Effects of Time-of-Day of Hypertension Treatment on Ambulatory Blood Pressure and Clinical Characteristics of Patients With Type 2 Diabetes

Generally, hypertensive patients ingest all their blood pressure (BP)-lowering agents in the morning. However, many published prospective trials have reported clinically meaningful morning-evening, treatment-time differences in BP-lowering efficacy, duration of action, and safety of most classes of hypertension medications, and it was recently documented that routine ingestion of ≥1 hypertension medications at bedtime, compared with ingestion of all of them upon awakening, significantly reduces cardiovascular disease (CVD) events. Non-dipping (<10% decline in asleep relative to awake BP mean), as determined by ambulatory BP monitoring (ABPM), is frequent in diabetes and is associated with increased CVD risk. Here, we investigated the influence of hypertension treatment-time regimen on the circadian BP pattern, degree of BP control, and relevant clinical and analytical parameters of hypertensive patients with type 2 diabetes evaluated by 48-h ABPM. This cross-sectional study involved 2429 such patients (1465 men/964 women), 65.9?±?10.6 (mean?±?SD) yrs of age, enrolled in the Hygia Project, involving primary care centers of northwest Spain and designed to evaluate prospectively CVD risk by ABPM. Among the participants, 1176 were ingesting all BP-lowering medications upon awakening, whereas 1253 patients were ingesting ≥1 medications at bedtime. Among the latter, 336 patients were ingesting all BP-lowering medications at bedtime, whereas 917 were ingesting the full daily dose of some hypertension medications upon awakening and the full dose of others at bedtime. Those ingesting ≥1 medications at bedtime versus those ingesting all medications upon awakening had lower likelihood of metabolic syndrome and chronic kidney disease (CKD); had significantly lower albumin/creatinine ratio, glucose, total cholesterol, and low-density lipoprotein (LDL) cholesterol; and had higher estimated glomerular filtration rate and high-density lipoprotein (HDL) cholesterol. Moreover, patients ingesting all medications at bedtime had lowest fasting glucose, serum creatinine, uric acid, and prevalence of proteinuria and CKD. Ingestion of ≥1 medications at bedtime was also significantly associated with lower asleep systolic (SBP) and diastolic BP (DBP) means than treatment with all medications upon awakening. Sleep-time relative SBP and DBP decline was significantly attenuated in patients ingesting all medications upon awakening (p?<?.001). Thus, the prevalence of non-dipping was significantly higher when all hypertension medications were ingested upon awakening (68.6%) than when ≥1 of them was ingested at bedtime (55.8%; p?<?.001 between groups), and even further attenuated (49.7%) when all of them were ingested at bedtime (p?<?.001). Additionally, prevalence of the riser BP pattern, associated with highest CVD risk, was much greater (23.6%) among patients ingesting all medications upon awakening, compared with those ingesting some (20.0%) or all medications at bedtime (12.2%; p?<?.001 between groups). The latter group also showed significantly higher prevalence of properly controlled ambulatory BP (p <?.001) that was achieved by a significantly lower number of hypertension medications (p?<?.001) compared with patients treated upon awakening. Our findings demonstrate significantly lower asleep SBP mean and attenuated prevalence of a blunted nighttime BP decline, i.e., lower prevalence of markers of CVD risk, and improved metabolic profile in patients with type 2 diabetes ingesting hypertension medications at bedtime than in those ingesting all of them upon awakening. These collective findings indicate that bedtime hypertension treatment, in conjunction with proper patient evaluation by ABPM to corroborate the diagnosis of hypertension and avoid treatment-induced nocturnal hypotension, should be the preferred therapeutic scheme for type 2 diabetes. (Author correspondence: rhermida@uvigo.es)     

Sleep-Time Blood Pressure: Prognostic Value and Relevance as a Therapeutic Target for Cardiovascular Risk Reduction

Correlation between blood pressure (BP) level and target organ damage, cardiovascular disease (CVD) risk, and long-term prognosis is greater for ambulatory BP monitoring (ABPM) than clinical BP measurements. Nevertheless, the latter continue to be the “gold standard” to diagnose hypertension, assess CVD risk, and evaluate hypertension treatment. Independent ABPM studies have found that elevated sleep-time BP is a better predictor of CVD risk than either the awake or 24-h BP mean. A major limitation of all previous ABPM-based prognostic studies is the reliance only upon a single baseline profile from each participant at the time of inclusion, without accounting for potential changes in the level and pattern of ambulatory BP thereafter during follow-up. Accordingly, impact of the alteration over time, i.e., during long-term follow-up, of specific features of the 24-h BP variation on CVD risk has never been properly investigated. We evaluated the comparative prognostic value of (i) clinic and ambulatory BP; (ii) different ABPM-derived characteristics, e.g., asleep or awake BP mean; and (iii) specific changes in ABPM characteristic during follow-up, mainly whether reduced CVD risk is more related to the progressive decrease of asleep or awake BP. We prospectively studied 3344 subjects (1718 men/1626 women), 52.6?±?14.5 (mean?±?SD) yrs of age, during a median follow-up of 5.6 yrs. Those with hypertension at baseline 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, and physical activity was simultaneously monitored every min by wrist actigraphy to accurately derive awake and asleep BP means. Identical assessment was scheduled annually and more frequently (quarterly) if treatment adjustment was required. Data collected either at baseline or the last ABPM evaluation per participant showed that the asleep systolic BP mean was the most significant predictor of both total CVD events and major CVD events (a composite of CVD death, myocardial infarction, and stroke). Moreover, when the asleep BP mean was adjusted by the awake mean, only the former was a significant independent predictor of outcome in a Cox proportional-hazard model adjusted for sex, age, diabetes, anemia, and chronic kidney disease. Analyses of changes in ambulatory BP during follow-up revealed 17% reduction in CVD risk for each 5?mm Hg decrease in the asleep systolic BP mean (p?<?.001), independent of changes in any other clinic or ambulatory BP parameter. The increased event-free survival associated with the progressive reduction in the asleep systolic BP mean during follow-up was significant for subjects with either normal or elevated BP at baseline. The ABPM-derived asleep BP mean was the most significant prognostic marker of CVD morbidity and mortality. Most important, the progressive decrease in asleep BP mean, a novel therapeutic target that requires proper patient evaluation by ABPM and best achieved by ingestion of at least one hypertension medication at bedtime, was the most significant predictor of event-free survival. (Author correspondence: rhermida@uvigo.es)     

Chronotherapy of hypertension: advantages of 48-h ambulatory blood pressure monitoring assessments in MAPEC and Hygia Chronotherapy Trial

ABSTRACT

The specific purpose of this communication is to summarize the relevant details of the methods utilized to conduct, analyze, and interpret the ambulatory blood pressure (BP) monitoring (ABPM)-obtained patient data in both MAPEC and Hygia Chronotherapy Trial, including details of the sampling requirements in terms of duration and frequency, proper calculation of ABPM-derived mean values, prognostic and therapeutic implications of BP dipping, and limitations of the 24 h BP mean as diagnostic/prognostic parameter still mistakenly recommended by some hypertension guidelines.     

Comparison of Ambulatory Blood Pressure Parameters of Hypertensive Patients With and Without Chronic Kidney Disease

There is strong association between chronic kidney disease (CKD) and increased prevalence of hypertension, risk of end-organ damage, and cardiovascular disease (CVD). Non-dipping, as determined by ambulatory blood pressure (BP) monitoring (ABPM), is frequent in CKD and has also been consistently associated with increased CVD risk. The reported prevalence of non-dipping in CKD is highly variable, probably due to relatively small sample sizes, reliance only on a single, low-reproducibility, 24-h ABPM evaluation per participant, and definition of daytime and nighttime periods by arbitrary fixed clock-hour spans. Accordingly, we assessed the circadian BP pattern of patients with and without CKD by 48-h ABPM to increase reproducibility of the results. This cross-sectional study involved 10 271 hypertensive patients (5506 men/4765 women), 58.0?±?14.2 (mean?±?SD) yrs of age, enrolled in the Hygia Project. Among the participants, 3227 (1925 men/1302 women) had CKD. At the time of recruitment, 568/2234 patients with/without CKD were untreated for hypertension. Patients with than without CKD were more likely to be men and of older age, have diagnoses of obstructive sleep apnea, metabolic syndrome, diabetes, and/or obesity, plus have higher glucose, creatinine, uric acid, and triglyceride, but lower cholesterol, concentrations. In patients with CKD, ambulatory systolic BP (SBP) was significantly elevated (p?<?.001), mainly during the hours of nighttime sleep, independent of presence/absence of BP-lowering treatment. In patients without CKD, ambulatory diastolic BP (DBP), however, was significantly higher (p?<?.001), mainly during the daytime. Differing trends for SBP and DBP between groups resulted in large differences in ambulatory pulse pressure (PP), it being significantly greater (p?<?.001) for the entire 24?h in patients with CKD. Prevalence of non-dipping was significantly higher in patients with than without CKD (60.6% vs. 43.2%; p?<?.001). The largest difference between groups was in the prevalence of the riser BP pattern, i.e., asleep SBP mean?>?awake SBP mean (17.6% vs. 7.1% in patients with and without CKD, respectively; p?<?.001). The riser BP pattern significantly and progressively increased from 8.1% among those with stage 1 CKD to a very high 34.9% of those with stage 5 CKD. Elevated asleep SBP mean was the major basis for the diagnosis of hypertension and/or inadequate BP control among patients with CKD; thus, among the uncontrolled hypertensive patients with CKD, 90.7% had nocturnal hypertension. Our findings document significantly elevated prevalence of a blunted nocturnal BP decline in hypertensive patients with CKD. Most important, prevalence of the riser BP pattern, associated with highest CVD risk among all possible BP patterns, was 2.5-fold more prevalent in CKD, and up to 5-fold more prevalent in end-stage renal disease. Patients with CKD also presented significantly elevated ambulatory PP, reflecting increased arterial stiffness and enhanced CVD risk. Collectively, these findings indicate that CKD should be included among the clinical conditions for which ABPM is mandatory for proper diagnosis and CVD risk assessment, as well as a means to establish the best therapeutic scheme to increase CVD event-free survival. (Author correspondence: rhermida@uvigo.es)     

Role of Time-of-Day of Hypertension Treatment on the J-Shaped Relationship Between Blood Pressure and Cardiovascular Risk

Several previous studies found that too great a reduction of clinic blood pressure (BP) by treatment increased cardiovascular disease (CVD) risk, whereas moderate reduction decreased it. Thus, it has been suggested that the relationship between BP and CVD events is J-shaped, with CVD risk decreasing as BP is lowered, and then rising as BP is further decreased. Correlation between BP level and CVD risk, however, is stronger for ambulatory BP monitoring (ABPM) than clinical BP measurements. We previously established that the hypertension treatment-time regimen, upon awakening versus at bedtime, exerts differential effect on BP control during the day and nighttime, which translates into a differential degree of CVD risk prevention. We, therefore, investigated the role of hypertension treatment-time scheme on the nature of the relationship between achieved clinic and ambulatory BP and CVD risk in the MAPEC (Monitorización Ambulatoria para Predicción de Eventos Cardiovasculares, i.e., Ambulatory Blood Pressure Monitoring for Prediction of Cardiovascular Events) study, a prospective, open-label, blinded-endpoint trial on 2156 hypertensive patients (1044 men/1112 women), 55.6?±?13.6 (mean?±?SD) yrs of age, randomized to ingest all prescribed once-a-day hypertension medications upon awakening or the entire daily dose of ≥1 of them at bedtime. Ambulatory BP was measured for 48-h at baseline and annually thereafter, and more frequently (quarterly) when adjustment of treatment was necessary. After a median follow-up of 5.6 yrs, a J-shaped relationship was detected between total CVD events and clinic as well as awake BP mean, but only for the group of patients ingesting all medications upon awakening. The relationship was different in the group of patients who ingested ≥1 medications at bedtime; the risk of CVD events progressively diminished in a linear, rather than J-shaped, manner with treatment-induced decrease in awake BP mean. The adjusted hazard ratio of CVD events was significantly lower with the progressive reduction in the asleep BP mean, independent of the hypertension treatment-time regimen. There was no single major event, i.e., CVD death, myocardial infarction, or stroke, in patients who achieved an asleep systolic BP mean <103?mm Hg. Our findings indicate that bedtime hypertension treatment is not associated with a J-shaped relationship between achieved BP and CVD risk. The decreased CVD risk associated with the progressive reduction in asleep BP, more feasible by bedtime than morning hypertension treatment, has clinical implications, in particular, the need to consider the proper timing of hypertension medications, in conjunction with ABPM for proper assessment of BP control, as an improved and potentially safer means of reducing CVD risk of hypertensive patients. (Author correspondence: rhermida@uvigo.es)     

Ambulatory Blood Pressure Monitoring: Importance of Sampling Rate and Duration—48 Versus 24 Hours—on the Accurate Assessment of Cardiovascular Risk

Independent prospective studies have found that ambulatory blood pressure (BP) monitoring (ABPM) is more closely correlated with target organ damage and cardiovascular disease (CVD) risk than clinic BP measurement. This is based on studies in which BP was sampled every 15–30?min for ≤24?h, without taking into account that reproducibility of any estimated parameter from a time series to be potentially used for CVD risk assessment might depend more on monitoring duration than on sampling rate. Herein, we evaluated the influence of duration (48 vs. 24?h) and sampling rate of BP measurements (form every 20–30?min up to every 2?h) on the prognostic value of ABPM-derived parameters. We prospectively studied 3344 subjects (1718 men/1626 women), 52.6?±?14.5 yrs of age, during a median follow-up of 5.6 yrs. Those with hypertension at baseline 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, and physical activity was simultaneously monitored every min by wrist actigraphy to accurately derive the awake and asleep BP means. Identical assessment was scheduled annually and more frequently (quarterly) if treatment adjustment was required. ABPM profiles were modified to generate time series of identical 48-h duration but with data sampled at 1- or 2-h intervals, or shorter, i.e., first 24?h, time series with data sampled at the original rate (daytime 20-min intervals/nighttime 30-min intervals). Bland-Altman plots indicated that the range of individual differences in the estimated awake and asleep systolic (SBP) and diastolic BP (DBP) means between the original and modified ABPM profiles was up to 3-fold smaller for data sampled every 1?h for 48?h than for data sampled every 20–30?min for the first 24?h. Reduction of ABPM duration to just 24?h resulted in error of the estimated asleep SBP mean, the most significant prognostic marker of CVD events, in the range of ?21.4 to +23.9?mm Hg. Cox proportional-hazard analyses adjusted for sex, age, diabetes, anemia, and chronic kidney disease revealed comparable hazard ratios (HRs) for mean BP values and sleep-time relative BP decline derived from the original complete 48-h ABPM profiles and those modified to simulate a sampling rate of one BP measurement every 1 or 2?h. The HRs, however, were markedly overestimated for SBP and underestimated for DBP when the duration of ABPM was reduced from 48 to only 24?h. This study on subjects evaluated prospectively by 48-h ABPM documents that reproducibility in the estimates of prognostic ABPM-derived parameters depends markedly on duration of monitoring, and only to a lesser extent on sampling rate. The HR of CVD events associated with increased ambulatory BP is poorly estimated by relying on 24-h ABPM, indicating ABPM for only 24?h may be insufficient for proper diagnosis of hypertension, identification of dipping status, evaluation of treatment efficacy, and, most important, CVD risk stratification. (Author correspondence: rhermida@uvigo.es)     

Circadian Pattern of Ambulatory Blood Pressure in Hypertensive Patients With and Without Type 2 Diabetes

There is strong association between diabetes and increased risk of end-organ damage, stroke, and cardiovascular disease (CVD) morbidity and mortality. Non-dipping (<10% decline in the asleep relative to awake blood pressure [BP] mean), as determined by ambulatory BP monitoring (ABPM), is frequent in diabetes and consistently associated with increased CVD risk. The reported prevalence of non-dipping in diabetes is highly variable, probably due to differences in the study groups (normotensive subjects, untreated hypertensives, treated hypertensives), relatively small sample sizes, reliance only on a single, low-reproducibility, 24-h ABPM evaluation per participant, and definition of daytime and nighttime periods by arbitrary selected fixed clock-hour spans. Accordingly, we evaluated the influence of diabetes on the circadian BP pattern by 48-h ABPM (rather than for 24?h to increase reproducibility of results) during which participants maintained a diary listing times of going to bed at night and awakening in the morning. This cross-sectional study involved 12 765 hypertensive patients (6797 men/5968 women), 58.1?±?14.1 (mean?±?SD) yrs of age, enrolled in the Hygia Project, designed to evaluate prospectively CVD risk by ABPM in primary care centers of northwest Spain. Among the participants, 2954 (1799 men/1155 women) had type 2 diabetes. At the time of study, 525/3314 patients with/without diabetes were untreated for hypertension, and the remaining 2429/6497 patients with/without diabetes were treated. Hypertension was defined as awake systolic (SBP)/diastolic (DBP) BP mean ≥135/85?mm Hg, or asleep SBP/DBP mean ≥120/70?mm Hg, or BP-lowering treatment. Hypertensive patients with than without diabetes were more likely to be men and of older age, have diagnoses of microalbuminuria, proteinuria, chronic kidney disease, obstructive sleep apnea, metabolic syndrome, and/or obesity, plus higher glucose, creatinine, uric acid, and triglycerides, but lower cholesterol and estimated glomerular filtration rate. In patients with diabetes, ambulatory SBP was significantly elevated (p?<?.001), mainly during the hours of nighttime sleep and initial hours after morning awakening, independent of presence/absence of BP-lowering treatment. Ambulatory DBP, however, was significantly higher (p?<?.001) in patients without diabetes, mainly during the daytime. Differing trends for SBP and DBP between groups resulted in large differences in ambulatory pulse pressure (PP), it being significantly greater (p?<?.001) throughout the entire 24?h in patients with diabetes, even after correcting for age. Prevalence of non-dipping was significantly higher in patients with than without diabetes (62.1% vs. 45.9%; p?<?.001). Largest difference between groups was in the prevalence of the riser BP pattern, i.e., asleep SBP mean greater than awake SBP mean (19.9% vs. 8.1% in patients with and without diabetes, respectively; p?<?.001). Elevated asleep SBP mean was the major basis for the diagnosis of hypertension and/or inadequate BP control among patients with diabetes; thus, among the uncontrolled hypertensive patients with diabetes, 89.2% had nocturnal hypertension. Our findings document significantly elevated prevalence of a blunted nocturnal BP decline in hypertensive patients with diabetes. Most important, prevalence of the riser BP pattern, associated with highest CVD risk among all possible BP patterns, was more than twice as prevalent in diabetes. Patients with diabetes also presented significantly elevated ambulatory PP, reflecting increased arterial stiffness and enhanced CVD risk. These collective findings indicate that diabetes should be included among the clinical conditions for which ABPM is recommended for proper CVD risk assessment. (Author correspondence: rhermida@uvigo.es)     

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)     

Bedtime hypertension chronotherapy best reduces cardiovascular disease risk as documented by MAPEC and Hygia Chronotherapy outcomes trials

ABSTRACT

The purpose of this communication is to describe the unique features of the investigative protocols of both MAPEC and Hygia Chronotherapy Trial and to discuss in detail the advantages, limitations, and potential implications of their findings, both for the diagnosis and management of true arterial hypertension that we propose must be defined according to ambulatory blood pressure monitoring (ABPM)-based criteria. In particular, the recommended approach for diagnosis and follow-up of hypertension derived from the findings of MAPEC and Hygia Chronotherapy Trial entails baseline 48-h ABPM assessment for both proper diagnosis of true arterial hypertension and establishment of the eventual need of therapeutic intervention, plus follow-up by periodic 48-h ABPM assessment, specifically for evaluation of timed treatment efficacy and safety.     

Blunted Sleep-Time Relative Blood Pressure Decline Increases Cardiovascular Risk Independent of Blood Pressure Level—The “Normotensive Non-dipper” Paradox

Numerous studies have consistently shown an association between blunted sleep-time relative blood pressure (BP) decline (non-dipping) and increased cardiovascular disease (CVD) risk in hypertension. Normotensive persons with a non-dipper BP profile also have increased target organ damage, namely, increased left ventricular mass and relative wall thickness, reduced myocardial diastolic function, increased urinary albumin excretion, increased prevalence of diabetic retinopathy, and impaired glucose tolerance. It remains a point of contention, however, whether the non-dipper BP pattern or just elevated BP, alone, is the most important predictor of advanced target organ damage and future CVD events. Accordingly, we investigated the role of dipping status and ambulatory BP level as contributing factors for CVD morbidity and mortality in the MAPEC (Monitorización Ambulatoria para Predicción de Eventos Cardiovasculares, i.e., Ambulatory Blood Pressure Monitoring for Prediction of Cardiovascular Events) study. We prospectively studied 3344 individuals (1718 men/1626 women), 52.6?±?14.5 (mean?±?SD) yrs of age, during a median follow-up of 5.6 yrs. BP was measured by ambulatory monitoring (ABPM) for 48?h at baseline, and again annually or more frequently (quarterly) if treatment adjustment was required in treated hypertensive patients. At baseline, those with ABPM-substantiated hypertension were randomized to one of two treatment-time regimen groups: (i) ingestion of all prescribed hypertension medications upon awakening or (ii) ingestion of the entire dose of ≥1 of them at bedtime. Those found to be normotensive at baseline were untreated but followed and evaluated by repeated ABPM like the hypertensive patients. Participants were divided into four investigated categories on the basis of dipping status and ambulatory BP: (i) dipper vs. non-dipper, and (ii) normal ambulatory BP if the awake systolic (SBP)/diastolic (DBP) BP means were <135/85?mm Hg and the asleep SBP/DBP means were <120/70?mm Hg, and elevated ambulatory BP otherwise. Cox survival analyses, adjusted for significant confounding variables, documented that non-dippers had significantly higher CVD risk than dippers, whether they had normal (p?=?.017) or elevated ambulatory BP (p?<?.001). Non-dippers with normal awake and asleep SBP and DBP means, who accounted for 21% of the studied population, had similar hazard ratio (HR) of CVD events (1.61 [95% confidence interval, CI: 1.09–2.37]) as dippers with elevated ambulatory BP (HR: 1.54 [95% CI: 1.01–2.36]; p?=?.912 between groups). These results remained mainly unchanged for treated and untreated patients analyzed separately. Our findings document that the risk of CVD events is influenced not only by ambulatory BP elevation, but also by blunted nighttime BP decline, even within the normotensive range, thus supporting ABPM as a requirement for proper CVD risk assessment in the general population. The elevated CVD risk in “normotensive” individuals with a non-dipper BP profile represents a clear paradox, as those persons do not have “normal BP” or low CVD risk. Our findings also indicate the need to redefine the concepts of normotension/hypertension, so far established on the unique basis of BP level, mainly if not exclusively measured at the clinic, independently of circadian BP pattern. (Author correspondence: rhermida@uvigo.es)     

Ambulatory Blood Pressure Thresholds for Diagnosis of Hypertension in Patients With and Without Type 2 Diabetes Based on Cardiovascular Outcomes

Currently recommended ambulatory blood pressure (BP) monitoring (ABPM) thresholds for diagnosis of hypertension do not differentiate, as international guidelines do for clinic BP, uncomplicated persons at low risk from those at higher risk, e.g., patients with diabetes, for target injury and cardiovascular disease (CVD) risk. We aimed to derive diagnostic thresholds for the awake and asleep systolic (SBP) and diastolic (DBP) BP means based upon CVD outcomes (death from all causes, myocardial infarction, angina pectoris, coronary revascularization, heart failure, acute arterial occlusion of the lower extremities, thrombotic occlusion of the retinal artery, hemorrhagic stroke, ischemic stroke, and transient ischemic attack) for patients with and without diabetes. We prospectively studied 3344 subjects (1718 men/1626 women), 52.6?±?14.5 (mean?±?SD) yrs of age, 607 with type 2 diabetes, during a median follow-up of 5.6 yrs. Those with hypertension at baseline were randomized to ingest all their prescribed hypertension medications upon awakening or the entire daily dose of ≥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, and physical activity was simultaneously monitored every minute by wrist actigraphy to accurately derive the awake and asleep BP means. Identical assessment was scheduled annually and more frequently (quarterly) if treatment adjustment was required. Cox regression analysis was used to derive outcome-based reference thresholds for ABPM in subjects with and without diabetes. CVD risk was consistently greater in patients with than without diabetes for awake SBP/DBP means ≥130/75?mm Hg and asleep means ≥110/65?mm Hg. Derived outcome-based reference thresholds for persons without diabetes were 135/85?mm Hg for the awake and 120/70?mm Hg for the asleep SBP/DBP means. In terms of CVD outcome, the equivalent cutoff threshold values for patients with diabetes were 120/75?mm Hg for the awake and 105/60?mm Hg for the asleep SBP/DBP means. Outcome-based reference thresholds for the diagnosis of hypertension were 15/10?mm Hg lower for ambulatory SBP/DBP in patients with than without diabetes. This marked difference indicates the need for revision of current guidelines that propose diagnostic thresholds for ambulatory BP without differentiation between the presence/absence of diabetes. (Author correspondence: rhermida@uvigo.es)     

Prevalence and Clinical Characteristics of Isolated-Office and True Resistant Hypertension Determined by Ambulatory Blood Pressure Monitoring

Hypertension is defined as resistant to treatment when a therapeutic plan including ≥3 hypertension medications failed to sufficiently lower systolic (SBP) and diastolic (DBP) blood pressures (BPs). Most individuals, including those under hypertension therapy, show a “white-coat” effect that could cause an overestimation of their real BP. The prevalence and clinical characteristics of “white-coat” or isolated-office resistant hypertension (RH) has always been evaluated by comparing clinic BP values with either daytime home BP measurements or the awake BP mean obtained from ambulatory monitoring (ABPM), therefore including patients with either normal or elevated asleep BP mean. Here, we investigated the impact of including asleep BP mean as a requirement for the definition of hypertension on the prevalence, clinical characteristics, and estimated cardiovascular (CVD) risk of isolated-office RH. This cross-sectional study evaluated 3042 patients treated with ≥3 hypertension medications and evaluated by 48-h ABPM (1707 men/1335 women), 64.2?±?11.6 (mean?±?SD) yrs of age, enrolled in the Hygia Project. Among the participants, 522 (17.2%) had true isolated-office RH (elevated clinic BP and controlled awake and asleep ambulatory BPs while treated with 3 hypertension medications), 260 (8.6%) had false isolated-office RH (elevated clinic BP, controlled awake SBP/DBP means, but elevated asleep SBP or DBP mean while treated with 3 hypertension medications), and the remaining 2260 (74.3%) had true RH (elevated awake or asleep SBP/DBP means while treated with 3 medications, or any patient treated with ≥4 medications). Patients with false, relative to those with true, isolated-office RH had higher prevalence of microalbuminuria and chronic kidney disease (CKD), significantly higher albumin/creatinine ratio (p <?.001), significantly higher 48-h SBP/DBP means by 9.6/5.3?mm Hg (p?<?.001), significantly lower sleep-time relative SBP and DBP decline (p?<?.001), and significantly greater prevalence of a non-dipper BP profile (96.9% vs. 38.9%; p?<?.001). Additionally, the prevalence of the riser BP pattern, which is associated with highest CVD risk, was much greater, 40.4% vs. 5.0% (p?<?.001), among patients with false isolated-office RH. The estimated hazard ratio of CVD events, using a fully adjusted model including the significant confounding variables of sex, age, diabetes, chronic kidney disease, asleep SBP mean, and sleep-time relative SBP decline, was significantly greater for patients with false compared with those with true isolated-office RH (2.13 [95% confidence interval: 1.95–2.32]; p?<?.001). Patients with false isolated-office hypertension and true RH, however, were equivalent for the prevalence of obstructive sleep apnea, metabolic syndrome, obesity, diabetes, microalbuminuria, and chronic kidney disease, and they had an equivalent estimated hazard ratio of CVD events (1.04 [95% confidence interval: .97–1.12]; p?=?.265). Our findings document a significantly elevated prevalence of a blunted nighttime BP decline in patients here categorized as either false isolated-office RH and true RH, jointly accounting for 82.8% of the studied sample. Previous reports of much lower prevalence of true RH plus a nonsignificant increased CVD risk of this condition compared with isolated-office RH are misleading by disregarding asleep BP mean for classification. Our results further indicate that classification of RH patients into categories of isolated-office RH, masked RH, and true RH cannot be based on the comparison of clinic BP with either daytime home BP measurements or awake BP mean from ABPM, as so far customary in the available literature, totally disregarding the highly significant prognostic value of nighttime BP. Accordingly, ABPM should be regarded as a clinical requirement for proper diagnosis of true RH. (Author correspondence: rhermida@uvigo.es)     

Cardiovascular Risk of Resistant Hypertension: Dependence on Treatment-Time Regimen of Blood Pressure–Lowering Medications

In resistant hypertension, ingesting one or more blood pressure (BP)-lowering medications at bedtime is associated with significant reduction of sleep-time BP, a sensitive prognostic marker of cardiovascular disease (CVD) risk. This randomized trial investigated if bedtime therapy with at least one hypertension medication exerts better BP control and CVD risk reduction than conventional, morning-time therapy with all medications. We conducted a prospective, open-label, blinded-endpoint trial on 776 patients (387 men/389 women) with resistant hypertension, 61.6?±?11.2 (mean?±?SD) yrs of age. Patients were randomized to ingest all their prescribed hypertension medications upon awakening or ≥1 of them at bedtime. BP was measured by ambulatory monitoring for 48?h at baseline, and again annually or more frequently (quarterly) if treatment adjustment was required. After a median follow-up of 5.4 yrs (range, .5–8.5 yrs), participants ingesting ≥1 hypertension medications at bedtime showed a significantly lower hazard ratio (HR) of total CVD events (adjusted by age, sex, and diabetes) than those ingesting all medications upon awakening (.38 [95% CI: .27–.55]; number of events 102 vs. 41; p?<?.001). The difference between groups in the adjusted HR of major CVD events (a composite of CVD death, myocardial infarction, ischemic stroke, and hemorrhagic stroke) was also statistically significant (.35 [95% CI: .18–.68]; number of events 32 vs. 12; p?=?.002). At the last evaluation, patients treated with the bedtime versus awakening-time-treatment regimen showed significantly lower sleep-time systolic/diastolic BP mean values (121.6/65.4 vs. 113.0/61.1?mm Hg; p?<?.001) and higher prevalence of controlled ambulatory BP (61% vs. 46%; p?<?.001). The progressive decrease in the sleep-time systolic BP mean during follow-up was the most significant predictor of event-free survival (15% risk reduction per 5?mm Hg decreased asleep systolic BP mean). Among patients with resistant hypertension, ingestion of at least one hypertension medication at bedtime, compared with all medications upon waking, resulted in improved ambulatory BP control and fewer hard and soft CVD events. (Author correspondence: rhermida@uvigo.es)     

Diagnosis and management of hypertension: around-the-clock ambulatory blood pressure monitoring is substantially more effective and less costly than daytime office blood pressure measurements

ABSTRACT

The cost-effectiveness of ambulatory blood pressure (BP) monitoring (ABPM) versus traditional office BP measurement (OBPM) for the diagnosis and management of hypertension has been evaluated only by few studies and based solely on the reduction of medical care expenses through avoiding treatment of isolated-office hypertension. Data from the 21963 participants in the Hygia Project, a multicenter outcomes study that incorporates into routine primary care periodic, at least yearly, 48 h ABPM evaluation, were utilized to assess the cost-effectiveness – relative to vascular pathology expenditures countrywide in Spain – of ABPM versus OBPM. The actual reported Spanish healthcare expenditure for vascular pathology in 2015 – aggregate costs of medical examinations, outpatient and inpatient care, therapeutic interventions, plus non-healthcare services (productivity losses due to morbidity/mortality and informal family/friends-provided care) – was used to compare yearly costs when diagnostic and treatment decisions for hypertension are based on the OBPM versus the ABPM-model. Our economic analysis is based on the more realistic and feasible approach of restricting ABPM solely to high-risk individuals of age ≥60 years and/or with diabetes, chronic kidney disease, and/or previous cardiovascular event, who in the Hygia Project accounted for >90% of all documented events. The projected net benefit countrywide in favor of the proposed ABPM-model is ~5294M€/year, i.e., 360.33€/year (95%CI [347.52–374.85]) per ABPM-evaluated person. This highly conservative economic analysis indicates ABPM is a much more cost-effective strategy than repeated OBPM not only for accurate diagnosis and management of true hypertension but marked reduction of expenditures on elevated BP-associated vascular pathology.     

Differences Between Men and Women in Ambulatory Blood Pressure Thresholds for Diagnosis of Hypertension Based on Cardiovascular Outcomes

Previous studies have reported sex differences in the pathophysiology of hypertension and responses to blood pressure (BP)-lowering medications. Moreover, men exhibit typically higher BP than women, the differences being greater for systolic (SBP) than diastolic (DBP) BP. These differences become apparent during adolescence and remain significant at least until 55–60 yrs of age. Despite such significant sex-related differences in BP regulation, the current recommended ambulatory BP monitoring (ABPM) thresholds for diagnosis of hypertension do not differentiate between men and women. We aimed to derive separate male and female diagnostic thresholds for the awake and asleep SBP and DBP means based upon cardiovascular disease (CVD) outcome. We prospectively studied 3344 subjects (1718 men/1626 women), 52.6?±?14.5 yrs of age, during a median follow-up of 5.6 yrs. Those with hypertension at baseline were randomized to ingest all their prescribed hypertension medications upon awakening or the entire daily dose of ≥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, and physical activity was simultaneously monitored every minute by wrist actigraphy to accurately derive the awake and asleep BP means. Identical assessment was scheduled annually and more frequently (quarterly) if treatment adjustment was required. Cox regression analysis was used to derive outcome-based reference thresholds for ABPM in men and women. Men exhibited greater event rates than women of CVD death, myocardial infarction, angina pectoris, coronary revascularization, and heart failure; however, event rates of non-CVD death and cerebrovascular events were comparable. The relationship between progressively higher ambulatory BP and CVD risk increased more rapidly in women than men for awake SBP/DBP means ≥125/75?mm Hg and asleep means ≥110/70?mm Hg. The derived outcome-based reference thresholds for men were 135/85?mm Hg for the awake and 120/70?mm Hg for the asleep SBP/DBP means. In terms of CVD outcome, the equivalent cutoff threshold values for women were 125/80?mm Hg for the awake and 110/65?mm Hg for the asleep SBP/DBP means. Outcome-based reference thresholds for the diagnosis of hypertension were 10/5?mm Hg lower for ambulatory SBP/DBP in women than men. This marked sex difference indicates the need for revision of current guidelines that propose diagnostic thresholds for ambulatory BP without differentiation between men and women. (Author correspondence: rhermida@uvigo.es)     

The Hygia Project and Hygia Chronotherapy Trial: insights of we clinical investigators on the impact of the embedded continuing medical education on primary-care practice and improved patient cardiovascular health

ABSTRACT

The participating doctors of the Hygia Chronotherapy Trial (HCT) are aware of the criticisms of its published findings, which have been unjustifiably misrepresented in letters to the editors and commentaries, perhaps because of lack of understanding of the foundations of the Hygia Project, in which the HCT is nested. Thus, our purpose through this communication is to highlight the unique features of the Hygia Project and HCT in terms of: (i) organization, management, and quality control, (ii) physician training/continuing medical education, and (iii) impact on every-day primary-care clinical practice specifically improved patient care through 48 h ambulatory blood pressure monitoring to diagnose and optimally manage by bedtime hypertension chronotherapy true arterial hypertension to markedly improve the cardiovascular health of our patients.     

Cardiovascular Risk of Essential Hypertension: Influence of Class,Number, and Treatment-Time Regimen of Hypertension Medications

A number of observational studies have found that treated hypertensive patients, even those with controlled clinic blood pressure (BP), might have poorer prognosis than untreated hypertensives. Different trials have also shown that relatively low cardiovascular disease (CVD) risk cannot be achieved in high-risk hypertensive patients, leading to the belief they have a “residual CVD risk” that cannot be attenuated by conventional treatment. All these conclusions disregard the facts that the correlation between BP level and CVD risk is stronger for ambulatory than clinic BP and that the BP-lowering efficacy and effects on the 24-h BP pattern of different classes of hypertension medications exhibit statistically and clinically significant treatment-time (morning versus evening) differences. Accordingly, we evaluated the potential differential administration-time-dependent effects on CVD risk of the various classes of hypertension medications and the number of them used for therapy in the MAPEC (Monitorización Ambulatoria para Predicción de Eventos Cardiovasculares, i.e., Ambulatory Blood Pressure Monitoring for Prediction of Cardiovascular Events) study, a prospective, open-label, blinded-endpoint trial on 2156 hypertensive patients (1044 men/1112 women), 55.6?±?13.6 (mean?±?SD) yrs of age, randomized to ingest all prescribed once-a-day hypertension medications upon awakening or the entire daily dose of ≥1 of them at bedtime. Ambulatory BP was measured for 48?h at baseline, and again annually or more frequently (quarterly) when adjustment of treatment was necessary to achieve ambulatory, i.e., awake and asleep, BP control. CVD risk according to the number and classes of medications used at the final evaluation was calculated by comparison with that of 734 normotensive subjects who were identically followed and remained untreated. After a median follow-up of 5.6 yrs, CVD risk of hypertensive patients randomized to ingest all medications upon awakening was progressively higher with increase in the number of medications (adjusted hazard ratio [HR]: 1.75, 2.26, 3.02, and 4.18 in patients treated with 1, 2, 3, and ≥4 medications daily, respectively; p?<?.001 compared with normotensive subjects). CVD risk was markedly lower in patients ingesting ≥1 medications at bedtime (HR: .35, 1.45, .94, and 2.28 with 1, 2, 3, and ≥4 medications daily, respectively), and even lower in patients ingesting all medications at bedtime (HR: .35, .39, .87, and .79 with 1, 2, 3, and ≥4 medications daily, respectively). Patients ingesting ≥1 medications at bedtime evidenced significantly lower CVD risk than those ingesting all medications upon awakening, independent of class. Greater benefits were observed for bedtime compared with awakening treatment with angiotensin-II receptor blockers (ARBs) (HR: .29 [95% confidence interval, CI .17–.51]; p?<?.001) and calcium channel blockers (HR: .46 [95% CI: .31–.69]; p?<?.001). CVD risk was similar for all six classes of tested hypertension medications in patients randomized to ingest all of them upon awakening. Among patients randomized to ingest ≥1 medications at bedtime, however, ARBs were associated with significantly lower HR of CVD events than ingestion of any other class of medication also at bedtime (p?<?.017). We document significantly reduced CVD risk among hypertensive patients ingesting medications at bedtime, independent of the number of hypertension medications required to achieve proper ambulatory BP control. These findings challenge the current belief of “residual CVD risk,” as a bedtime-treatment regimen of current hypertension medications, even in risk-high patients, can reduce such risk. (Author correspondence: rhermida@uvigo.es)     

Administration-Time Differences in Effects of Hypertension Medications on Ambulatory Blood Pressure Regulation

Specific features of the 24-h blood pressure (BP) pattern are linked to progressive injury of target tissues and risk of cardiovascular disease (CVD) events. Several studies have consistently shown an association between blunted asleep BP decline and risk of fatal and nonfatal CVD events. Thus, there is growing focus on ways to properly control BP during nighttime sleep as well as during daytime activity. One strategy, termed chronotherapy, entails the timing of hypertension medications to endogenous circadian rhythm determinants of the 24-h BP pattern. Significant and clinically meaningful treatment-time differences in the beneficial and/or adverse effects of at least six different classes of hypertension medications, and their combinations, are now known. Generally, calcium channel blockers (CCBs) are more effective with bedtime than morning dosing, and for dihydropyridine derivatives bedtime dosing significantly reduces risk of peripheral edema. The renin-angiotensin-aldosterone system is highly circadian rhythmic and activates during nighttime sleep. Accordingly, evening/bedtime ingestion of the angiotensin-converting enzyme inhibitors (ACEIs) benazepril, captopril, enalapril, lisinopril, perindopril, quinapril, ramipril, spirapril, trandolapril, and zofenopril exerts more marked effect on the asleep than awake systolic (SBP) and diastolic (DBP) BP means. Likewise, the bedtime, in comparison with morning, ingestion schedule of the angiotensin-II receptor blockers (ARBs irbesartan, olmesartan, telmisartan, and valsartan exerts greater therapeutic effect on asleep BP, plus significant increase in the sleep-time relative BP decline, with the additional benefit, independent of drug terminal half-life, of converting the 24-h BP profile into a more normal dipping pattern. This is the case also for the bedtime versus upon-awakening regimen of combination ARB-CCB, ACEI-CCB, and ARB-diuretic medications. The chronotherapy of conventional hypertension medications constitutes a new and cost-effective strategy for enhancing the control of daytime and nighttime SBP and DBP levels, normalizing the dipping status of their 24-h patterning, and potentially reducing the risk of CVD events and end-organ injury, for example, of the blood vessels and tissues of the heart, brain, kidney, and retina. (Author correspondence: rhermida@uvigo.es)     

PERSPECTIVES ON THE CHRONOTHERAPY OF HYPERTENSION BASED ON THE RESULTS OF THE MAPEC STUDY

Appreciation of chronotherapy in hypertension continues to lag, despite clear demonstrations by many studies of (i) clinically relevant dosing-time differences of the beneficial and adverse effects of most blood pressure (BP) medications and (ii) significant association between reduced sleep-time BP decline of non-dippers and their heightened risk of cardiovascular disease (CVD). The Syst-Eur and HOPE outcome trials showed evening administration of nitrendipine and ramipril in these respective studies impacts sleep-time BP, converting the 24-h BP pattern to a more dipper one and in the HOPE study decreasing CVD risk. The CONVINCE study intended to compare BP control and CVD protection afforded by conventional β-blocker and diuretic medications versus a special drug-delivery verapamil formulation as a bedtime hypertension chronotherapy; however, the trial was terminated prematurely, not based on inadequate performance of the chronotherapy but on a corporate business decision. The just completed MAPEC study is the first trial specifically designed to prospectively test the hypothesis that bedtime administration of ≥1 conventional medications exerts better BP control and CVD risk reduction than the traditional approach of scheduling all medications in the morning. The results of this 5.6-yr median follow-up study establish that bedtime chronotherapy more effectively improves BP control, better decreases prevalence of non-dipping, and, most importantly, best reduces CVD morbidity and mortality. This chronotherapeutic approach to hypertension is justified by the fact that BP is usually lowest at night as is sodium excretion, but when sodium intake is excessive or its daytime excretion hampered, nocturnal BP is adjusted higher, to a level required for compensation overnight, via the pressure/natriuresis mechanism, resulting in non-dipping 24-h BP patterning. In diurnally active persons, the entire circadian BP pattern may be reset to a lower mean level and to a “more normal” day-night variation, simply by enhancing natriuresis during the night—the time-of-day when it can be most effective. A modification as simple and inexpensive as switching ≥1 hypertension medications from morning to evening may be all that is needed to normalize nighttime BP, exerting an effect exactly like sodium restriction. Current clinical concepts such as “normotensive non-dipper” (with higher CVD risk than a hypertensive dipper), broad recommendation of pharmacotherapy with exclusively high “smoothness index” medications (without attention to individual patient needs defined by the features of the 24-h BP pattern), and reliance upon static daytime diagnostic BP thresholds based solely on single office cuff assessment necessitate urgent reconsideration. (Author correspondence: prf@unife.it)