovascular risk.

OBJECTIVES We investigated whether reduced cardiovascular risk is more related to the progressive decrease of asleep or awake blood pressure. BACKGROUND Independent studies have concluded that elevated sleep-time blood pressure is a better predictor of cardiovascular risk than awake or 24-h blood pressure means. However, the impact on cardiovascular risk of changes in these ambulatory blood pressure characteristics has not been properly investigated. METHODS We prospectively studied 3,344 subjects (1,718 men and 1,626 women), 52.6 ± 14.5 years of age, during a median follow-up of 5.6 years. Those with hypertension at baseline were randomized to ingest all their prescribed hypertension medications upon awakening or ≥1 of them at bedtime. Blood pressure was measured for 48 h at baseline and again annually or more frequently (quarterly) if treatment adjustment was required. RESULTS With data collected at baseline, when asleep blood pressure was adjusted by awake mean, only the former was a significant predictor of outcome in a Cox proportional hazards model also adjusted for sex, age, and diabetes. Analyses of changes in ambulatory blood pressure during follow-up revealed a 17% reduction in cardiovascular risk for each 5-mm Hg decrease in asleep systolic blood pressure mean (p < 0.001), independently of changes in any other ambulatory blood pressure parameter. CONCLUSIONS The sleep-time blood pressure mean is the most significant prognostic marker of cardiovascular morbidity and mortality. Most importantly, the progressive decrease in asleep blood pressure, a novel therapeutic target that requires proper patient evaluation by ambulatory monitoring, was the most significant predictor of event-free survival. (Prognostic Value of Ambulatory Blood Pressure Monitoring in the Prediction of Cardiovascular Events and Effects of Chronotherapy in Relation to Risk [the MAPEC Study]; NCT00295542).

Bedtime Dosing of Antihypertensive Medications Reduces Cardiovascular Risk in CKD

Time of ingestion of hypertension medications can affect circadian patterns of BP, but whether this translates into an effect on clinical outcomes is unknown. Here, in an open-label trial, we randomly assigned 661 patients with CKD either to take all prescribed hypertension medications upon awakening or to take at least one of them at bedtime. We measured 48-hour ambulatory BP at baseline and 3 months after any adjustment in treatment or, at the least, annually. After a median follow-up of 5.4 years, patients who took at least one BP-lowering medication at bedtime had an adjusted risk for total cardiovascular events (a composite of death, myocardial infarction, angina pectoris, revascularization, heart failure, arterial occlusion of lower extremities, occlusion of the retinal artery, and stroke) that was approximately one-third that of patients who took all medications upon awakening (adjusted HR 0.31; 95% CI 0.21 to 0.46; P < 0.001). Bedtime dosing demonstrated a similar significant reduction in risk for a composite outcome of cardiovascular death, myocardial infarction, and stroke (adjusted HR 0.28; 95% CI 0.13 to 0.61; P < 0.001). Furthermore, patients on bedtime treatment had a significantly lower mean sleep-time BP and a greater proportion demonstrated control of their ambulatory BP (56% versus 45%, P = 0.003). Each 5-mmHg decrease in mean sleep-time systolic BP was associated with a 14% reduction in the risk for cardiovascular events during follow-up (P < 0.001). In conclusion, among patients with CKD and hypertension, taking at least one antihypertensive medication at bedtime improves control of BP and reduces the risk for cardiovascular events.

Influence of Time of Day of Blood Pressure–Lowering Treatment on Cardiovascular Risk in Hypertensive Patients With Type 2 Diabetes

OBJECTIVE We prospectively investigated in hypertensive patients with type 2 diabetes if bedtime treatment with ≥1 hypertension medications exerts better blood pressure control and cardiovascular risk reduction than conventional therapy, in which all medications are ingested in the morning. RESEARCH DESIGN AND METHODS We conducted a prospective, randomized, open-label, blinded end point trial on 448 hypertensive patients with type 2 diabetes, 255 men/193 women, mean ± SD age 62.5 ± 10.8 years, randomized to ingest all their prescribed hypertension medications upon awakening or ≥1 of them at bedtime. Ambulatory blood pressure was measured for 48 h at baseline and again annually or even more frequently (quarterly) after adjustments in treatment. RESULTS After a median follow-up of 5.4 years, patients ingesting ≥1 hypertension medications at bedtime showed a significantly lower cardiovascular risk (adjusted by age and sex) than subjects ingesting all medications upon awakening (hazard ratio 0.33 [95% CI 0.21–0.54]; P < 0.001). The difference between groups in the adjusted risk of major events (cardiovascular death, myocardial infarction, and stroke) was also statistically significant (0.25 [0.10–0.61]; P = 0.003). Patients treated at bedtime showed significantly lower sleep time blood pressure mean and higher prevalence of controlled ambulatory blood pressure (62.5 vs. 50.9%; P = 0.013). There was a significant 12% cardiovascular risk reduction per each 5 mmHg decrease in asleep systolic blood pressure during follow-up (P < 0.001). CONCLUSIONS Among patients with diabetes, treatment with ≥1 hypertension medications at bedtime, compared with all medications upon waking, resulted in improved ambulatory blood pressure control and significantly reduced cardiovascular morbidity and mortality.

Blood Pressure Patterns in Normal Pregnancy, Gestational Hypertension, and Preeclampsia

Abstract —With the aim to describe the daily pattern of blood pressure during the trimesters of pregnancy in clinically healthy women as well as in pregnant women who developed gestational hypertension or preeclampsia, we analyzed 1494 blood pressure series systematically sampled by ambulatory monitoring for 48 hours every 4 weeks after the first obstetric visit in 124 women with uncomplicated pregnancies, 55 with gestational hypertension, and 23 with a final diagnosis of preeclampsia. The circadian pattern of blood pressure variation for each group and trimester of gestation was established by population multiple-component analysis. A highly statistically significant circadian pattern represented by a linear model that includes components with periods of 24 and 12 hours is demonstrated for systolic and diastolic blood pressure for all groups of pregnant women in all trimesters ( P P P P =0.022) but not for diastolic blood pressure ( P =0.986). In the third trimester, the difference in circadian mean is highly statistically significant for both variables ( P

Administration Time-Dependent Effects of Valsartan on Ambulatory Blood Pressure in Hypertensive Subjects

Abstract—This study investigated the administration time–dependent antihypertensive efficacy of valsartan, an angiotensin II receptor blocker. We studied 90 subjects (30 men and 60 women), 49.0±14.3 (mean±SD) years of age with stage 1 to 2 essential hypertension; they were randomly assigned to receive valsartan (160 mg/d) as a monotherapy either on awakening or at bedtime. Blood pressure was measured by ambulatory monitoring every 20 minutes during the day and every 30 minutes at night for 48 consecutive hours before and after 3 months of treatment. Physical activity was simultaneously monitored every minute by wrist actigraphy to accurately calculate the diurnal and nocturnal means of blood pressure on a per-subject basis. The highly significant blood pressure reduction after 3 months of treatment with valsartan (P <0.001) was similar for both treatment times (17.0 and 11.3 mm Hg reduction in the 24-hour mean of systolic and diastolic blood pressure with morning administration and 14.6 and 11.4 mm Hg reduction with bedtime administration; P >0.174 for treatment time effect). Valsartan administration at bedtime as opposed to on wakening resulted in a highly significant average increase by 6% (P <0.001) in the diurnal-nocturnal ratio of blood pressure; this corresponded to a 73% relative reduction in the number of nondipper patients. The findings confirm that valsartan efficiently reduces blood pressure throughout the entire 24 hours, independent of treatment time. They also suggest that time of treatment can be chosen according to the dipper status of a patient to optimize the effect of antihypertensive therapy, an issue that deserves further investigation.

Relationship between physical activity and blood pressure in dipper and non-dipper hypertensive patients.

Background The lack of nocturnal decline in blood pressure has been associated with an increase in end-organ damage and cardiovascular events, although results remain controversial, partly because of the inability to reproduce correctly, over time, the classification of patients into dippers and non

Effects of Time of Day of Treatment on Ambulatory Blood Pressure Pattern of Patients With Resistant Hypertension

Patients with resistant hypertension present high prevalence of a non-dipper blood pressure pattern. Recent results indicate that non-dipping is related partly to the absence of 24-hour therapeutic coverage in patients treated with single morning doses. Accordingly, we investigated the impact of treatment time on the blood pressure pattern in 700 patients with resistant hypertension on the basis of clinic measurements who were studied by 48-hour ambulatory monitoring. Among them, 299 patients received all their medication on awakening, and 401 were taking ≥1 antihypertensive drug at bedtime. The percentage of patients with controlled ambulatory blood pressure was double in patients taking 1 drug at bedtime (P=0.008). Among the 578 patients with true resistant hypertension, subjects receiving 1 drug at bedtime showed a significant reduction in the 24-hour mean of systolic and diastolic blood pressure (3.1 and 1.6 mm Hg, respectively; P<0.011). This reduction was much more prominent during nighttime (5.1 and 3.0 mm Hg; P<0.001). Accordingly, the diurnal/nocturnal blood pressure ratio was significantly increased by 2.7 and the prevalence on non-dipping reduced (56.9 versus 81.9%; P<0.001) in patients taking 1 drug at bedtime. Compared with patients receiving all drugs on awakening, subjects with 1 drug at bedtime also showed significant reductions in the average values of glucose, cholesterol, fibrinogen, and urinary albumin excretion (P<0.011). In patients with resistant hypertension, pharmacological therapy should take into account when to treat with respect to the rest–activity cycle of each patient to improve control and to avoid the non-dipper pattern associated to higher cardiovascular risk.

2013 Ambulatory Blood Pressure Monitoring Recommendations for the Diagnosis of Adult Hypertension, Assessment of Cardiovascular and other Hypertension-associated Risk, and Attainment of Therapeutic Goals

Correlation between systolic (SBP) and diastolic (DBP) blood pressure (BP) level and target organ damage, cardiovascular disease (CVD) risk, and long-term prognosis is much greater for ambulatory BP monitoring (ABPM) than daytime office measurements. The 2013 ABPM guidelines specified herein are based on ABPM patient outcomes studies and constitute a substantial revision of current knowledge. The asleep SBP mean and sleep-time relative SBP decline are the most significant predictors of CVD events, both individually as well as jointly when combined with other ABPM-derived prognostic markers. Thus, they should be preferably used to diagnose hypertension and assess CVD and other associated risks. Progressive decrease by therapeutic intervention of the asleep BP mean is the most significant predictor of CVD event-free interval. The 24-h BP mean is not recommended to diagnose hypertension because it disregards the more valuable clinical information pertaining to the features of the 24-h BP pattern. Persons with the same 24-h BP mean may display radically different 24-h BP patterns, ranging from extreme-dipper to riser types, representative of markedly different risk states. Classification of individuals by comparing office with either the 24-h or awake BP mean as “masked normotensives” (elevated clinic BP but normal ABPM), which should replace the terms of “isolated office” or “white-coat hypertension”, and “masked hypertensives” (normal clinic BP but elevated ABPM) is misleading and should be avoided because it disregards the clinical significance of the asleep BP mean. Outcome-based ABPM reference thresholds for men, which in the absence of compelling clinical conditions are 135/85 mmHg for the awake and 120/70 mmHg for the asleep SBP/DBP means, are lower by 10/5 mmHg for SBP/DBP in uncomplicated, low-CVD risk, women and lower by 15/10 mmHg for SBP/DBP in male and female high-risk patients, e.g., with diabetes, chronic kidney disease (CKD), and/or past CVD events. In the adult population, the combined prevalence of masked normotension and masked hypertension is >35%. Moreover, >20% of “normotensive” adults have a non-dipper BP profile and, thus, are at relatively high CVD risk. Clinic BP measurements, even if supplemented with home self-measurements, are unable to quantify 24-h BP patterning and asleep BP level, resulting in potential misclassification of up to 50% of all evaluated adults. ABPM should be viewed as the new gold standard to diagnose true hypertension, accurately assess consequent tissue/organ, maternal/fetal, and CVD risk, and individualize hypertension chronotherapy. ABPM should be a priority for persons likely to have a blunted nighttime BP decline and elevated CVD risk, i.e., those who are elderly and obese, those with secondary or resistant hypertension, and those diagnosed with diabetes, CKD, metabolic syndrome, and sleep disorders. (Author Correspondence: rhermida@uvigo.es or prf@unife.it).

Treatment of non-dipper hypertension with bedtime administration of valsartan.

Background Previous results have indicated that valsartan administration at bedtime, as opposed to upon wakening, may improve the diurnal: nocturnal ratio of blood pressure without loss in 24-h coverage and efficacy. Objectives To investigate the administration time-dependent antihypertensive efficacy of valsartan in non-dipper patients. Methods We studied 148 non-dipper patients with grade 1–2 essential hypertension, aged 53.0 ± 12.6 years, who were randomly assigned to receive valsartan (160 mg/day) as a monotherapy either on awakening or at bedtime. Blood pressure was measured every 20 min during the day and every 30 min at night for 48 consecutive hours before and after 3 months of treatment. Physical activity was simultaneously monitored every minute by wrist actigraphy to accurately calculate the diurnal and nocturnal means of blood pressure on a per subject basis. Results The significant blood pressure reduction after 3 months of valsartan (P < 0.001) was similar for both treatment times (13.1 and 8.5 mmHg reduction in the 24-h mean of systolic and diastolic blood pressure with morning administration; 14.7 and 10.3 mmHg with bedtime administration; P > 0.126 for treatment-time effect). The diurnal: nocturnal ratio of blood pressure was significantly increased only when valsartan was administered before bedtime, which resulted in 75% of the patients in this group reverting to dippers, a significant increase in the percentage of patients with controlled blood pressure over 24 h, and a reduction in urinary albumin excretion. Conclusions In non-dipper hypertensive patients, dosing time with valsartan should be chosen at bedtime, for improved efficacy during the nocturnal resting hours, as well as the potential associated reduction in cardiovascular risk.